• Signed Informed Consent Form.
• Age ≥ 18 years.
• Subject meets the following corresponding requirements for the part of the study they will enroll into:
  • During Part A, subjects must have a histologically or cytologically documented, incurable or metastatic solid tumor that has progressed on (or they have been intolerant to) standard systemic therapy options for their tumor type in the metastatic setting or must have a tumor type for which no such standard systemic option exists.
  • During Part B, subjects must have a histologically or cytologically documented diagnosis of esophageal or gastric carcinoma, cholangiocarcinoma, neuroendocrine tumor (NET) of the gastrointestinal tract and pancreas, sarcomas, both soft tissue sarcoma (excluding leiomyosarcoma) and chondrosarcoma, or with agreement of the Sponsor, other tumors (including NPC and HCC) that have been treated with at least one line of standard systemic therapy for their respective tumor type in the metastatic setting with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent. Patients with MSI-H/dMMR tumors are eligible to enroll:
    • Subjects with nasopharyngeal cancer must have received (or been intolerant to) to a platinum-based combination as part of their prior therapy for advanced/metastatic disease;
    • Subjects with soft tissue sarcoma and chondrosarcoma must have radiographic evidence of progression within the previous 6 months and must have received at least 1 line of systemic therapy;
    • Subjects with esophageal cancer must have received (or been intolerant to) platinum-based combination as part of their prior therapy for advanced/metastatic disease;
    • Subjects with gastric cancer must have received (or been intolerant to) a fluoropyrimidine-platinum combination as part of their prior therapy for advanced/metastatic disease;
    • Subjects with HCC must have received (or been intolerant to) sorafenib as part of their prior therapy for advanced metastatic disease.
• Measurable disease per RECISTv1.1 and irRECIST.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ and marrow function, as defined below:
  1. Hemoglobin ≥ 8.0 g/dL within first 2 weeks prior to first dose of toripalimab;
  2. Absolute neutrophil count (ANC) ≥ 1.2 x 10^9/L (1,200/mm^3);
  3. Platelet count ≥ 75 x 10^9/L (75,000/mm^3);
  4. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) except subjects with documented Gilbert’s syndrome who must have a baseline total bilirubin ≤ 3.0 mg/dL;
  5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; for subjects with hepatic metastases, ALT and AST ≤ 5 × ULN;
  6. Serum creatinine ≤ 1.5 × ULN OR calculated creatinine clearance (CrCl) or 24-hour urine CrCl ≥ 40 mL/minute;
  7. Cockcroft-Gault formula will be used to calculate CrCl.(9.4); 24-hour urine CrCl will be derived using the measured creatinine clearance formula (9.5);
  8. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN; applies only to subjects who do not receive therapeutic anticoagulation; subjects receiving therapeutic anticoagulation (such as low-molecular weight heparin or warfarin) should be on a stable dose.
• Willingness to provide consent for biopsy samples (In Part A, fresh pre-treatment biopsies will be requested from subjects with safely accessible lesions. For subjects who cannot provide a fresh pre-treatment biopsy, an archival specimen will be required. In Part B, fresh pre-treatment biopsies will be required from subjects with safely accessible lesions. Archival specimens will be requested).
• Females of childbearing potential who are sexually active with a nonsterilized male partner must use effective contraception from time of screening, and must agree to continue using such precautions for 90 days after the final dose of toripalimab; cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal  ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as at least 12 months with no menses confirmed by follicle-stimulating hormone [FSH] levels. FSH testing will be conducted at the Screening visit to confirm post-menopausal status).
• Subjects must use effective contraception as described in below:
  • Barrier Methods
    • Male condom plus spermicide;
    • Copper T intrauterine device;
    • Levonorgestrel-releasing intrauterine system;
    • (e.g., MirenaR)*
    • * this is also considered a hormonal method.
  • Hormonal Methods
    • Implants;
    • Hormone shot or injection;
    • Combined pill;
    • Minipill;
    • Patch.
• Nonsterilized males who are sexually active with a female partner of childbearing potential must use effective contraception from Day 1 and for 90 days after receipt of the final dose of toripalimab.

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
  • NOTE: Local treatment of isolated lesions for palliative intent is acceptable (e.g., by local surgery or radiotherapy).
• Receipt of any investigational anticancer therapy within 4 weeks prior to the first dose of toripalimab.
• Current or prior use of immunosuppressive medication within 2 weeks prior to the first dose of toripalimab, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids not to exceed 10 mg/day of prednisone or equivalent.
• In Part A: Prior exposure to immunotherapy such as but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccines.
• In Part B: Exclusion of prior immunotherapy exposure will be limited to anti-PD-1, anti-PD-L1, or anti-PD-L2.
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• Major surgery (as defined by the investigator) within 4 weeks prior to first dose of toripalimab or still recovering from prior surgery.
• Unresolved toxicities from prior anticancer therapy, defined as having not resolved to baseline or to NCI-CTCAE v4.03 Grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria with the exception of alopecia. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by toripalimab may be included (e.g., hearing loss) after consultation with the medical monitor.
• Active or prior documented autoimmune disease within the past 2 years.
  • NOTE: Subjects with vitiligo, Grave’s disease not requiring systemic treatment other than thyroid hormone replacement (within the past 2 years), or psoriasis not requiring systemic treatment are not excluded. Subjects with a history of autoimmune hypothyroidism requiring only thyroid hormone replacement therapy will not be excluded.
• Known history of tuberculosis.
• Subjects who are known to be human immunodeficiency virus (HIV) positive.
• Subjects with evidence of hepatitis B or C virus infection, unless their hepatitis is considered to have been cured. (Note that subjects with prior hepatitis B virus [HBV] infection must have HBV viral load [VL] <100 IU/mL before study enrollment, and must be treated according to local standards; hepatitis C virus [HCV] infection must have, before study enrollment, no detectable VL and must be treated according to local standards).
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
• History of primary immunodeficiency.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure according to New York Heart Association (NYHA) Functional Classification ≥3, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs from toripalimab, or compromise the ability of the subject to give written informed consent.
• Symptomatic or untreated central nervous system metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging metastases, and are off steroids.
• Receipt of live attenuated vaccination within 4 weeks prior to study entry or within 4 weeks of receiving toripalimab.
• Any condition that, in the opinion of the investigator or sponsor, would interfere with evaluation of toripalimab or interpretation of subject safety or study results.
• Pregnant or breastfeeding women.

• Male ≥ 18 years of age at the time the informed consent form is signed.
• Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate (pure small-cell histologies or pure high-grade neuroendocrine histologies are excluded; neuroendocrine differentiation is allowed) that is metastatic.
• Surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM). If currently being treated with luteinizing hormone–releasing hormone (LHRH) analogs (patients who have not undergone an orchiectomy), therapy must be continued throughout the study.
• Eligible for treatment with physician’s choice of comparator treatment, selected prior to randomization, per the corresponding prescribing information.
• Evidence of disease progression after treatment with one prior next-generation AR-targeted therapy (abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted agent); treatment with the older anti-androgen therapies such as bicalutamide, flutamide, and nilutamide are not counted toward this limit.
• Disease progression after initiation of most recent therapy is based on any of the following criteria:
  • Rise in PSA: a minimum of two consecutive rising levels, with an interval of ≥ 1 week between each determination. The most recent screening measurement must have been ≥ 2 ng/mL;
  • Transaxial imaging: new or progressive soft tissue masses on CT or MRI scans as defined by modified RECIST Version 1.1;
  • Radionuclide bone scan: at least two new metastatic lesions.
• All patients must have a deleterious gene mutation in BRCA1/2 or ATM. Mutations may be identified by local testing or through central testing by the sponsor of plasma or tumor tissue.
• For local test results, the classification of the mutation as deleterious must be documented in the patient’s medical record.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Have adequate organ function confirmed by the following clinical laboratory values obtained within 14 days prior to the first dose of study drug:
  • Bone Marrow Function i. ANC ≥ 1.5 × 109/L:
    • Platelets > 100 × 109/L;
    • Hemoglobin ≥ 10 g/dL independent of transfusion within 14 days.
  • Hepatic Function:
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN);
    • Bilirubin ≤ 1.5 × ULN (< 2 x ULN if hyperbilirubinemia is due to Gilbert’s syndrome).
  • c. Renal Function:
    • Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-Gault formula.
• Male patients who are committed to undertaking the following measures for the duration of the study and after the last dose of study drug for the time period specified:
  • Use a condom during sex while being treated and for 3 months after the last dose of study drug;
  • Do not make semen donations during treatment and for 3 months after the last dose of rucaparib;
  • Those with female partners of childbearing potential may be enrolled if they are:
    • Documented to be surgically sterile (ie, vasectomy);
    • Committed to practicing true abstinence during treatment and for 3 months after the last dose of study drug; or
    • Committed to using a highly effective method of contraception (refer to Section 6.5) with their partner during treatment and for 3 months following the last dose of study drug.
• Have a life expectancy of at least 6 months.

• Active second malignancy, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or superficial bladder cancer:
  • Patients with a history of malignancy that has been completely treated, and currently with no evidence of that cancer, are permitted to enroll in the study provided all therapy was completed > 6 months prior and/or bone marrow transplant (BMT) > 2 years prior to first dose of rucaparib.
• Prior treatment with any PARPi.
• Prior treatment with chemotherapy (eg docetaxel, mitoxantrone, cyclophosphamide, platinum-based agents) for mCRPC. Prior treatment with docetaxel (or other taxane chemotherapy) administered for castration-sensitive disease is permitted .
• Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic, previously treated CNS metastases are eligible provided they have been clinically stable (not requiring steroids for at least 4 weeks prior to first dose of study drug) and have appropriate scans at screening assessment.
• Symptomatic or impending spinal cord compression unless appropriately treated, clinically stable, and asymptomatic.
• Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with absorption of study drug.
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C, with the exception of patients with sustained virologic response after completion of treatment for hepatitis C.
• Received treatment with chemotherapy, antibody therapy, immunotherapy, gene therapy, angiogenesis inhibitors, or experimental drugs within < 14 days prior to first dose of study drug. Treatment with hormonal therapies (with the exception of LHRH analog) must be discontinued at least 7 days prior to the first dose of study drug.
• Adverse effect of prior therapy not resolved to CTCAE Grade 1 or below with the exception of alopecia. Ongoing Grade 2 non-hematologic toxicity related to most recent treatment regimen may be permitted with prior advanced approval from the sponsor.
• Initiated low-dose corticosteroid, bisphosphonate, or denosumab therapy or adjusted low-dose corticosteroid, bisphosphonate, or denosumab dose/regimen within < 28 days prior to first dose of study drug. Patients on a stable low-dose corticosteroid, bisphosphonate, or denosumab regimen are eligible and may continue treatment.
• Non-study related minor surgical procedure within < 5 days, or major surgical procedure within < 21 days, prior to first dose of study drug; in all cases, the patient must be sufficiently recovered and stable before treatment administration.
• Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study.

• Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
• Men and women 18 years of age or older.
• For Phase 1, histologically and / or cytological confirmed unresectable or metastatic solid malignancy.
• For Phase 2, five cohorts will be enrolled:
  • Cohort A-1: NSCLC EXON 14 skip mutation (c-Met naïve) for first line treatment;
  • Cohort A-2: NSCLC EXON 14 skip mutation (c-Met naïve) pretreated subjects with no more than 3 lines of prior therapy in the metastatic setting;
  • Cohort B: NSCLC EXON 14 skip mutation (c-Met experienced; radiographic progression on prior c-Met inhibitor);
  • Cohort C: basket of tumor types with c-Met high level amplification (NSCLC EXON 14 skip mutation excluded);
  • Cohort D: basket of tumor type with c-Met fusions.
• Cohort A-1: EXON 14 Non-small-Cell Lung Cancer – c-Met inhibitor naïve:
  • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations as determined by MI Transcriptome™ companion diagnostic (CDx) by central laboratory, Caris Life Sciences;
  • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
  • Unresectable or metastatic disease (Stage 3b/4);
  • Treatment naïve subjects in first line;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Cohort A-2: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor naïve (≥ 2L):
  • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations;
  • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
  • Unresectable or metastatic disease (Stage 3b/4);
  • Pretreated subjects refractory to or intolerable to standard therapies with no more than three lines of prior therapy in the metastatic setting;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Cohort B: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor experienced:
  • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations; 
  • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
  • Unresectable or metastatic disease (Stage 3b/4);
  • Refractory to standard therapies with no more than three prior lines of therapy in the metastatic setting.
• Cohort C: Basket Tumor Types (c-Met high-level amplifications):
  • Any tumor type regardless of histology, including osimertinib relapsed/refractory NSCLC, excluding NSCLC EXON 14 skip mutation, that meets inclusion criteria c-Met high-level amplification;
  • Unresectable or metastatic disease, refractory to or intolerant of standard therapies, or refused standard therapies, or if therapy was unavilable or unfeasible, with no more than three prior lines of therapy in the metastatic setting;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Cohort D: Basket Tumor Types (c-Met fusions):
  • Any other tumor type histology that meets inclusion criteria c-Met fusions;
  • Unresectable or metastatic disease, refractory to or intolerant of standard therapies. or refused standard therapies, or if therapy unavailable or unfeasible, with no more than three prior lines of therapy in the metastatic setting;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Abnormal c-Met dysregulation, by tissue and/or plasma, defined as the following from archival/local results or molecular pre-screening evaluations. 
• Phase 1 (100, 200, and 300 mg Cohorts):
  • c-Met overexpression by IHC 2+ ≥ 50% of tumor cells; or
  • c-Met amplification (c-Met/Cep-7 ratio ≥ 2.2 or GCN ≥ 6 gene copy); or
  • c-Met EXON 14 skip mutation per NGS or RT-PCR; or
  • c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34- MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1- MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1- MET; KIF5B-MET and any other known c-Met activating mutations.
• Phase 1 (400 mg Cohort) and Phase 2 RP2D:
  • c-Met high-level amplification (c-Met/Cep-7 ratio of ≥ 2.2 or GCN of ≥ 6 copy). A minimum of five subjects of the high-level amplification (c-Met/Cep-7 ratio of ≥ 5 or GCN ≥ 10 gene copy) for the Stage 1 of the Simon 2 stage design is required); or
  • c-Met EXON 14 skip mutation per NGS; or
  • c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34- MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1- MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1- MET; KIF5B-MET; or
  • other c-Met mutations in Dose Escalation (400 mg Cohort).
• Local/archival result of a positive c-Met dysregulation is required (except in Cohort A-1 in US). In Phase 2, Cohorts A-2 and D require provision of tumor tissue samples (archival or fresh tumor biopsy) either from the primary or a metastatic site. For Cohorts B and C, provision of tumor tissue (archival or fresh tumor biopsy) or blood (plasma) sample for entry is acceptable.
• In Phase 2, treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease is allowed. 
• Measurable disease according to RECIST v1.1 (or relevant criteria per tumor type).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
  • Acceptable organ function, as evidenced by the following laboratory data during Screening period: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN;
  • Total serum bilirubin ≤ 1.5 x ULN;
  • For subjects with liver metastases: Total bilirubin ≤ 3.0 x ULN, AST/ ALT ≤ 5 x ULN;
  • Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3 (1.5 x 10^9 /L); 
  • Platelet count ≥ 100,000 cells/mm^3 (100 x 10^9 /L);
  • Serum creatinine levels ≤ 1.5 ULN or Creatinine Clearance (CrCl) ≥ 60 mL/min as calculated by the Cockcroft-Gault method;
  • Hemoglobin ≥ 9 g/dL.
• For all prior anticancer treatment, including radiotherapy, chemotherapy, or targeted agents or hormonal therapy, a duration of 30 days or 5 half-lives of the agents used, whichever is shorter, must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria prior to the first dose of study treatment. Palliative radiotherapy to non-target lesions should be completed within 2 weeks prior to APL-101 administration.
• Adequate cardiac function (≤ NYHA class II) or normal cardiac function with left ventricular ejection fraction (LVEF) ≥ 50% at screening.
• Women of child-bearing potential (WOCBP) must have a negative serum or β-human chorionic gonadotropin (β-hCG) at screening or evidence of surgical sterility or evidence of postmenopausal status. Post-menopausal status is defined as any of the following: natural menopause with menses > 1 year ago; radiation or chemotherapy inducted oophorectomy with menses > 1 year ago and follicle stimulating hormone (FSH) level in the menopausal range.
• All subjects with reproductive potential must agree, and site must document as such, the use of effective contraceptive measures (e.g., oral contraceptives, intrauterine device, or double barrier method of condom and spermicide) during the study and for 7 months (WOCBP) or 4 months (men) following the last dose of study drug.
  • Notes: A postmenopausal woman will be defined as having no menses for 12 months without an alternative medical cause. Male sterility will be defined as only men sterilized surgically. For male subjects with a pregnant partner, a condom should be used for contraception. For male subjects with a non-pregnant female partner of child-bearing potential and woman of childbearing potential one of the following birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended:
  • Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally;
  • Progesterone-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant;
  • Intrauterine device (IUD);
  • Intrauterine hormone-releasing system (IUS);
  • Bilateral tubal occlusion;
  • Vasectomized partner;
  • Sexual abstinence (considered a highly effective method only if defined as refraining from hetersexual intercourse during the entire period of risk associated with the study treatment. The reliabiity of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject).
• Birth control methods unacceptable for this clinical trial are:
  • Periodic abstinence (calendar, symptothermal, or post-ovulation methods);
  • Withdrawal (coitus interruptus);
  • Spermicide only;
  • Lactational amenorrhea method.
• Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade ≤ 1, except for alopecia.
• No planned major surgery within 4 weeks of first dose of APL-101.
• Willing and able to participate in all required evaluations and procedures in this study including swallowing APL-101 in accordance administration schedule outlined.

• Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.
• Known actionable mutation/gene rearrangement of EGFR (except for Cohort C), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
• Use or intended use of any other investigational product, including herbal medications, through Study Treatment Termination.
• Active uncontrolled systemic bacterial, viral, or fungal infection or clinically significant, active disease process, which in the opinion of the investigator makes the risk:benefit unfavorable for the participation of the trial. Screening for chronic conditions is not required.
• Life-threatening illness, significant organ system dysfunction or comorbid conditions, or other reasons that, in the investigator’s opinion, could compromise the subject’s safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of APL-101.
• Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101, symptomatic or unstable arrhythmia requiring medical therapy, history of congenital prolonged QT syndrome, prolonged QT interval corrected by Fridericia formula (QTcF) at screening (> 450 msec based on the average of 3 measurements), or concurrent treatment with a medication that is a known risk for prolonging the QT interval.  Concomitant Therapy). Chronic controlled atrial fibrillation is not excluded.
• Historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) with high viral loads not actively managed with antiviral therapy and human immunodeficiency virus (HIV) positive patients who are not clinically stable or on). If history is unclear, a test at Screening will be required.
• Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
• Unable to swallow orally administered medication whole.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., Crohn’s, ulcerative colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
• Women who are breastfeeding.
• Subjects with complications from prior radiation therapy will not be eligible until AEs return to baseline or ≤ Grade 1.
• History of another malignancy within 3 years prior to Cycle 1 Day 1. A subject with the following malignancies is eligible for this study if, in the opinion of the Investigator, they do not pose a significant risk to life expectancy:
  • Carcinoma of the skin without melanomatous features;
  • Curatively treated cervical carcinoma in situ;
  • Bladder tumors considered superficial such as noninvasive (TIa) and carcinoma in situ (TIs), thyroid papillary cancer with prior treatment, prostate cancer which has been surgically or medically treated and not likely to recur within 3 years.
• Subjects who are unable or unwilling to discontinue excluded mediciations for at least 5 half-lives prior to first dose of study drug.
• Subjects with active COVID-19 infection.

Eligibility last updated 9/9/21. Questions regarding updates should be directed to the study team contact.

• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• ECOG Performance Status of ≤ 2 within 28 days prior to registration
• Archival tissue must be available and identified during screening and shipped prior to Day -21. If archival tissue is not available and the subject is not undergoing a standard of care biopsy, the subject must undergo a research biopsy to obtain fresh tissue prior to start of treatment.
• Carcinoma of unknown primary after the following diagnostic procedures have been performed if clinically indicated and are unrevealing of the primary site:
  • Complete history and clinically appropriate physical
  • CT scan of chest, abdomen, and pelvis
  • Directed evaluation of symptomatic areas
  • Mammogram in women
  • Colonoscopy in patients with liver metastasis or an elevated CEA
  • Direct pathologic comparison with prior tumor specimens, where possible, even if prior tumor is early-stage or clinically remote from current disease
• Histologic confirmation of metastatic adenocarcinoma, poorly differentiated non-small cell carcinoma, or poorly differentiated squamous carcinoma. NOTE: Pathology consultation at Mayo Clinic is recommended if clinically indicated. One scenario is where unknown primary is the most likely diagnosis but immunostains show relatively site-specific marker staining (e.g., CD45, TTF1, chromogranin, GATA3, PAX8, PSA, melanocytic markers). Information provided for pathology consultation should include recent H&P and imaging reports.
• If available, submission of genomic sequencing or expression profiling results is mandatory.
• At least one measurable lesion (per RECIST 1.1) outside the planned RT fields.
• Stable or progressive disease after, or was unable to tolerate, at least one line of prior anticancer therapy for this disease. NOTE: For patients with stable disease, it is strongly encouraged to confirm the presence of active disease (eg, demonstrating FDG avidity via PET or repeat biopsy).
• Radiation oncology consultation at enrolling site ≤ 56 days prior to registration to confirm at least two metastatic lesions which are targetable by RT at doses and schedule prescribed in this study and which reside in non-overlapping RT fields.
• Absolute Neutrophil Count (ANC) ≥ 900 K/mm3
• Hemoglobin (Hgb) ≥ 8.5 g/dL without transfusion or EPO dependency (≤ 7 days prior to assessment)
• Platelets ≥ 90,000 / mcL
• Creatinine OR Calculated creatinine clearance: ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Bilirubin Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN OR total bilirubin ≤2 X ULN if liver metastases are present
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
• Albumin > 2.5 g/dL
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration. NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: breast milk cannot be stored for future use while the mother is being treated on study
• Females of childbearing potential and males must be willing to abstain from heterosexual activity (abstinence) or use effective methods of contraception as described in Section 5.5 from the time of informed consent until 120 days after treatment discontinuation. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Willingness to return to the enrolling institution for follow up
• Willingness to provide tissue and blood samples for correlative research purposes

• Prior radiation to an area of the body which, if included in the current radiation field, poses an unacceptably high risk of toxicity in the opinion of the investigator. NOTE: A prior field that overlaps with the current field, by itself, does not exclude the patient.
• Any of the following
  • Melanoma. NOTE: Positive tumor staining for S-100 or HMB45 alone does not exclude patients.
  • If immunostains are performed, and any of the below tests are positive:
    • Hematologic CD45+ (others such as CD2, CD20, CD30, CD43 also suggest hematologic origin)
    • Lung or thyroid origin (Thyroid Transcription Factor [TTF-1]). NOTE: Patients with biopsy proven TTF-1 positive tumor who do not have clinical evidence for either lung or thyroid cancer (e.g. a dominant lung mass) are still eligible.
• Progressed on 4 or more lines of prior chemotherapy for this cancer. NOTE: Bisphosphonates and neoadjuvant/adjuvant anticancer therapies (including locally directed therapies) do not count as a line of therapy with regard to this exclusion criteria.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. NOTE: Inhaled steroids or steroid injections for joint disease are allowed.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Prior severe allergic reactions to a monoclonal antibody or hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Other active malignancy which requires current treatment and which in the opinion of the site investigator is likely to interfere with evaluation of disease assessment. NOTE: Continuation of hormonal therapies is allowed.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Major surgery ≤ 4 weeks from registration. NOTE: Diagnostic laparoscopy (without other intervention) and/or biopsies (needle aspirate, core biopsy, open biopsy, etc…) are not considered major surgery
• Uncontrolled intercurrent illness which in the opinion of the investigator poses unacceptably high risk when combined with study treatment, including but not limited to the following:
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Severely impaired lung function
  • Known history of active TB (Bacillus Tuberculosis)
  • Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (NOTE: Optimal glycemic control should be achieved before starting trial therapy.)
  • Significant underlying liver disease such as cirrhosis or severe hepatic impairment
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• For patients in whom planned RT fields will include the heart, any of the following heart conditions, if in the opinion of the investigator they pose unacceptably high risk when combined with study treatment:
  • Prior symptomatic congestive heart failure
  • Documented myocardial infarction ≤6 months prior to registration (pretreatment ECG evidence of infarct only will not exclude patients)
  • Prior significant ventricular arrhythmia requiring medication
  • Prior 2nd or 3rd degree heart block or other types of clinically significant conduction delay ≤ 6 months prior to registration
  • Clinically significant pericardial disease (including pericardial effusion, pericarditis) or cardiac valvular disease ≤12 months prior to registration

NOTE: As part of history and physical, all patients must be assessed for signs or symptoms of cardiac disease, or for prior history of cardiac disease. These conditions include but are not limited to diseases related to cardiac valves, pericardium, myocardium, atrioventricular delays or arrhythmias. It is strongly recommended that signs or symptoms of potentially clinically significant disease be evaluated with comprehensive cardiac echo.

• For patients in whom planned RT fields during the study will include the chest, any of the following, if in the opinion of the site investigator they pose unacceptably high risk when combined with study treatment:
  • Prior fistula within thorax, including bronchoalveolar or esophageal.
  • Respiratory condition that required oxygen supplementation ≤ 3 months prior to registration
  • Clinically significant pulmonary hypertension ≤ 12 months prior to registration
  • Pneumonia requiring treatment ≤ 1 month prior to registration
  • Pulmonary embolism requiring treatment ≤ 6 months prior to registration
  • Pleural effusion requiring drainage ≤ 12 months prior to registration
• Has known history of or any evidence of active, non-infectious pneumonitis
• Currently uncontrolled hyper/hypothyroidism or hyper/hypocortism if in the opinion of the investigator they pose unacceptably high risk when combined with study treatment
• Received live vaccine ≤ 30 days prior to registration. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

• Age ≥ 65 years.
• Histologically confirmed newly diagnosed Grade IV malignant glioma.
• Planned radiation treatments at Mayo Clinic Arizona or Mayo Clinic Rochester.
• Willing to sign release of information for any radiation and/or follow-up records.
• Provide informed written consent.
• Patients with eGFR ≥ 60 mg/min/1.72m^2.
• Ability to complete questionnaire(s) by themselves or with assistance.
• ECOG performance status 0, 1, 2.

• Patients diagnosed with Grades I-III glioma.
• Currently on Avastin at time of treatment.
• Unable to undergo MRI scans with contrast (e.g., cardiac pacemaker, defibrillator, kidney failure).
• Unable to undergo an 18F-DOPA-PET scan (e.g., Parkinson’s Disease, taking anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from discontinuance of dopamine agonists).
  • NOTE: Other potentially interfering drugs: amoxapine, amphetamine, benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, paroxetine, citalopram, and sertraline. If a patient is on any of these drugs, list which ones on the On-Study form.
• Pregnant women, nursing women, or men or women of childbearing potential who are unwilling to employ adequate contraception.
  • NOTE: All women enrolled in this study will be age 65 or over, and at the determination of the PI, will not be of childbearing potential.  If the radiology department requires a pregnancy test before administering the 18FDOPA injection, they may perform one per their standard of care.

• Part A
  •Have a histologically or cytologically confirmed metastatic solid tumor for which there is no available therapy that may convey clinical benefit.
• Part B – Have 1 of the following histologically or cytologically confirmed tumor types:
  • HNSCC that is considered incurable by local therapies. Subjects should have progressed after receiving platinum-containing systemic therapy. Systemic therapy given as part of multimodal treatment for locally advanced disease is allowed. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Subjects may not have a primary tumor site of nasopharynx (any histology). Subjects enrolled in the PD-1-treatment-naïve HNSCC cohort may not have been treated with prior anti-PD-1/PD-L1 therapy.
  • Subjects enrolled in the PD-1-treatment-failure HNSCC cohort must be refractory to an FDA approved anti-PD-1/PD-L1 monoclonal antibody (mAb) as either monotherapy or in combination with other approved checkpoint inhibitors or other therapies according to their label, defined as (subjects must meet all of the following criteria):
    • Have received at least 2 doses of anti-PD-1/PD-L1 mAb.
    • Have progressive disease after anti-PD-1/PD-L1 mAb defined according to RECIST 1.1. The initial evidence of PD is to be confirmed by a second assessment, no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression.
    • Note:  this determination is made by investigator. If PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
    • Have documented PD within 24 weeks of the last dose of anti-PD-1/PD-L1 mAb. Patients who were re-treated with anti-PD-1/PD-L1 mAb and patients who were on maintenance with anti-PD-1/PD-L1 mAb will be allowed to enter the trial as long as there is documented PD within 24 weeks of the last treatment date (with anti-PD-1/PD-L1 mAb).
  • Adenocarcinoma of the stomach and/or gastric-esophageal junction (GEJ) that is considered inoperable and that has received, and progressed on, at least 1 prior chemotherapy regimen or HER2/neu-targeted approved therapy (if HER2/neu-positive). In both cases, subjects must not have been treated with prior anti-PD-1/PD-L1 therapy.
  • CRC for Arm 1 and Arm 2: CRC originating in either the colon or rectum that is locally advanced unresectable or metastatic (i.e., Stage IV) and that has received, and progressed on, all available standard-of-care therapies including fluoropyrimidine, oxaliplatin, and irinotecan but has not been treated with prior anti-PD-1/PD-L1 therapy.
  • CRC for Arm 3 and Arm 4: CRC originating in either the colon or rectum that is locally advanced unresectable or metastatic (i.e., Stage IV) and has been treated with ≤1 line of systemic therapy but has not been treated with prior anti-PD-1/PD-L1 therapy. Subjects eligible to receive EGFR-targeted therapy must have previously received this treatment in order to be eligible for the study.
    • Note – Subjects with known MSI high or MMR deficient gastric cancer or CRC (as determined by either PCR or IHC) are excluded from participating in this study. MSI high is defined as at least 2 allelic shifts occurring among the 5 analyzed microsatellite markers as detected by PCR. MMR deficient is defined as loss of expression of at least 1 of 4 proteins (MLH1, MSH2, MSH6, and/or PMS2) by IHC. If a subject’s MSI status is unknown, testing is not required to determine eligibility.
    • Note – Subjects who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of that treatment and precluding retreatment with the same agent before progression of disease will also be eligible.
    • Note – Subjects with CRC enrolled into Arm 3 or Arm 4 are not eligible to be re-enrolled in the study on Arm 1 or Arm 2 following discontinuation.
• Have measureable disease by irRECIST 1.1 criteria.
• Be ≥ 18 years of age on the day of signing informed consent.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Demonstrate adequate organ function as defined in Table 3 (labs to be obtained within 7 days of initiation of treatment).
• If female of childbearing potential, have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• If female of childbearing potential, be willing to use an adequate method of contraception. Contraception, for the course of the study through 120 days after the last dose of study medication.
  • Note: Abstinence is acceptable if this is the usual lifestyle-preferred contraception for the subject.
• Male subjects are eligible to participate if they agree to the following during the intervention period and for at least 95 days after the last dose of chemotherapy or 7 days after the last dose of lenvatinib, whichever occurs last:
  • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; OR
  • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
  • Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
  • Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
• Voluntarily agree to participate by giving written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
• Submit an evaluable baseline tumor sample for PD-L1 analysis (either a newly obtained or archival tumor sample) as specified in the Procedure Manual.

• Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or who has not recovered to CTCAE Grade 0 or 1 from the AEs due to cancer therapeutics administered more than 4 weeks earlier (this includes subjects who received previous immunomodulatory therapy with residual immune-related adverse events [irAEs]). Subjects receiving ongoing replacement hormone therapy for endocrine irAEs will not be excluded from participation in this study.
  • Note: Subjects with Grade 2 neuropathy are excluded from Arm 3 of Part B but may be eligible for all other arms of Part B.Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks of the first dose of study treatment.
• Has received previous treatment with another agent targeting the LAG-3 receptor.
• Has received previous treatment with an immunomodulatory therapy (i.e., anti-PD-1/PD-L1 or CTLA-4 agent) and was discontinued from that therapy due to a Grade 3 or higher irAE.
• Is expected to require any other form of antineoplastic therapy while on study.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses, or on any other form of immunosuppressive medication. Subjects (i.e., with asthma) that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
• Has a history of a previous, additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years.
  • Note: The time requirement for no evidence of disease for 5 years does not apply to the tumor for which a subject is enrolled in the study. The time requirement does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer, or other in situ cancers.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable; i.e., without evidence of progression for at least 4 weeks by repeat imaging
  • Note that the repeat imaging should be performed during study screening, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment.
• Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Has an active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy. Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has an active infection requiring therapy.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has had a prior stem cell or bone marrow transplant.
• Has a known history of or screens positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or an active chronic or acute Hepatitis B (i.e., hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C infection (i.e., hepatitis C virus [HCV] RNA [qualitative] is detected).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is a regular user as determined by investigator judgment (including "recreational use") of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol), at the time of signing informed consent.
• Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has clinically significant heart disease that affects normal activities.
• Has had major surgery in the past 4 weeks.
• Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
• Subjects being considered for enrollment into Arm 4 with CRC in Part B are also excluded if any of the following additional criteria apply:
  • Has plans to use, or is using, any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 3A 4/5 ≤1 week prior to the start of study treatment.
  • Has received previous treatment with irinotecan.
  • Has a known diagnosis of Gilbert’s Syndrome.
• Prolongation of QTcF interval to > 480 ms.
• NOTE: If the QTcF is prolonged to > 480 ms in the presence of a pacemaker, contact the Sponsor to determine eligibility.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.

• Able to provide written informed consent.
• Adult and adolescent (age ≥ 12 years) subjects.
• Diagnosis of either:
  • Histologically or cytologically confirmed well-differentiated low or intermediate-grade (WHO Grade 1 or 2) NET of pancreatic, gastrointestinal, lung, or undetermined origin that is locally advanced or metastatic and has progressed within the past 12 months;
  • Histologically confirmed GIST that is locally advanced or metastatic.
    • Note: NET and GIST tumors must be unresectable.
• NET subjects must have progressed on or been ineligible for treatment with somatostatin analogues (SSA) and at least one other targeted therapy. SSA therapy may continue if the subject has been on a stable dose for at least 3 months.
• GIST subjects must have previously received all FDA-approved therapies (imatinib mesylate, sunitinib malate, and regorafenib) for which they are eligible.
• Subjects must have disease measurable by RECIST 1.1 criteria using either CT or magnetic resonance imaging (MRI) scan.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Female subjects of childbearing potential must agree to use a highly effective method of birth control during and for 4 weeks after completion of study.
• Women are considered to be of childbearing potential unless it is documented that they are:
  • over the age of 60; or
  • postmenopausal by history with no menses for 1 year and confirmed by FSH (using local reference ranges); or
  • have a history of hysterectomy and/or bilateral oophorectomy; or have a history of bilateral tubal ligation. Highly effective methods of birth control include hormonal birth control (oral, intravaginal, transdermal, implantable, or intrauterine), intrauterine devices (IUDs), vasectomy, or any double-barrier methods (combination of male condom and spermicide with cap, diaphragm, or sponge).
• Able and willing to complete the entire study according to the study schedule.

• Diagnosis of high-grade (WHO Grade 3) or poorly differentiated NET; high-grade neuroendocrine carcinoma; adenocarcinoid or goblet cell carcinoid tumor; and large cell neuroendocrine carcinoma, small cell carcinoma, or mixed small and large cell carcinoma.
• Subjects currently receiving anti-cancer therapies (other than SSAs, which may continue).
• Subjects who have received anti-cancer therapies within 2 weeks of the start of study drug (including chemotherapy, radiation therapy, immunotherapy, etc.).
• Failure to recover from Grade 3 or 4 toxicity from previous anti-cancer treatment.
• Known central nervous system involvement by malignant disease.
• Platelet count < 50 × 10^9 /L.
• Absolute neutrophil count < 1.0 x 10^9/L.
• Aspartate aminotransferase (AST) ≥ 3 × upper limit of normal (ULN), or if subject has known liver metastases, AST ≥ 7 × ULN.
• Alanine aminotransferase (ALT) ≥ 3 × ULN, or if subject has known liver metastases, ALT ≥ 7 × ULN.
• Estimated creatinine clearance < 50 mL/min calculated by the Cockroft Gault or Modification of Diet in Renal Disease formulas at screening.
• Poorly controlled diabetes mellitus as evidenced by an HbA1c level ≥ 10%, or significant diabetes-related dietary or therapeutic regimen changes within 12 weeks of enrollment.
• Active heart failure of New York Heart Association (NYHA) Functional Capacity Class III or IV.
• Active autoimmune disease.
• History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease (including, but not limited to, cardiopulmonary, renal, metabolic, hematologic or psychiatric) other than their primary malignancy that in the opinion of the Investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
• Treatment for any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to study entry.
• Positive test for HIV or hepatitis C antibodies.
• Positive test for HBsAg or HBcAb (a subject whose HBsAg is negative and HBcAb is positive may be enrolled if an HBV DNA test is negative and either the subject is treated with potent anti-viral therapy or is re-tested for HBsAg and HBV DNA every month).
• Subject is pregnant or breastfeeding, or planning to become pregnant while enrolled in the study, up to the EOS visit.
• Positive serum pregnancy test (i.e., urine human chorionic gonadotropin) at screening.

• Age ≥ 18 years and ≤ 80 years old.
• High risk smoldering myeloma, which is untreated, as defined by presence of any two of the following:
  • Serum M spike > 2 gm/dL; OR
  • An involved to uninvolved FLC ratio > 20; OR
  • Bone marrow PC% > 20%.
• Total score of 9 or above using the following scoring system:
  • FLC Ratio >10-25
    • Score:  2
  • FLC Ratio >25-40
    • Score:  3
  • FLC Ratio > 40
    • Score:  5
• Serum M protein (g/dL)
  • > 1.5-3
    • Score: 3
  • > 3
    • Score:  4
• BMPC%
  • >15-20
    • Score: 2
  • > 20-30
    • Score: 3
  • > 30-40
    • Score:  5
  • > 40
    • Score:  6
• FiSH abnormality (t(4,14), t(14,16), 1q gain, or del13q
  • Score:  2
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Calculated creatinine clearance (using Cockcroft-Gault equation below)* ≥ 30 mL/min;
  • Absolute neutrophil count (ANC) ≥ 1000/mm³ (without the use of growth factors);
  • Platelet count  ≥ 75000/mm ³;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤ 1.5 x ULN;
  • ALT and AST ≤ 3 x ULN;
• *Cockcroft-Gault Equation:
  • Creatinine clearance for males = (140
    •age)(actual body weight in kg)/ (72)(serum creatinine in mg/dL);
  • Creatinine clearance for females = (140
    •age)(actual body weight in kg)(0.85)/(72)(serum creatinine in mg/dL).
• LVEF ≥ 40%.
• ECOG performance status (PS) 0 or 1.
• Previously untreated.
• Provide informed written consent.
• Negative pregnancy test done ≤ 14 days prior to C1D1, for women of childbearing potential only.
• All study participants must be registered into the mandatory Revlimid REMSR program and be willing and able to comply with the requirements of the REMSR program.
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMSR program.
• Willing to follow strict birth control measures as outlined in the protocol.  Female subjects: If they are of childbearing potential, agree to one of the following:
  • Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of trial drug; AND
  • Must also adhere to the guidelines of any treatmentspecific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Male subjects: even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
  • Agree to practice effective barrier contraception during the entire trial treatment period and through 90 days after the last dose of trial drug; OR
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Willing to return to enrolling institution for follow-up during the Active Treatment Phase of the trial.
• Male subjects must agree not to donate sperm for at least 90 days after the last dose of study treatment.
• Willing to provide samples for planned research.
• Life expectancy > 6 months.
• Able to take aspirin (325 mg) daily as prophylactic anticoagulation. Subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.

• MGUS, standard risk smoldering myeloma, active myeloma by current IMWG definition, light chain amyloidosis with organ involvement or patients with extramedullary disease.
• Diagnosed or treated for another malignancy ≤ 2 years before trial enrollment or previously diagnosed with another malignancy and have any evidence of residual disease.
  • NOTE: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol).
• Other co-morbidity which would interfere with subject's ability to participate in trial; e.g., uncontrolled infection, uncompensated heart or lung disease.
• Other concurrent chemotherapy, or any ancillary therapy considered investigational.
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Peripheral neuropathy ≥ Grade 3 on clinical examination or grade 2 with pain within 30 days prior to C1D1.
• Major surgery ≤ 14 days prior to C1D1.
• Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
  • Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• NYHA II, III, IV heart failure.
• Known human immunodeficiency virus (HIV) positive.
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
  • EXCEPTION: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Known or suspected active hepatitis C infection.
• Any medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
• Prior radiation therapy for bony lesions or plasmacytomas
• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products. Known allergies, hypersensitivity, or intolerance to trial drugs.
• Inability to comply with protocol/procedures.

• Cytologically or histologically and radiologically confirmed solid tumor that is inoperable locally advanced, metastatic, or recurrent:

Dose-Escalation Stage:

• Subjects with UC (including renal pelvis, ureter, urinary bladder, urethra) after prior platinum-based therapy, or
• Subjects with RCC (clear cell, non-clear cell histology) with or without prior systemic anticancer therapy.

Expansion Stage:

• Expansion Cohort 1: Subjects with RCC with clear cell histology (including those with mixed sarcomatoid component) and without prior systemic anticancer therapy.
• Expansion Cohort 2: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after platinum-containing chemotherapy including subjects who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from the end of last therapy.
• Expansion Cohort 3: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic anticancer therapy for inoperable locally advanced or metastatic disease.
  • Ineligible for cisplatin-based chemotherapy is defined by meeting one of the following criteria:
  • Impaired renal function (glomerular filtration rate [GFR] < 60 mL/min/1.73 m2), hearing loss of ≥ 25 dB at two contiguous frequencies, or ≥ Grade 2 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE) v4.
  • Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence took place > 12 months from end of last therapy.
• Expansion Cohort 4: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic anticancer therapy for inoperable locally advanced or metastatic disease.
  • Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence took place > 12 months from end of last therapy.
• Expansion Cohort 5: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) for the treatment of inoperable locally advanced or metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat inoperable locally advanced or metastatic UC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior combination therapy of an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with a VEGFR-targeting TKI.
• Expansion Cohort 6: Subjects with metastatic CRPC (adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features) who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
  • Note: prostate-specific antigen [PSA] progression or bone progression alone are not allowed to determine eligibility.
  • Prior chemotherapy is not allowed with the exception of docetaxel given in combination with androgen deprivation therapy (ADT) for progressive castration-sensitive disease prior to treatment with enzalutamide and/or abiraterone acetate.
  • Subject must have castrate-level testosterone (< 50 ng/dL [< 2 nM]) following bilateral orchiectomy or by ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analog that was initiated ≥ 4 weeks prior to first dose of study treatment and must be continued throughout the study.
• Expansion Cohort 7: Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) for metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat metastatic NSCLC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior VEGFR-targeting TKI.
  • Excluded are subjects who have been diagnosed with an EGFR sensitizing mutation, ALK rearrangement, ROS1 rearrangement, or BRAF V600E mutation.
• Expansion Cohort 8: Subjects with Stage IV non-squamous NSCLC with positive PD-L1 expression (TC ≥ 1% [TC = tumor cell]) and without prior systemic anticancer therapy for metastatic disease.
  • Acceptable reports for prior PD-L1 expression testing by immunohistochemical (IHC) assessment include the following:
    • US sites: FDA-approved Dako PD-L1 IHC 22C3 pharmDx assay;
    • Ex-US sites: health authority-approved or CE-marked Dako PD-L1 IHC 22C3 pharmDx assay.
  • A prior local laboratory PD-L1 report using a validated assay may be accepted if slides can be provided to the central laboratory to assess PD-L1 expression using the FDA-approved Dako PD-L1 IHC 22C3 pharmDx assay.
  • Excluded are subjects who have been diagnosed with an EGFR sensitizing mutation, ALK translocation, ROS1 rearrangement, or BRAF V600E mutation.
• Expansion Cohort 9: Subjects with Stage IV nonsquamous NSCLC with documentation of a sensitizing EGFR mutation who have radiographically progressed during or following prior treatment with an EGFR targeting TKI (e.g., osimertinib, gefitinib, erlotinib, afatinib) for metastatic disease.
  • There is no limit on the number of prior lines of systemic anticancer therapy including chemotherapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Prior treatment with ICIs (anti-PD-1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
• Expansion Cohort 10: Subjects with RCC with non-clear cell histology (including those with sarcomatoid component)
  • Allowed is prior therapy with up to one VEGFR-targeting TKI (eg, sunitinib, pazopanib) for inoperable locally advanced, recurrent, or metastatic disease.
  • TKIs targeting MET or prior therapy with immune checkpoint inhibitors is not allowed.
• Expansion Cohort 15: Subjects with gastric or gastroesophageal junction adenocarcinoma who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Prior HER-2/neu directed therapy is allowed if given combined with systemic chemotherapy.
• Expansion Cohort 16: Subjects with colorectal adenocarcinoma who have radiographically progressed during or following systemic chemotherapy that contained fluoropyrimidine in combination with oxaliplatin or irinotecan for metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Prior EGFR-targeted therapy given with concurrent chemotherapy is allowed.
  • Subjects with known microsatellite instability-high (MSI-H) and/or mismatch repair (MMR) deficient disease are excluded.

Exploratory Single-Agent Cabozantinib (SAC) Cohorts:

• Single-Agent Cohort 19: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior ICI (anti-PD-1 or anti-PD-L1) for the treatment of inoperable locally advanced or metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat inoperable locally advanced or metastatic UC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior combination therapy of an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with a VEGFR-targeting TKI.
• Single-Agent Cohort 20: Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior ICI (anti-PD-1 or anti-PD-L1) for metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat metastatic NSCLC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior combination therapy of an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with a VEGFR-targeting TKI and subjects who have been diagnosed with an EGFR sensitizing mutation, ALK translocation, ROS1 rearrangement, or BRAF V600E mutation.
• Exploratory Single-Agent Cabozantinib (SAC) Cohort 21, Exploratory Single-AgentAtezolizumab (SAA) Cohort 22, and Combination-Therapy Expansion Cohort 23:Subjects with metastatic CRPC who have histologically or cytologically confirmedadenocarcinoma of the prostate without small cell component (Note: Neuroendocrinedifferentiation and other histologic components are permitted if adenocarcinoma is theprimary histology) with the following requirements:
  • Prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide,darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) ormetastatic castration-sensitive prostate cancer (mCSPC), M0 CRPC, or mCRPC. Note: Subjects may have previously received taxane-based chemotherapy for mCSPCbut no other approved or experimental nonhormonal systemic therapies formetastatic prostate cancer.
  • Bilateral orchiectomy or ongoing androgen deprivation therapy with a GnRHagonist/antagonist (surgical or medical castration), with serum testosterone≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
  • Progressive disease at study entry as defined by at least one of the following two criteria:
    • a. PSA progression defined by a minimum of 2 rising PSA values from 3 or 4 consecutive assessments with an interval of at least 7 days between assessments.The most recent qualifying PSA value must be drawn within 28 days of plannedenrollment. (Note: If qualifying solely by PSA progression, the screening central lab PSA value must be at least 2 ng/mL [2 μg/L] but need not serve as last PSA value for determination of PSA progression; up to one PSA decrease is permitted as long as it is not the most recent value), OR
    • Soft tissue disease progression in the opinion of the Investigator. Note: Bone disease progression alone does not qualify.

• High risk metastatic disease per Investigator read as defined by at least one of the
following:

• Measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen), OR
• Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation)
• Combination-Therapy Expansion Cohort 24: Subjects with metastatic CRPC who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell component (Note: Neuroendocrine differentiation and other histologic componentsare permitted if adenocarcinoma is the primary histology) with the following requirements:
  • Prior taxane-based chemotherapy initiated for mCRPC (Note: Subjects may have previously received taxane-based chemotherapy for CSPC but no other approved or experimental nonhormonal systemic therapies for metastatic prostate cancer.)
  • Prior treatment with at least one NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (mCSPC), M0 CRPC, or mCRPC.
  • Bilateral orchiectomy or ongoing androgen deprivation therapy with a GnRH agonist/antagonist (surgical or medical castration), with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
  •  Progressive disease at study entry as defined by at least one of the following two criteria:
    •  Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 or 4 consecutive assessments with an interval of at least 7 days between assessments. The most recent qualifying PSA value must be drawn within 28 days of planned enrollment. (Note: If qualifying solely by PSA progression, the screening central lab PSA value must be at least 2 ng/mL [2 μg/L] but need not serve as last PSA value for determination of PSA progression; up to one PSA decrease is permitted as long as it is not the mostrecent value), OR
    • Soft tissue disease progression in the opinion of the Investigator. Note: Bone disease progression alone does not qualify.
  • High risk metastatic disease per Investigator read as defined by at least one of the following:
    • Measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen, but not bladder or other pelvic structure) OR
    • Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation)
• Measurable disease per RECIST 1.1 as determined by the investigator. Measurable disease must be outside the radiation field if prior radiation therapy was administered.
• Tumor tissue material available (archival or recent tumor biopsy).
• Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• Age eighteen years or older on the day of consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
  • Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection.
  • White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).
  • Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion within 2 weeks before screening laboratory sample collection. For subjects with HCC ≥ 75,000/mm3 (≥ 75 GI/L).
  • Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening laboratory sample collection.
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN with documented bone metastases. For subjects with HCC: ALT, AST, and ALP ≤ 5 × ULN.  For subjects with mCRPC with documented bone metastases: ALT ≤ 3 × ULN, AST ≤ 3 × ULN, and ALP ≤ 10 × ULN. If ALP > 5 × ULN in mCRPC subjects, then it must be demonstrated that it is predominantly bone-specific ALP.
  • Total bilirubin ≤ 1.5 × ULN (for subjects with Gilbert’s disease ≤3 × ULN). For subjects with HCC ≤ 2 mg/dL (≤ 34.2 μmol/L).
  • Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft-Gault equation (see Table 5-2 for Cockcroft-Gault formula).
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol). For subjects with UC: ≤ 2 mg/mg (≤ 226.4 mg/mmol) creatinine.
• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 5 months after the last dose of study treatment.  An additional contraceptive method, such as a barrier method (eg, condom), is recommended.
• Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria are met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 45 years-of-age in the absence of other biological or physiological causes. In addition, females under 55 years-of-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

• Prior treatment with cabozantinib or ICIs including anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-OX-40, anti-CD137 therapy except for Expansion Cohorts 5 and 7 and SAC Cohorts 19 and 20 in which prior anti-PD-1 or anti-PD-L1 therapy is required for eligibility (see Inclusion Criteria 1g, 1i, 1u, and 1v, respectively, for details).
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• For CRPC subjects: receipt of abiraterone within 1 week before first dose of study treatment or receipt of any other androgen-receptor inhibitors within 2 weeks before first dose of study treatment.
• HCC subjects who meet any of the following criteria are ineligible:
  • a. Received prior local anticancer therapy (including embolization and ablation) within 4 weeks before first dose of study treatment. For prior radiation for bone metastases, refer to Exclusion Criteria 6.
  • b. Subjects with fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma.
• Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before first dose of study treatment, except in Expansion Cohorts 5 and 7 and SAC Cohorts 19 and 20 for which receipt of a PD-1, PD-L1, or CTLA-4 targeting antibody is permitted within 4 weeks before first dose of study treatment.
• Radiation therapy for bone metastasis within 2 weeks, any other local radiation therapy within 4 weeks before first dose of study treatment. Subjects who have received systemic treatment with radionuclides within 6 weeks before first dose of study treatment are not eligible. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• Concomitant anticoagulation with oral anticoagulants except for those specified below.
  • Allowed anticoagulants are:
    • Prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
    • Therapeutic doses of LMWH or specified direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects (excluding HCC subjects) without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatent and without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. Note: Subjects with HCC may be treated with therapeutic LMWH but must have a screening platelet count > 100,000/μL. Direct inhibitors of thrombin or factor Xa are not permitted in subjects with HCC.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment. Inhaled and topical corticosteroids and mineralocorticoids are allowed.
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
  • Cardiovascular disorders:
    • Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
    • Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
    • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis of DVT within 6 months are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks before first dose.
  • Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
    • Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction.  Presence of primary GI tumor is not excluded.
    • Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
    • Gastric or esophageal varices that are untreated or incompletely treated with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible.
  • Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose.
  • Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
  • Lesion invading a major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. HCC subjects with lesions invading the hepatic portal vasculature are eligible.
  • Other clinically significant disorders such as:
    • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis. Subjects with the following conditions are eligible for the study:
      • A history of autoimmune-related hypothyroidism and on thyroid replacement hormone therapy
      • Controlled Type 1 diabetes mellitus and on an insulin regimen
      • Asthma
      • Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only provided all of following are true:
      • Rash covers < 10% of body surface area
      • Disease is well controlled at baseline and requires only low-potency topical corticosteroids
      • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
    • Active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, acute or chronic hepatitis B or C infection in non-HCC tumor cohorts, or positive test for tuberculosis.  Subjects with history of COVID-19 must have recovered from the disease at least 30 days prior to enrollment.
    • History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
    • Serious non-healing wound/ulcer/bone fracture.
    • Malabsorption syndrome.
    • For all subjects except Cohort 18 (DTC): Free thyroxine (FT4) outside the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after sponsor approval.
    • Moderate to severe hepatic impairment (Child-Pugh B or C; Appendix K).
    • Requirement for hemodialysis or peritoneal dialysis.
    • History of solid organ or allogenic stem cell transplant.
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 4 weeks or minor surgery (eg, simple excision, tooth extraction) within 10 days before first dose of study treatment. Complete wound healing from surgery must have occurred before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment (see Section 5.6.4 for Fridericia formula).
  • Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these  three consecutive results for QTcF will be used to determine eligibility (ie, if the average is ≤ 500 ms the subject is eligible).
• Pregnant or lactating females.
• Inability to swallow tablets.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations. Subjects with a history of infusion-related reaction to prior therapy with atezolizumab may be eligible by sponsor approval if the reaction was considered mild and manageable with appropriate supportive care (eg, use of premedication according to standard of care).
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.

• For Dose escalation: subjects with cervical, ovarian, bladder and colorectal cancer (CRC), head and neck, gastric and hepatocellular cancer naive to immuno-oncology agents; 1st line melanoma and 1st line/2nd line NSCLC; Renal Cell Carcinoma naive to IO; NSCLC progressing while on or after therapy with anti-PD1/anti-PDL-1 and melanoma subjects progressed while-on or after treatment with anti-PD1 or anti-PDL1 with or without anti-CTLA-4.
• For Dose Expansion: all of the above in escalation except for cervical, ovarian, and CRC
• Progressed, or been intolerant to, at least one standard treatment regimen, except for subjects in 1st line cohorts.
• ECOG performance status of 0 or 1
• At least 1 lesion with measurable disease at baseline
• Availability of an existing tumor biopsy sample (and consent to allow pre-treatment tumor biopsy)

• Primary central nervous system (CNS) tumors or solid tumors with CNS metastases as the only site of active disease
• Autoimmune disease
• Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
• Uncontrolled CNS metastases

• Patient is at least 18 years of age.
• Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements.
• Patient has histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) that is not amenable to treatment with curative intent.
• Prior treatment status:
  • Cohorts 1 and 2: Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC;
  • Cohorts 3 and 4: Patient is treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with poziotinib as determined by the Investigator. Adjuvant/neo-adjuvant therapies (chemotherapy, radiotherapy, or investigational agents) are permissible as long as they end at least 15 days prior to study entry;
  • Cohort 5: Patients who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed;
  • Cohort 6: Patients with EGFR mutation-positive NSCLC who progressed while on treatment with first-line osimertinib;
  • Cohort 7: Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC.
• Tissue and plasma samples for mutation confirmation:
  • Cohorts 1 to 5: Patient has adequate tumor tissue obtained from a biopsy or surgical procedure to enable molecular profiling for retrospective central laboratory confirmation of the mutation. If tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy to provide an appropriate tissue sample prior to receiving treatment in the study;
  • Cohort 6: A tissue sample must be provided after osimertinib progression;
  • Cohort 7: Either tissue or plasma samples are acceptable for enrollment.
• Patient is positive for EGFR or HER2 mutations based on:
  • Cohorts 1 and 3: Documented EGFR exon 20 insertion mutation (including duplication mutations) using a next generation sequencing diagnostic test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, or by an FDA approved test (eg, cobas® EGFR mutation test v2 or therascreen EGFR RGQ PCR kit) performed by a US CLIA certified and locally licensed clinical laboratory or similarly accredited lab for ex-US sites using tissue samples;
  • Cohorts 2 and 4: Documented HER2 exon 20 insertion mutation (including duplication mutations) using a next generation sequencing diagnostic test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, performed by a US CLIA certified and locally licensed clinical laboratory or similarly accredited lab for ex-US sites using tissue samples;
  • Cohort 5: Documented EGFR or HER2 exon 20 insertion mutations using tissue samples using the criteria described for Cohorts 1 to 4;
  • Cohort 6: Documented acquired EGFR mutation who have progressed while on first-line osimertinib treatment using tissue tested with a next-generation sequencing assay;
  • Cohort 7: Documented EGFR or HER2 activating mutations (see table below) using tissue tested with a next-generation sequencing assay or plasma tested with a Guardant assay.
• Patient has measurable NSCLC disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Metastatic lesions in CNS or in brain cannot be used for target lesions.
• Brain metastases may be allowed if patient’s condition is stable, defined as clinically asymptomatic, no requirement for high dose or increasing dose of systemic corticosteroids, and no need for any anticonvulsant therapy for metastatic brain disease. For the patient who has had radiation therapy, sequential post-treatment MRI tests, at least 4-6 weeks apart, should show no increases in brain lesion size/volume within 4 weeks prior to the study.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and has a life-expectancy of more than 6 months.
• Patient has recovered from prior systemic therapy for metastatic disease to Grade ≤1 for non-hematologic toxicities (except for Grade ≤ 2 peripheral neuropathy) and has adequate hematologic, hepatic, and renal function at Baseline, as defined by:
  • Leukocytes ≥ 3.0×10^9/L;
  • Absolute neutrophil count (ANC) must be ≥ 1.5×10^9/L;
  • Platelet count ≥ 100×10^9/L;
  • Hemoglobin ≥ 9.0 g/dL;
  • Total bilirubin ≤ 2 mg/dL; if hepatic metastases are present, ≤ 2.5 × ULN;
  • SGOT (AST) and SGPT (ALT) ≤ 2.5×ULN with the following exception; Patients with liver metastases AST, ALT ≤ 5×ULN;
  • Creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault equation;
  • Patient is willing to practice 2 forms of contraception, one of which must be a barrier method, from study entry until at least 30 days after the last dose of poziotinib;
  • Females of childbearing potential must have a negative pregnancy test within 30 days prior to enrollment. Females who are postmenopausal for at least 1 year (defined as more than 12 months since last menses) or who are surgically sterilized do not require this test.

• Patient has:
  • All Cohorts: EGFR T790M;
  • Cohorts 1 to 5: EGFR exon 20 point mutation;
  • Cohort 7: EGFR Exon 19 deletion and L858R or HER2 T798I mutations, EGFR and HER2 Exon 20 insertion mutation.
• Patient has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study participation. The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible (Cohorts 1 to 4).
• Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks; local radiation therapy for bone pain may be allowed.
• Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment.
• Patient has a high risk of cardiac disease, as determined by the Investigator, may undergo either echocardiogram (ECHO) or multi-gated acquisition (MUGA) during Screening and has a cardiac ejection fraction < 50%.
• Patient has had other malignancies within the past 3 years, except for stable non-melanoma skin cancer, fully-treated and stable, early-stage prostate cancer, or carcinoma in situ of the cervix or breast without need of treatment.
• Patient is confirmed to have clinically significant or recent acute gastrointestinal disease presenting as diarrhea and/or coloenteritis as a main symptom (ie, acute enteritis, malabsorption, or Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) Grade 2 or above diarrhea due to other etiologies).
• Patient has an active Grade ≥ 2 skin disorder, rash, mucositis, or skin infection that needs medication or therapy or existing Grade ≥ 2 skin toxicity from previous therapies; Grade ≥ 2 neuropathy, Grade ≥ 2 pneumonitis.
• Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function, such as inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy.
• Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, asymptomatic biliary stones, liver metastasis, or stabilized chronic liver diseases).
• Patient has known hypersensitivity to poziotinib or has a history of allergic reactions attributed to chemically similar compounds or other tyrosine kinase inhibitors (TKIs).
• Patient has an active uncontrolled infection, underlying medical condition, or other serious illness that would not be appropriate for this study.
• Patient has unstable, uncontrolled, active bleeding disorders that the investigator considers that the patient could be at increased risk or not be suitable for treatment in this study.
• Patient is pregnant or breast-feeding.
• Cohort 5 only: Patient is eligible for treatment in an open cohort (Cohorts 1 to 4).

• Age ≥ 18 years of age.
• Histological confirmation of WM. Patients may have newly diagnosed, relapsed, or refractory disease.
  • Definition: Newly diagnosed; Patients previously untreated for WM, Relapse; patients who have received prior treatment for WM and now have disease recurrence. Refractory; patients who have received anti-WM therapy and are noted to have progressive disease while on therapy, or those patients who demonstrated disease progression within 6 months of the last anti-WM treatment).
    • NOTE: Ibrutinib naïve patients are allowed. If previously treated with ibrutinib, subject must have reached a response of at least SD and cannot have progressed while on ibrutinib. If subject stopped taking ibrutinib for reasons other than progression, they cannot have progressed for at least 6 months post last dose of ibrutinib.
• Presence of measurable disease as defined by: presence of immunoglobulin M (IgM) paraprotein, measurable lymphadenopathy on imaging studies and/or physical exam, and/or bone marrow infiltration > 10%.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2.
• Obtained ≤ 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1000/mm³;
  • Platelet count ≥ 75,000/mm³;
    • NOTE: platelet transfusions in order to help patients meet eligibility criteria are not allowed.
  • Hemoglobin > 9.0 g/dL;
  • Total bilirubin ≤1.5 upper limit of normal (ULN) unless due to Gilbert's syndrome, in which case the direct bilirubin must be ≤ 1.5  x ULN;
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3  x ULN;
  • Calculated creatinine clearance must be ≥ 30 ml/min using the Cockcroft Gault formula.
• Negative pregnancy test done at screening and  ≤ 3 days (72 hours) prior to registration, for women of childbearing potential.
• Provide written informed consent.
• Willingness to provide mandatory blood specimens and bone marrow specimens for correlative research.
• Willingness to return to enrolling institution for follow-up.

• Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior treatment for WM.
• Major surgical procedure (including open biopsy, excluding central line IV and portacath placement) within ≤ 14 days prior to initiating study treatment, or anticipation of the need for major surgery during the course of the study treatment.
• Radiotherapy ≤ 14 days prior to registration. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the Ixazomib.
• Systemic treatment, ≤ 14 days before registration, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or St. John’s wort.
• Systemic anti-cancer therapy or participation in other clinical trials, including those with other investigational agents not included in this trial, ≤ 28 days of registration and throughout the duration of active treatment in this trial.
• Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.
• Prior bortezomib treatment is allowed as per:
  • Patients with prior exposure to bortezomib will be allowed if they do not have disease refractory to bortezomib).
• Central nervous system involvement (Bing-Neel syndrome).
• Infection requiring systemic antibiotic therapy or other serious infection ≤ 7 days prior to registration.
• a Evidence of current uncontrolled cardiovascular conditions,  including  uncontrolled hypertension, serious cardiac arrhythmia requiring medication (other than adequately rate-controlled atrial fibrillation), symptomatic congestive heart failure, unstable angina, stroke/TIA within the past 6 months or myocardial infarction within the past 6 months.
• Known allergy to any of the study medications, their analogues, or excipients in  the various formulations of any agent.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or ibrutinib, including difficulty swallowing.
• History of any other prior malignancy.
  • NOTE: Exception to this are adequately treated non-melanoma skin cancers, any in situ cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least two years prior to study enrollment.
• Patient has ≥ Grade 2 peripheral neuropathy or Grade 1 peripheral neuropathy  with pain on clinical examination during the screening period.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of child bearing potential (WCBP) who are unwilling to employ effective contraception. Effective contraception would be defined as utilizing 2 simultaneous methods of contraception from the time of signing consent through 90 days after the last dose of the study drugs unless they agree to participate in true abstinence when this is in line with the preferred and usual lifestyle of the subject. [WCBP: A female who is sexually mature and who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)].
• Evidence of any other serious medical condition (such as psychiatric illness, infectious diseases, physical or laboratory findings) that may interfere with the planned treatment, affect compliance or place the patient at high risk from treatment-related complications or potentially interfere with the completion of  the treatment as per the protocol.
• Ongoing, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
• Liver disease with Child-Pugh class B or C liver dysfunction.
• Current treatment with a combination of ibrutinib and strong CYP3A inhibitors.

• Age > 21 years old.
• Patients with histologic diagnosis of epithelial ovarian carcinoma, primary peritoneal carcinoma, or fallopian tube carcinoma that has recurred >6 months since platinum-based chemotherapy (first recurrence) and who are scheduled for secondary surgical evaluation/cytoreduction.
• Histologic epithelial cell types include serous, endometrioid, clear cell, or undifferentiated carcinomas, transitional cell carcinoma, mixed epithelial carcinoma, malignant Brenner‟s tumor, or adenocarcinoma N.O.S.
• Karnofsky Performance Status (KPS) of ≥ 70%.
• Disease-free interval < 30 months.
• No prior chemotherapy in the recurrent setting. Prior hormonal therapy is permitted. Concomitant anti-neoplastic anti-hormonal therapy (including tamoxifen, aromatase inhibitors etc.) is not allowed for patients participating in study treatment. Low-dose (physiologic) estrogen hormone-replacement therapy (HRT) may be given.
• Patients receiving maintenance biologic therapy are eligible, provided their recurrence is documented more than 6 months from completion of primary cytotoxic chemotherapy (includes maintenance chemotherapy) and a minimum of 3 weeks has elapsed since their last infusion of biologic therapy at the start of protocol intervention, day 1.
• Patients must be, after evaluation by the investigator, appropriate candidates for the administration of 5 to 6 cycles of standard platinum-based combination chemotherapy (carboplatin and paclitaxel, carboplatin and liposomal doxorubicin, or carboplatin and gemcitabine) following CRS with or without HIPEC.

Physical and Laboratory Test Findings

• Bone marrow function:
  • Hemoglobin ≥ 8.5 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1,000/mm3;
  • Platelets ≥ 100,000/mm3.
• Renal function:
  • Creatinine ≤ 1.5mg/dl.
• Hepatic function:
  • Bilirubin ≤ 1.5 times ULN;
  • ALT ≤ 3 times the ULN;
  • AST ≤ 3 times the ULN.
• Neurologic function:
  • Peripheral neuropathy ≤ CTC AE grade 2.
• Blood coagulation parameters:
  • PT with an INR of ≤ 1.5 and a PTT ≤ 1.5 times the ULN. For patients on full-dose oral anti-coagulation (such as warfarin or rivaroxaban), in-range INR (usually between 2 and 3) and a PTT <1.2 times the ULN.
• Patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to CRS and must be practicing an effective form of contraception during the study period.

Inclusion Criteria for Eligibility post-surgery

• Patients will be consented prior to the surgical evaluation/cytoreductive surgery. Patients must have less than or equal to 0.5 cm residual disease at the completion of the secondary surgery to be eligible for the study.

• Tumors of low malignant potential (borderline carcinomas).
• Subjects who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded.
• Patients with a history of primary endometrial cancer are excluded unless the following conditions are met:
  • Stage not greater than IA;
  • Not a poorly differentiated subtype (including papillary serous, clear cell or other FIGO grade 3 lesions).
• With the exception of non-melanoma skin cancer and other specific malignancies as noted above, subjects with other invasive malignancies, who had any evidence of the other cancer present within the last 1 year or whose previous cancer treatment contraindicates this protocol therapy, are excluded.
• Subjects with known active acute hepatitis.
• Subjects with active infection that requires parenteral antibiotics.
• Active coronary artery disease (defined as unstable angina or a positive cardiac stress test).
• Patients with a history of coronary artery disease may be included if they have had a normal stress test within 30 days of enrollment.
• Uncontrolled hypertension defined as > 140/90 and not cleared for surgery at the time of consent.
• New York Heart Association (NYHA) Class II or higher congestive heart failure.
• History of cerebrovascular disease.
• Immune deficiency: Clinically significant primary or acquired immune deficiency (i.e., AIDS or on immunosuppressive medication after organ transplant)
• Patients with other concurrent severe medical problems unrelated to the malignancy that would significantly limit full compliance with the study or places them at an unacceptable risk for participation in the study.
• Patients with known carboplatin or cisplatin allergy.
• Life expectancy < 12 weeks.

Exclusion Criteria for Eligibility post-surgery

• Evidence of extensive intraperitoneal adhesions at the time of surgery, as determined by the operating surgeon which prohibits intraperitoneal therapy.

1. Women must be >/= 30 and </= 50 years of age.
2. Premenopausal women with a documented deleterious mutation in one of the following ovarian cancer genes: BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, BARD1, MSH2, MSH6, MLH1, PMS2, or EPCAM. (Please note: Menopause is defined as >/= 12 months of amenorrhea. However, for those patients with >/= 12 months of amenorrhea who may be pre-menopausal, levels of FSH, LH, and estradiol in the pre-menopausal range will be acceptable).
3. Willing to undergo two surgical procedures (if participant chooses the ISDO arm)
4. Presence of at least 1 fallopian tube and 1 ovary. (Please note: Prior unilateral salpingectomy is allowed; prior bilateral salpingectomy is not allowed)
5. Patients who have undergone a prior tubal ligation will be eligible.
6. Participants may have a personal history of non-ovarian malignancy, but must: a) be without evidence of disease at enrollment b) remain premenopausal c) have completed treatment (including surgery, chemotherapy, radiotherapy or hormonal therapy) >3 months prior to enrollment (other than non-melanoma skin cancer)
7. Willingness to return to the enrolling site for the study surgical procedures, including pre-operative and post-operative care. (Patients in the ISDO arm must be willing to return to the enrolling site for yearly ovarian cancer assessment)
8. Patients must understand that they will be permanently sterilized

1. Women with a personal history of ovarian, fallopian tube, or primary peritoneal cancer
2. Current treatment with Tamoxifen or Aromatase Inhibitors
3. Medical comorbidities making surgery unsafe as determined by the patient's surgeon
4. Women who are pregnant or post-partum (within 3 months of delivery). -Patients are deemed not pregnant by virtue of urine pregnancy test (UPT), transvaginal ultrasound, beta HCG, or best judgement of the investigator. Pregnancy testing is not required per protocol to determine study eligibility -Women who become pregnant on the ISDO arm via reproductive technology can remain on study. However, data collection will be suspended during pregnancy and 3 months post-partum
5. Women with elevated levels of CA125 (>50) or transvaginal ultrasound suggesting cancer, unless findings are consistent with endometriosis. CA125 and transvaginal ultrasounds must be the most recent, but no older than 1 year from the date of enrollment.
6. Inability to provide informed consent.
7. Inability to read or speak English.

• Patient is ≥ 18 years of age.
• Diagnosis during dose escalation (Part 1) – Pathologically documented, definitively diagnosed non-resectable advanced solid tumor.
  • All patients treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood;
  • Part 1 enrichment patients must have MTC or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
• Diagnosis during dose expansion (Part 2) – All patients (with the exception of patients with MTC enroled in Groups 3, 4 and 9) must have an oncogenic RET fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below:
  • Group 1 – patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy.
  • Group 2 – patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy.
  • Group 3 – patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.
  • Group 4 – patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib or vandetanib.
  • Group 5 – patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received SOC appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate) and must not eligible for any of the other groups.
  • Group 6 – patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, previously treated with a selective TKI that inhibits RET, such as selpercatinib.
  • Group 7 – patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups.
  • Group 8 – patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum-based chemotherapy (China only).
  • Group 9 – patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only).
• Patient must have non-resectable disease that has progressed following standard therapy or has not adequately responded to standard therapy, or the patient must be intolerant to, or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.
• Dose expansion (Part 2) patients in all groups (ecept Group 7) must have measurable disease per RECIST v1.1 (or RANO, if appropriate for tumor type).
• Patient agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Part 2, Group 6, patients are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.
• Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
• Patient provides informed consent to participate in the study.

• Patient’s cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1, or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation. Investigators should discuss enrollment with Sponsor regarding co-mutations.
• Patient has any of the following within 14 days prior to the first dose of study drug:
  • Platelet count < 75 × 109/L;
  • Absolute neutrophil count (ANC) < 1.0 × 109/L;
  • Hemoglobin < 9.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug;
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present;
  • Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert’s disease;
  • Estimated (Cockroft-Gault formula) or measured creatinine clearance < 40 mL/min;
  • Total serum phosphorous > 5.5 mg/dL.
• Patient has a QTcF > 470 msec. Patient has a history of prolonged QT syndrome or Torsades de pointes. Patient has a familial history of prolonged QT syndrome.
• Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g., Type II second degree heart block or third degree heart block).
• Patient has central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding C1D1.
• Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
• Patient received the following anticancer therapy:
  • Any systemic anticancer therapy (except for immunotherapy or other antibody therapies) and all forms of radiotherapy, within 14 days or 5 half-lives prior to the first dose of study drug. Pralsetinib may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval;
  • Any immunotherapy or other antibody therapy within 28 days prior to the first dose of study drug (immune related toxicities must have resolved to < Grade 2 prior to starting Pralsetinib).
• Dose expansion patients in Groups 1-5 and 7 (Part 2): patient has previously received treatment with a selective RET inhibitor such as selpercatinib.
• Patient received neutrophil growth factor support within 14 days of the first dose of study drug.
• Patient requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration. Pralsetinib may be started within 14 days or 5 half-lives of prior therapy if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
• Patient has had a major surgical procedure within 14 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
• Patient has a history of another primary malignancy that has been diagnosed or required therapy (except maintenance anti-hormonal therapy) within the past year. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site.
• Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
• Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 90 days after the last dose of study drug.
• Pregnant females, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of study drug. Females with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor, after pregnancy has been ruled out. Females of non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require a serum β-hCG test.
• If female, patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s or Sponsor's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.

• Patients must have histopathologic or molecular confirmation of either IDH-mutant DA or IDH-mutant AA. Acceptable IDH mutations for study eligibility include any IDH1 mutation at codon 132 or any IDH2 mutation at codon 172. 
• Age ≥ 16 years. The intended neurocognitive tests have not been validated in children below the age of 16. 
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%). 
• Hemoglobin > 9.0 g/dL. 
• Leukocytes >= 3.0 x 10^9/L.
• Absolute neutrophil count >= 1.5 x 10^9/L.
• Platelets >= 100 x 10^9/L.
• International normalized ratio (INR) =< 1.5 x upper limit of normal (ULN).
• Partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) =< 1.5 x ULN. 
• Patients on a stable dose of anti-coagulation therapy will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the investigator's discretion.
• Total bilirubin =< 1.5 x institutional ULN and < 3 mg/dL for patients with Gilbert's disease.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) & alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN. 
• Creatinine =< 1.5 x institutional ULN or creatinine clearance >= 60 mL/minute.
• If there is history of human immunodeficiency virus (HIV) infection, patients must be on effective antiretroviral therapy and HIV viral load must be undetectable within 6 months of study enrollment. 
• If there is history of chronic hepatitis B virus (HBV) infection, patients must have either been treated or are on suppressive therapy (as indicated), and HBV viral load must be undetectable.
• If there is history of hepatitis C virus (HCV) infection, patients must have been treated and HCV viral load must be undetectable. 
• Patient must have measurable disease by RANO criteria (dose expansion cohort only). 
• Patient must be at least 7 days beyond stereotactic biopsy and/or at least 14 days beyond open craniotomy.
• Patients must have been on a stable or decreasing dose of corticosteroids over the last 7 days.
• Patients must have been on a stable or decreasing dose of antiepileptic therapy over the last 14 days. 
• Females of childbearing potential must have a negative pregnancy test (=<14 days) prior to start of trial treatment. The effects of CB-839 HCl on the developing human fetus are unknown. For this reason and because alkylating agents as well as TMZ are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CB-839 HCl administration.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients must not have received prior chemotherapy to treat the glioma. 
• Patients who are receiving any other investigational agents. 
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CB-839 HCl or TMZ. 
• Patient must not have received prior radiation therapy to the brain. Prior radiation therapy to the head and neck is also excluded if radiation fields overlap. 
• No prior use of Gliadel wafers. 
• Patient must have no evidence of either infratentorial or spinal involvement with tumor. 
• Patients who are unable to swallow tablets.
• Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory vomiting, gastric resection/bypass, and duodenal/jejunal resection. 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than 3 years. 
• Pregnant women are excluded from this study because CB-839 HCl is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with CB-839 HCl, breastfeeding should be discontinued if the mother is treated with CB-839 HCl. These potential risks may also apply to TMZ.

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

• Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary prior to step 1 registration; submission of hematoxylin and eosin (H&E) stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the biospecimen bank at University of California, San Francisco (UCSF) for central review for oropharyngeal and unknown primaries and for p16 analysis for all other non-oropharyngeal primaries is mandatory for all patients; investigators should check with their pathology department regarding release of biospecimens before approaching patients about participation in the trial; for oropharyngeal and unknown primaries, submission of H&E and p16 stained slides (with the required block for PD-L1) to the biospecimen bank at UCSF for central review is also required prior to step 2 registration.
  • Note: fine needle aspirates (FNA) samples are not acceptable since they do not provide enough material for PD-L1 and p16 testing; however, if a cell block derived from the FNA is available, it is allowable if there are sufficient cells present in the block for PD-L1 testing; Dr. Jordan will determine this upon receipt; for sites submitting FNA cell blocks for ALL patients they must do so within 7-10 business days from registering the patient; sites must confirm with their cytology/pathology labs to make sure they can provide the required material as the bank must be able to retain these samples for the mandatory testing.
• Patients must have locoregionally advanced head and neck squamous cell carcinoma (HNSCC).
• For p16-positive oropharyngeal/unknown primaries, American Joint Committee on Cancer [AJCC] 8th edition stage III and selected stage I-II based on smoking status in pack-years.
• For laryngeal, hypopharyngeal, and oral cavity primaries and p16-negative oropharyngeal/unknown primaries, AJCC 8th edition stage III-IVB.
• Based on the following minimum diagnostic workup within 60 days prior to step 1 registration:
  • General history and physical examination by a radiation oncologist or medical oncologist or ear, nose and throat (ENT) or head & neck surgeon;
  • For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required, unless the patient cannot tolerate or refuses;
  • Imaging of the head and neck with a neck CT or magnetic resonance imaging (MRI) (with contrast, unless contraindicated) or PET/CT; note that the CT portion of the PET/CT must be of diagnostic quality, including contrast administration unless contraindicated;
  • If the CT portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or MRI study with contrast (unless contraindicated) is required;
  • Chest imaging: chest CT with and without contrast (unless contraindicated) or PET/CT.
• Patients must have a contraindication to cisplatin as defined in the following bullet points; sites must complete the online tool at comogram.org prior to step 1 registration to determine if the patient is eligible; the scores must be recorded on a case report form (CRF).
• Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 30 days prior to step 1 registration:
  • Modified Charlson Comorbidity Index ≥ 1;
  • Adult Comorbidity Evaluation (ACE)-27 Index ≥ 1;
  • Generalized Competing Event Model for Cancer Risk (GCE) omega PFS score < 0.80;
  • Geriatric screening (G-8) score ≤ 14;
  • Cancer and Aging Research Group (CARG) toxicity score ≥ 30%;
  • Cumulative Illness Rating scale for Geriatrics (CIRS-G) score ≥ 4; OR
• Age < 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 30 days prior to step 1 registration:
  • Modified Charlson Comorbidity Index ≥ 1;
  • ACE-27 Index ≥ 1;
  • GCE omega PFS-score < 0.80;
  • G-8 score ≤ 14;
  • CARG Toxicity score ≥ 30%;
  • CIRS-G score ≥ 4; OR
• Age ≥ 18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following within 30 days prior to step 1 registration:
  • Creatinine clearance (CC) > 30 and < 60 cc/min; for this calculation, use the Cockcroft-Gault formula;
  • For this calculation, use the Cockroft-Gault formula: CC = 0.85 (if female)* ((140–Age) / (Serum Creatinine)) * (Weight in kg / 72).
  • Patient must be greater than 18 years old;
  • Zubrod performance status 2 prior to Step 1 registration;
  • Pre-existing peripheral neuropathy grade ≥ 1;
  • History of hearing loss, defined as either:
    • Existing need of a hearing aid; OR ≥ 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated.
• Adequate hematologic function within 14 days prior to Step 1 registration defined as follows:
  • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3 (within 14 days prior to step 1 registration);
• • Platelets ≥ 100,000 cells/mm^3 (within 14 days prior to step 1 registration);
  • Hemoglobin ≥ 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 9.0 g/dl is acceptable) (within 14 days prior to step 1 registration).
• Adequate hepatic and renal function within 14 days prior to Step 1 registration defined as follows:
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 times institutional upper limit of normal (within 14 days prior to step 1 registration);
  • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (within 14 days prior to step 1 registration);
  • Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (within 14 days prior to step 1 registration).
• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to step 1 registration.
  • Note: women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:
  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
  • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration.

PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA

• For patients with oropharyngeal or unknown primaries: p16 determination by immuno-histochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review.
  • Note: for patients with oral cavity, laryngeal, and hypopharyngeal primaries, analysis of p16 status prior to step 2 registration/ randomization is not required (p16 status will be analyzed centrally post-hoc); step 2 registration for these patients can be completed after step 1 registration.

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

• Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer); synchronous head and neck primaries are ineligible.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
  • Note: Prior external beam radiotherapy is excluded, but iodine 131 is allowed.
• Prior immunotherapy.
• Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer.
• Major surgery within 28 days prior to step 1 registration.
• Proven evidence of distant metastases.
• If both of the following conditions are present, the patient is ineligible:
  • ≤ 10 pack-year smoking history;
  • p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-1 (AJCC 8th Edition);
  • Note: in the event that a registered patient with ≤ 10 pack-years has a p16-positive result on central review with the tumor and nodal stage T0-3, N0-1 (AJCC 8th Edition), then the site will be notified that the patient is ineligible.
• Zubrod performance status ≥ 3.
• Body weight ≤ 30 kg .
• Patients with oral cavity cancer are excluded from participation if the patient is medically operable and resection of the primary tumor is considered technically feasible by an oral or head and neck cancers surgical subspecialist;(please consult the surgical oncology co-principal investigator [PI], Steven Chang, Doctor of Medicine [MD], if clarification is needed on an individual case).
• Any of the following severe laboratory abnormalities within 14 days of Step 1 registration, unless corrected prior to Step 1 registration:
  • Sodium < 130 mmol/L or > 155 mmol/L (within 14 days of step 1 registration, unless corrected prior to step 1 registration);
  • Potassium < 3.5 mmol/L or > 6 mmol/L (within 14 days of step 1 registration, unless corrected prior to step 1 registration);
  • Fasting glucose < 40 mg/dl or > 400 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration);
  • Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration);
  • Magnesium < 0.9 mg/dl or > 3 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration);
• Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to step 1 registration
• Transmural myocardial infarction within 3 months prior to step 1 registration
• Respiratory illness requiring hospitalization at the time of step 1 registration
  • Note: if the respiratory illness is resolved and the patient meets the eligibility status above, then the patient can be considered for the trial
• Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to step 1 registration
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Clinically apparent jaundice and/or known coagulation defects
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.])
• The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the medical oncology study chair;
  • Patients with celiac disease controlled by diet alone;
  • History of active primary immunodeficiency including, but not limited to acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition.
  • Note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatment involved in this protocol may be immunosuppressive; patients with known HIV, CD4 counts ≥ 200/uL, and undetectable viral loads who are stable on an antiretroviral regimen may be included.
• Current or prior use of immunosuppressive medication within 14 days before step 1 registration, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
• Receipt of live attenuated vaccination within 30 days prior to step 1 registration.
• Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after the last dose of cetuximab or MEDI14736 (durvalumab); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic; women who are breastfeeding are also excluded.
• Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) or any of study drug excipients.
• History of allogenic organ transplantation.
• Uncontrolled hypertension.
• Uncontrolled cardiac arrhythmia.
• Uncontrolled serious chronic gastrointestinal condition associated with diarrhea.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C; patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

• Signed informed consent obtained prior to initiation of any study-specific procedures and treatment.

For dose escalation phase:

• Histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy known to confer clinical benefit exists OR standard therapy has failed recruited from among patients with squamous or non-squamous non-small cell lung cancer
• (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), urothelial carcinoma (UC), metastatic castrate resistant prostate cancer (mCRPC), and metastatic breast cancer (mBC).

For dose confirmation phase:

• Cohort A will enroll patients with metastatic or locally advanced, squamous or non-squamous NSCLC (NSCLC) who had previously received no more than four prior lnes of therapy, including a PD-1/PD-L1 containing therapy and a platinum-containing regimen. Patients must have received no more than one taxane containing regimen and no more than one investigational agent.
• Cohort B will enroll patients with histologically or cytologically confirmed transitional cell carcinoma of the urothelium including bladder, urethra, renal pelvis, or ureter (mUC). Patients must have received no more than three prior regimens, with PD-1 / PD-L1-containing therapy administered as their most recent therapy and have failed to achieve a PR or CR. Additionally for patients that did not progress while on the previous PD-1/PD-L1 containing therapy, the period of SD must be a minimum of four (4) months.
• Patients with metastatic or locally advanced NSCLC, metastatic or locally advanced UC, metastatic or locally advanced SCCHN and mBC must have measurable disease by RECIST criteria, with at least one uni-dimensional measurable lesion.
• Patients with mCRPC must meet PCWG3 criteria for disease progression at trial entry.
• Availability of tumor specimens is optional for patients in dose escalation cohorts and mandatory for patients in the dose confirmation phase. In the dose confirmation phase, an archived formalin-fixed, paraffin-embedded tumor tissue block sufficient in size to allow for sectioning of at least 15 slides should be provided if available from the most recent primary or metastatic tumor biopsy or resection obtained within 3 months prior to start of study therapy. If such an archived sample is not available, a fresh tumor sample must be obtained prior to enrollment. If blocks cannot be provided, then at least 15 freshly prepared slides must be provided. Core needle or excision biopsies are required.
• Male or female patients aged ≥ 18 years at time of informed consent.
• ECOG Performance Status 0 to 1.
• Estimated life expectancy of at least 3 months.
• Adequate bone marrow reserve, hepatic, and renal function, defined by:
  • absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L;
  • platelet count ≥ 100 x 10^9/L;
  • hemoglobin ≥ 9 g/dL (may have been transfused);
  • alanine aminotransferase (ALT, SGPT) ≤ 3.5 x upper limit of normal (ULN);
  • aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN;
  • total bilirubin ≤ 1.5 x ULN;
  • calculated creatinine clearance, estimated glomerular filtration rate 9eGFR ≥ 60 mL/min (MDRD formula).
  • normal bood urea nitrogen (BUN) unless considered unrelated to renal dysfunction as assessed by the investigator and Sponsor.
• Female patients of child-bearing potential must have a negative pregnancy test and be nonlactating and use at least one form of contraception as approved by the Investigator for 4 weeks prior to initiating study treatment and continuing for 6 months after the last dose of study drug. For the purposes of this study, child-bearing potential is defined as “all female patients unless they are post-menopausal for at least 3 years or surgically sterile."
• If the risk of conception exists, male patients must use a form of barrier contraception approved by the Investigator during the study and for 6 months after the last dose of study drug.
• Willing and able to comply with study procedures and follow-up.

• Concurrent cancer treatment with cytoreductive therapy, radiotherapy, cytokine therapy, cytotoxic agents, or targeted small molecule therapy within 2 weeks prior to the start of study treatment (except 5 weeks from last dose of nitrosourea compound) OR treatment with monoclonal antibodies within 4 weeks prior to the start of study treatment, with the following exceptions:
  • PD-1 / PD-L1 containing checkpoint inhibitor therapy is permitted;
  • palliative bone-directed radiotherapy is permitted unless involving an area of ≥ 25% of bone marrow reserves and occurring within 5 weeks prior to the start of study treatment;
  • erythropoietin and darbopoietin-α are permitted; and
  • hormonal therapies acting on the hypothalamic-pituitary-gonadal axis (i.e., LHRH agonist/antagonist) are permitted. No other hormonal therapy is permitted.
• Known symptomatic central nervous system (CNS) metastases requiring steroids. Patients with previously diagnosed CNS metastases are eligible if they:
  • have completed their treatment and have recovered from the acute effects of radiation therapy and/or surgery prior to enrollment;
  • have discontinued corticosteroid treatment for these metastases for at least 14 days; and
  • are neurologically stable.
• Persisting toxicity related to prior therapy is Grade >1 by NCI-CTCAE v4.03 criteria. However, alopecia or other Grade ≤ adverse events (AEs) not constituting a safety risk based on Investigator’s judgement are acceptable.
• Diagnosis of any other malignancy within 2 years prior to enrollment. However, adequately treated basal cell or squamous cell skin cancer or non-invasive superficial bladder cancer or carcinoma in situ of the bladder, breast or cervix; or prostate cancer of low grade (Gleason ≤ 6) prostate cancer or surveillance without any plans for treatment intervention (e.g., surgery, radiation, or castration) are allowed.
• Prior organ transplantation including allogeneic stem cell transplantation.
• Major surgery (as deemed by the Investigator) for any reason OR not fully recovered from surgery within 4 weeks prior to the start of study treatment.
• Vaccination within 4 weeks of the first dose of study treatment is prohibited except for administration of inactivated vaccines.
• Current use of immunosuppressive medication at study entry, with the following exceptions:
  • intranasal, inhaled, or topical steroids or local steroid injections; (e.g., intra-articular injection) are permitted;
  • systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent are permitted; and
  • steroids as premedication for hypersensitivity reactions are permitted.
• Active or prior autoimmune disease that might deteriorate with receiving an immunostimulatory agent. However, patients with diabetes type 1, vitiligo, psoriasis, or hypo- or hyper-thyroid disease not requiring immunosuppressive treatment are eligible.
• Acute or chronic infections requiring systemic therapy, including, among others:
  • active infection requiring systemic therapy;
  • history of testing positive to human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome;
  • hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive);
  • active tuberculosis (history of exposure or history of positive TB test with presence of clinical symptoms, physical or radiographic finding).
• Clinically significant or active cardiovascular disease, including:
  • ongoing cardiac dysrhythmias of NCI CTCAE v4.03 grade ≥ 2 or prolongation of the QTcF interval to > 450 msec for males, and ≥ 470 msec for females;
  • cerebrovascular accident/stroke < 6 months prior to study entry;
  • myocardial infarction < 6 months prior to study entry;
  • unstable angina;
  • congestive heart failure (New York Heart Association Classification ≥ Class II);
  • symptomatic arrhythmia requiring medication (excluding anemia-related sinusal tachycardia grade ≤ 2 by NCI CTCAE v4.03 criteria). However, subjects with stable atrial fibrillation on treatment are allowed provided they do not meet any other cardiac or prohibited drug exclusion criterion.
• Known history of autoimmune colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.
• Uncontrolled intercurrent illness, including, but not limited to:
  • hypertension uncontrolled by standard therapies;
  • uncontrolled diabetes;
  • Known alcohol or drug abuse;
• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk of study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the patient inappropriate for entry into the study.
• Known intolerance to checkpoint inhibitor therapy, defined by the occurrence of an AE leading to drug discontinuation.
• Known prior severe hypersensitivity reaction to monoclonal antibodies (grade ≥ 3 by NCI CTCAE v4.03 criteria).
• Known allergy or hypersensitivity to platinum (Pt)-containing agents, or known intolerance to prior Pt-containing agent which, in the judgement of the Principal Investigator, precludes exposure to Pt-containing agent.
• Known allergic reaction to methotrexate (trace methotrexate may be present in the avelumab drug product).
• Participation in other studies involving investigational drug(s) used to treat malignancy during study participation.
• Legal incapacity or limited legal capacity or any psychiatric condition that would prohibit the understanding or rendering or informed consent or that might limit compliance with study requirements.
• Abnormal blood urea nitrogen (BUN) due to renal compromise or dysfunction (e.g., hydronephrosis).
• Any waiver of these exclusion criteria should be exceptional and justified and must be approved by the Investigator and the Sponsor on a case-by-case basis prior to enrolling the patient. Such waivers must be documented by both the Investigator and Sponsor.

• ave previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC.
• Be able to undergo protocol therapy, including necessary surgery. A positron emission tomography (PET) scan may be utilized as a surrogate for pathologic staging of N1 lymph nodes for participants with T2b and T4 tumors.
• If male, must agree to use contraception or practice abstinence as well as refrain from donating sperm for at least 180 days after the last dose of neoadjuvant cisplatin.
• If female, may participate if not pregnant or breastfeeding, and at least one of the following conditions apply: 1) not a woman of childbearing potential (WOCBP); or 2) a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment.
• Have available formalin-fixed paraffin embedded (FFPE) tumor tissue sample blocks for submission. If blocks are not available, have unstained slides for submission for central programmed death-ligand 1 (PD-L1) testing.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days of randomization.
• Have adequate organ function.

• A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment.
• Has one of the following tumor locations/types:1) NSCLC involving the superior sulcus; 2) Large cell neuro-endocrine cancer (LCNEC); or 3) Sarcomatoid tumor.
• Has a history of (non-infectious) pneumonitis /interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
• Has an active infection requiring systemic therapy.
• Has had an allogenic tissue/sold organ transplant.
• Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance and/or any of its excipients.
• Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or to any of their excipients.
• Has an active autoimmune disease that has required systemic treatment in past 2 years.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known history of Hepatitis B or Hepatitis C.
• Has a known history of active tuberculosis.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate.
• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor.
• Has received prior systemic anti-cancer therapy including investigational agents for the current malignancy prior to randomization/allocation.
• Has received prior radiotherapy within 2 weeks of start of trial treatment.
• Has received a live vaccine within 30 days prior to the first dose of trial drug.
• Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.
• Has a diagnosis of immunodeficiency or is receiving either systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.
• Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment.

Eligibility last updated 11/10/21. Questions regarding updates should be directed to the study team contact.

• Subject is ≥ 18 years and ≤ 75 years of age and has voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP Guidelines and applicable local regulations.
• Histologically confirmed HCC, not amenable to transplant or resection. Subjects may undergo loco-regional therapy after enrolment but should not be amenable to further loco-regional therapy at the time of lymphodepletion; OR g-histologically confirmed diagnosis of another AFP expressing tumor (e.g., cholangiocarcinoma).
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria prior to lymphodepletion.
• Progressive disease following or intolerant of or refuses standard of care systemic therapy prior to lymphodepletion.
• Positive for HLA-A*02:01 (or any A*02:01 P group allele). The Sponsor will review the results of HLA typing for inclusion alleles, and will adjudicate subject eligibility based on HLA results.
• Group 1, 2, 3, (HCC) Subjects must have biopsy tissue available for AFP expression evaluation prior to enrollment unless considered unsafe. Either an archival specimen (taken within the past 12 months from Screening) or a new biopsy will be required for AFP expression in tumor tissue. Non-cancerous biopsy is also required prior to enrolment. Subjects will be eligible for enrollment if they meet either one of these AFP expression criteria:
  • AFP expression of ≥ 1+ in ≥ 20% of tumor cells by immunohistochemistry and their non-cancerous liver tissue has ≤ 5% cells stained for AFP at any intensity by immunohistochemistry;
  • Serum AFP levels of ≥100ng/mL and their non-cancerous liver tissue has ≤ 5% cells stained for AFP at any intensity by immunohistochemistry. Subjects with serum AFP levels within the normal range at the time of screening are unlikely to have AFP expressing tumors and generally should not undergo new tumor biopsy for the purpose of participating in this study.
  • Group 4 (other AFP expressing tumor types) Subjects must have biopsy tissue available for AFP expression evaluation prior to enrollment unless considered unsafe. Either an archival specimen (taken within the past 12 months from Screening) or a new biopsy will be required for AFP expression in tumor tissue. Non-cancerous biopsy is also required prior to enrolment, for subjects with underlying liver disease. Subjects will be eligible for enrollment if they meet the following AFP expression criterion:
    • Serum AFP levels of ≥ 100ng/mL and their non-cancerous liver tissue (if applicable) has ≤ 5% cells stained for AFP at any intensity by immunohistochemistry. Subjects with serum AFP levels within the normal range at the time of screening are unlikely to have AFP expressing tumors and generally should not undergo new tumor biopsy for the purpose of participating in this study.
• Life expectancy of > 4 months.
• Child-Pugh score ≤ 6.
• Eastern Cooperative Oncology Group (ECOG) 0-1.
• Female subjects of childbearing potential (FCBP) must have a negative serum pregnancy test.
• NOTE: FCBP is defined as premenopausal and not surgically sterilized. FCBP must agree to use effective birth control or to abstain from heterosexual activity throughout the study, starting at the first dose of chemotherapy for at least 12 months thereafter or 4 months after there is no evidence of persistence or gene modified cells are in the subject’s blood, whichever is longer. FCBP must also agree to refrain from egg donation, storage, or banking during these same time periods. Effective contraceptive methods include intra-uterine device, oral and injectable hormonal contraception, or 2 adequate barrier methods (e.g., diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide). Spermicides alone are not an adequate method of contraception; OR male subjects must be surgically sterile or agree to use a double barrier contraception method or abstain from heterosexual activity with a female of childbearing potential starting at the first dose of chemotherapy and for at least 6 months thereafter. Male subjects must also agree to refrain from sperm donation, storage, or banking during these same time periods.
  Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable by local Regulatory Agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.

• Positive for any HLA-A*02 allele other than HLA-A*02:01 P Group, HLA-A*02:03 P group or null alleles, or positive for the following alleles: HLA-C*04:04 or HLA-B*51:03. The Sponsor will review the results of HLA typing for exclusion alleles, and will adjudicate subject eligibility based on HLA results.
• Prior liver transplant.
• Received the following prior to leukapheresis:
  • Cytotoxic chemotherapy, immune therapy and biological therapy within 3 weeks;
  • Corticosteroids or any other immunosuppressive therapy within 2 weeks.
  • NOTE: Use of inhaled or topical steroids is not exclusionary.
  • Sorafenib/Regorafenib/Lenvatinib within 1 week;
  • Cabozantinib within 2 weeks;
  • Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune Study Physician.
• Received the following prior to lymphodepleting chemotherapy:
  • Cytotoxic chemotherapy or loco-regional therapy within 3 weeks, liver directed radiation therapy within three months;
  • Corticosteroids or any other immunosuppressive therapy within 2 weeks.
  • NOTE: Use of inhaled or topical steroids is not exclusionary.
  • Bone/soft tissue directed palliative radiotherapy within 4 weeks;
  • Investigational treatment or clinical trial within 4 weeks;
  • Sorafenib/Regorafenib/Lenvatinib within 1 week;
  • Cabozantinib within 2 weeks;
  • Prior cancer-directed immunotherapy within 4 weeks, including monoclonal antibodies against PD-1 receptor or ligand;
  • Use of an experimental vaccine within 2 months in the absence of tumor response. The subject should be excluded if their disease is responding to an experimental vaccine given within 6 months;
  • Any previous gene therapy using an integrated vector;
  • Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune Study Physician.
• Toxicity persisting from previous anti-cancer therapy of ≥ Grade 2 (except for non-clinically significant toxicities; e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) can be enrolled on a case-by-case basis with prior consultation and agreement with the Sponsor Study Physician.
• Major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical related toxicities.
• Bleeding ≥ Grade 2 in the past 3 months prior to lymphodepletion.
• Therapeutic anticoagulation from lymphodepletion until platelet count recovery (prophylactic heparin allowed).
• Clinically or radiographically detectable ascites (beyond trace/rim of ascites) or ascites requiring medication.
• Clinically detectable hepatic encephalopathy or hepatic encephalopathy requiring medication.
• Active viral hepatitis.  
• Subjects positive for hepatitis B surface antigen not on antiviral treatment/prophylaxis or subjects with detectable hepatitis B DNA:
  • Subjects with resolved (surface antigen negative, core antibody positive) or chronic stable (surface antigen positive) hepatitis B on antiviral treatment/prophylaxis with DNA levels of ≤ 100 IU/mL are allowed with HBV DNA monitoring after treatment;
  • Subjects with hepatitis C allowed provided they meet all other eligibility criteria.
• Positive serology for HIV.
• Positive serology for HTLV 1 or 2.
• History of chronic or recurrent (within the last year) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments. Subjects with history of idiopathic autoimmune hepatitis are excluded. Subjects who experienced hepatitis during treatment with check point inhibiting antibodies are not excluded.
• Subject has brain metastases.
• Other active malignancy besides HCC or other eligible AFP expressing tumor types within 3 years:
  • Subjects must be in complete remission from prior malignancy in order to be eligible to enter the study;
  • Adequately treated malignancies not likely to require therapy (e.g., completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma) are eligible to enter the study.
• Electrocardiogram (ECG) showing clinically significant abnormality at Screening or showing a QTc interval ≥ 450 msec in males and ≥ 470 msec in females (≥ 480 msec for subjects with Bundle Branch Block (BBB) over consecutive ECGs).
• Bacterial or opportunistic infection within 3 months of treatment (upper respiratory infection and uncomplicated urinary tract infection allowed).
• Uncontrolled intercurrent illness considered by the Investigator to add appreciable risk to study participation, including but not limited to:
  • Clinically significant cardiac disease defined by CHF New York Heart Association (NYHA) > Class 1; uncontrolled clinically significant arrhythmia in last 6 months; Acute Coronary Syndrome (ACS) (angina or myocardial infarction) in last 6 months;
  • Oxygen dependent lung disease;
  • Clinically significant psychiatric illness/social situations that would limit compliance with study requirements;
  • History of stroke or central nervous system bleeding; transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months.
• Pregnant or breastfeeding.
• Alcohol or illicit drug dependency.
• Known contraindication to cyclophosphamide, fludarabine, mesna, G-CSF or other agents associated with study treatment.

Eligibility last updated 12/30/21. Questions regarding updates should be directed to the study team contact.

REGISTRATION TO STEP 1
•ELIGIBILITY CRITERIA:

• Age ≥ 18 years.
• Patients must have histologically proven stage IIB (T3N0M0 only), IIIA (T2N1M0), IIIB (T4N0M0), or IIIC (T3N1M0, T4N1M0) invasive squamous cell carcinoma of the anus or anorectum, according to the AJCC 8th edition. This may include tumors of non-keratinizing histology such as basoloid, transitional cell, or cloacogenic histology. 
• Individuals with squamous cell carcinoma of the anal margin are eligible if there is evidence of extension of the primary tumor into the anal canal.
• For patients registering to Arm T, patients must not have received prior chemoradiotherapy for anal cancer.
• Patients must have ECOG performance status of 0-2.
• Adequate hematologic function must be documented within 2 weeks prior to registration:
  • Patients must have hemoglobin levels of > 9g/dL;
  • Patient must have a platelet count of > 100,000/mm3;
  • Patient’s ANC level must be > 1500/mm3.
• Serum creatinine must be ≤ 1.5X ULN.
• Adequate hepatic function must be documented within 2 weeks prior to registration:
  • Total bilirubin must be < 2 X ULN. AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal;
  • Albumin ≥ 3.0 g/dL.
• Patients known to be Human immunodeficiency virus (HIV)+ are permitted. Patients with CD4>200 and Serum HIV viral load of < 200 copies/mm3 are eligibile, and in addition:
  • Participants must be PPD negative. Alternatively, the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia) can be used. An individual is considered positive for M. tuberculosis infection if the IFN-γ response to TB antigens is above the test cut-off (after subtracting the background IFN-γ response in the negative control). The result must be obtained within 20 weeks prior to enrollment. PPD positive (or Quantiferon assay positive) participants are permitted if prophylaxis has been completed prior to enrollment.
• No history of AIDS-related complications within past year other than a history of low CD4+ T-cell count >200/mm3 prior to initiation of combination antiretroviral therapy. On study CD4+ T-cell count may not be informative due to chemoradiotherapy and should not be used as an exclusion criterion if low.
• Patient must be healthy on the basis of HIV disease with high likelihood of near normal life span were it not for the anal cancer
• Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications when clinically indicated, and should be under the care of a physician experienced in HIV management. Participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 12 weeks following enrollment.
• Patient must have ≤ grade 2 diarrhea (participants with grade 1 diarrhea are eligible provided stool for ova/parasites and stool cryptosporidium studies are negative
  • NOTE: HIV testing is not required for eligibility.
• For patients registering prior to start of chemoradiotherapy, baseline scans must have been completed within 4 weeks prior to registration.
• Patients with an allogenic bone marrow/stem, cell or solid organ transplant are excluded.
• Women of child bearing potential and sexually active males must use accepted and effective method(s) of contraception and/or abstain from sexual intercourse while on protocol treatment and for at least 5 months after the last dose of nivolumab (for female patients) and for at least 7 months after the last dose of nivolumab (for male patients).
• Women MUST NOT be pregnant or breast-feeding due to the potential teratogenic harm or abortifacient effectsto an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients must also not expect to conceive or father children from study registration and throughout their time on study treatment . For female patients this must continue until at least 5 months after the last dose of nivolumab and for male patients until at least 7 months after the last dose of nivolumab. 
• All females of child bearing potential must have a serum or urine pregnancy test to rule out pregnancy within 2 weeks prior to registration.
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Female of child bearing potential? ______ (Yes or No)
  • Date of blood test or urine study: ___________
• Patients will be excluded if they have any T1 or M1, and T2N0 cancer.
• Patients must not have had prior potentially curative surgery (abdominal, peritoneal resection) for carcinoma of the anus.
• Participants may not be receiving any other standard anti-cancer therapy or experimental agent concurrently with the study drugs.
• Any surgery must have been completed ≥ 4 weeks prior to starting study treatment.
• No uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Individuals with a history of a different malignancy are ineligible except if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Patient must not have active autoimmune disease Rev. Add2 in the past 2 years.
  • NOTE: This does not include patients with autoimmune disease controlled by medication, such as hypothyroidism.
• No prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal antibody).
• No patients with immunodeficiency or receiving Nivolumab equivalent to > 10 mg prednisone per day or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication. Topical corticosteroid or occasional inhaled corticosteroids are allowed.
• No live vaccines within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.
  • NOTE: No live vaccines may be administered while participating in the trial
• Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Previously irradiated patients (Arm S) must have received radiation per NCCN guidelines. Details of the prior radiation are captured in Rave. Radiation therapy delivered on protocol (Arm T) will be reviewed.

REGISTRATION TO STEP 2
•ELIGIBILITY CRITERIA:

• Patients will be registered within 63 days following completion of standard chemoradiation for anal cancer. Standard chemoradiation therapy is as defined in Appendix VII.
• Patients must have histologically proven stage IIB (T3N0M0 only), IIIA (T2N1M0), IIIB (T4N0M0), or IIIC (T3N1M0, T4N1M0) invasive squamous cell carcinoma of the anus or anorectum, according to the AJCC 8th edition. This may include tumors of non-keratinizing histology such as basoloid, transitional cell, or cloacogenic histology.
• Individuals with squamous cell carcinoma of the anal margin are eligible if there is evidence of extension of the primary tumor into the anal canal.
• Patients must have received at least 54 Gy of radiation to the PTVp (primary) and 45 Gy to PTVn (elective nodal region) for the treatment of the anal cancer.
• Patients must have ECOG performance status of 0-2.
• Adequate hematologic function must be documented within 2 weeks prior to registration:
• Patients must have hemoglobin levels of > 10g/dL.
• Patient must have a platelet count of > 100,000/mm3.
• Patient’s ANC level must be > 1500/mm3.
• Serum creatinine must be ≤ 1.5 X ULN.
• Adequate hepatic function must be documented within 2 weeks prior to registration:
  • Total bilirubin must be < 2 X ULN. AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal;
  • Albumin ≥ 3.0 g/dL.
• Patients known to be Human immunodeficiency virus (HIV)+ are permitted. Patients with CD4 > 200 and Serum HIV viral load of < 200 copies/mm3 are eligible. In addition:
  • Participants must be PPD negative. Alternatively, the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia) can be used. An individual is considered positive for M. tuberculosis infection if the IFN-γ response to TB antigens is above the test cut-off (after subtracting the background IFN-γ response in the negative control). The result must be obtained within 20 weeks prior to enrollment. PPD positive (or Quantiferon assay positive) participants are permitted if prophylaxis has been completed prior to enrollment.
  • NOTE: If patient completed chemoradiation on Step 1, PPD testing does not need to be performed again.
• No history of AIDS-related complications within past year other than a history of low CD4+ T-cell count >200/mm3 prior to initiation of combination antiretroviral therapy. On study CD4+ T-cell count may not be informative due to chemoradiotherapy should not be used as an exclusion criterion if low.
• Patient must be healthy on the basis of HIV disease with high likelihood of near normal life span were it not for the anal cancer.
• Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications when clinically indicated, and should be under the care of a physician experienced in HIV management. Participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 12 weeks following enrollment.
• Patient must have ≤ grade 2 diarrhea (participants with grade 1 diarrhea are eligible provided stool for ova/parasites and stool cryptosporidium studies are negative).
  • NOTE: HIV testing is not required for eligibility
• Scans done within 4 weeks of randomization to Step 2.
• Patient must be able to have recovered from all toxicities associated with chemoradiotherapy for anal cancer, to Grade ≤ 1 with the exception of alopecia.
• Patients with an allogenic bone marrow/stem, cell or solid organ transplant are excluded.
• Women of child bearing potential and sexually active males must use accepted and effective method(s) of contraception and/or abstain from sexual intercourse while on protocol treatment and for at least 5 months after the last dose of nivolumab (for female patients) and for at least 7 months after the last dose of nivolumab (for male patients).
• Women MUST NOT be pregnant or breast-feeding due to the potential teratogenic harm or abortifacient effectsto an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients must also not expect to conceive or father children from study registration and throughout their time on study treatment . For female patients this must continue until at least 5 months after the last dose of nivolumab and for male patients until at least 7 months after the last dose of nivolumab.
• All females of child bearing potential must have a serum or urine pregnancy test to rule out pregnancy within 2 weeks prior to registration.
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
    • Female of child bearing potential? ______ (Yes or No)
    • Date of blood test or urine study: ___________
• Patients must not have had prior potentially curative surgery (abdominal, peritoneal resection) for carcinoma of the anus.
• Participants may not be receiving any other standard anti-cancer therapy or experimental agent concurrently with the study drugs.
• No uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Individuals with a history of a different malignancy are ineligible except if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Patient must not have active autoimmune disease that has required systemic treatment in past 2 years.
• No prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal antibody).
• No patients with immunodeficiency or receiving systemic steroid therapy equivalent to > 10 mg prednisone per day or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication. Topical corticosteroid or occasional inhaled corticosteroids are allowed.
• No live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.
• Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab.

• Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases).
• Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy.
• The largest brain metastasis must measure < 2.5 cm in maximal diameter. The total tumour volume must be 30 cm3 or less. Lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g., xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumour volume.
• Centre must either have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system, or access to a centre at which the trial is open which can treat with using one of these systems.
• Patient must be ≥ 18 years of age.
• Patient is able (i.e., sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance. The baseline assessment must be completed within required timelines, prior to randomization.
• Patient must also be able and willing to complete the neurocognitive testing without assistance from family and companions. Because this is one of the primary goals of this study, patients must be fluent in English or French, and fully testable in one of those languages.
• A patient that is able but unwilling to complete the questionnaires will be considered ineligible.
• ECOG performance status 0, 1, or 2.
• Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration.
• The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training.
• The enrolling facility is credentialed by IROC to perform SRS and HA-WBRT
  •or have access to a centre where these treatments are credentialed and the study is open. The treating centre must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients. The treating centre must have completed IMRT credentialing of the specific IMRT system(s) to be used in study patients for the purposes of HA-WBRT.
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures.
• Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment.
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. A woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
• Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy.

• Pregnant or nursing women.
• Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Inability to complete a brain MRI.
• Known allergy to gadolinium.
• Prior cranial radiation therapy.
• Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT.
• Primary germ cell tumour, small cell carcinoma, or lymphoma.
• Widespread definitive leptomeningeal metastasis. This includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumour cells.
• A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve.
• Surgical resection of a brain metastasis (stereotactic biopsies will be allowed).
• More than 15 brain metastases on a volumetric T1 contrast MRI (voxels of 1mm3 or smaller) performed within the past 14 days, or more than 10 metastases in the case of a non-volumetric MRI.
• Prior allergic reaction to memantine, or hypersensitivity to any excipients of memantine.
• Current alcohol or drug abuse.
• Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan.
• Diagnosis of chronic liver disease/cirrhosis of the liver (e.g., Child-Pugh class B or C).
• Clinically significant untreated or uncontrolled cardiovascular conditions, and/or symptomatic cardiac dysfunction (i.e., unstable angina, congestive heart failure, myocardial infarction within the previous year, cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects, uncontrolled hypertension).
• Current active or uncontrolled urinary tract infections (UTI).
• History of epilepsy or seizures, and not currently taking anti-epileptic medication.
• Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patients safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines.
• Patients with architectural distortion of lateral ventricular systems which, in the opinion of the local investigator, makes hippocampal delineation challenging.

• Participant has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size ≥ 2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2.
  • Note: Multifocal tumors defined as the presence of 2 or more foci of cancer within the same quadrant are allowed; at least 1 of the tumors needs to be ≥ 2 cm.
• ER+/HER2– status needs to be confirmed for each focus.
  • Note: Inflammatory breast cancer is allowed.
  • Note: Participants with node negative disease will be capped at 20% of the total population.
• Has centrally confirmed ER+/HER2–, Grade 3 breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines. Refer to Appendix 6 for country-specific requirements.
• Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, grade, and PD-L1 status.
  • Note: Adequacy of the biopsy specimen for the above analyses must be confirmed by the central laboratory. Submission of another tumor specimen may be required, if adequate tumor tissue was not provided the first time.
  • Note: Sponsor agreement is required for formalin-fixed paraffin-embedded (FFPE) tumor tissue sample or slides that were obtained greater than 60 days prior to the date that the informed consent was signed.
• Is a male or female ≥ 18 years of age on the day of signing informed consent.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment.
• A male participant must agree to use a contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP); OR
• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo. 
• The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
• Has adequate organ function; all screening laboratory tests should be performed within 10 days prior to initiation of study treatment:
• Hematological
  • Absolute neutrophil count ≥ 1,500 cells/μL;
  • Platelets* ≥ 100,000 cells/μL;
  • Hemoglobin* ≥ 9 g/dL or ≥ 5.6 mmol/L.
• Renal
  • Creatinine ≤ 1.5 × ULN; OR
  • Measured or calculated** creatinine clearance (GFR can also be used instead of CrCl) ≥ 50 mL/min for participants with creatinine levels ≥ 1.5 × institutional ULN.
• Hepatic
  • Total bilirubin ≤ 1.5 × ULN; OR
  • Direct bilirubin ≤ ULN for participants with total bilirubin levels ≥ 1.5 × ULN;
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN.
• Coagulation
  • INR or PT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT/PTT is within therapeutic range of intended use of anticoagulants;
  • Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT).
• Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; GFR = glomerular filtration rate; INR = international normalized ratio; PT = prothrombin time; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal.
• *  Platelet and hemoglobin requirements cannot be met by use of recent transfusion or growth factor support (granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage colony stimulating factor [GM-CSF], or erythropoietin) within 2 weeks prior to initiation of study treatment.
• ** Creatinine clearance should be calculated per institutional standard.

• Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.
• Has breast cancer with lobular histology.
• Has bilateral invasive breast cancer.
• Has metastatic (Stage IV) breast cancer.
• Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
• Has any of the following clinical lymph node staging per current AJCC staging criteria for breast cancer staging based on radiological and/or clinical assessment:
  • cN3, cN3a, cN3b, or cN3c.
• Has ER–, progesterone receptor positive breast cancer.
• Participants who have undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or have undergone sentinel lymph node biopsy prior to study treatment.
• Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years.
  • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, breast ductal carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
  • Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• Has a known history of active tuberculosis (Bacillus tuberculosis).
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition (e.g., transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would may interfere with cooperation with the requirements of the study.
• Has left ventricular ejection fraction (LVEF) of < 50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
• Has other significant cardiac disease, such as:
  • History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months;
  • Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
• Has a known history of human immunodeficiency virus (HIV) infection.
  • Note: No HIV testing is required unless mandated by local health authority.
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HbsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for hepatitis B or hepatitis C is required unless mandated by local health authority.
• A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

• Participant must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is metastatic or unresectable. Participants must have either progressed after prior standard of care therapy (Cohort C and hepatocyte growth factor receptor gene [MET]-1: epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]; Cohort D and MET-2: platinum-based chemotherapy) for metastatic disease, or be ineligible for, or have refused all other currently available therapeutic options. In cases where participants refuse currently available therapeutic options, this must be documented in the study records.
• For Part 1 Chemotherapy Combination Cohort only:
  • Participants must have histologically or cytologically confirmed NSCLC that is metastatic or unresectable and be eligible for treatment with combination carboplatin and pemetrexed, in accordance with standard of care, and be willing to receive additional investigational therapy with Amivantamab
• For Part 1 Combination Dose Escalation with lazertinib only:
  • Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation and (a) be treatment naïve for metastatic disease, without access to third generation TKI in the front-line setting, or (b) have progressed after front-line treatment with first (erlotinib or gefitinib) or second generation (afatinib) TKI and are ineligible for Cohort MET-1, or (c) have been treated with a third generation TKI (eg, osimertinib) in either the front line or second-line setting, and are not eligible for enrollment in either Cohort C or MET-1.
• For Part 1 Chemotherapy Combination Cohort:
  • Participants may be diagnosed with EGFR mutated or EGFR wild type NSCLC. For Part 2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2). Documentation of primary activating EGFR or cMet mutation eligibility by CLIA-certified laboratory (or equivalent) testing is required.
• For Part 1:
  • Participant must have evaluable disease. For Part 2: Participant must have measurable disease according to Response Criteria in Solid Tumors (RECIST) v1.1
• For Part 2: Cohorts A and B:
  • Participants EGFR mutated disease must have most recently progressed following treatment with a marketed EGFR inhibitor. Exception: In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required.
• Cohort C:
  • Participants with primary EGFR mutated disease, with a documented EGFR alteration (example, C797S) mediating resistance to previous treatment with a third generation EGFR TKI (for example, osimertinib), in participants with primary Exon 20ins disease, the documented EGFR alteration may arise following treatment with a TKI with known activity against Exon 20ins disease (for example, poziotinib).
• Cohort D:
  • Pparticipants must have been previously diagnosed with an EGFR Exon 20 insertion and have not been previously treated with a TKI with known activity against Exon 20ins disease (exampe, poziotinib).
• Cohort MET-1:
  • Participants with documented primary EGFR mutated disease and documented MET amplification or MET mutation after progression on any EGFR TKI. Participants with disease characterized by both MET amplification and EGFR resistance mutations to prior third generation EGFR TKI will be preferentially enrolled into Cohort C. Participants may have received or have been intolerant to prior platinum-based chemotherapy.
• Cohort MET-2:
  • Participants with documented primary MET Exon 14 skipping mutation non-small cell lung cancer (NSCLC).
• Cohort E (combination Amivantamab and lazertinib):
  • Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation, and have progressed after first or second-line treatment with a third generation TKI (e.g., osimertinib).
• Participant must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

• Participant has uncontrolled inter-current illness, including but not limited to poorly controlled hypertension, or diabetes, ongoing or active infection, (that is, has discontinued all antibiotics for at least one week prior to first dose of study drug), or psychiatric illness/social situation that would limit compliance with study requirements. Participants with medical conditions requiring chronic continuous oxygen therapy are excluded.
• For Part 1 Chemotherapy Combination Cohort only:
  • additionally, participants with active bleeding diathesis.
• Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives whichever is longer, before the first administration of study drug. For agents with long half-lives, the maximum required time since last dose is 4 weeks. Toxicities from previous anti-cancer therapies should have resolved to baseline levels or to Grade 1 or less, (except for alopecia [any grade], Grade less than or equal to [≤] 2 peripheral neuropathy, and Grade less than [<] 2 hypothyroidism stable on hormone replacement).
• For Part 1 Combination Dose Escalation:
  • Any previous treatment with systemic anti cancer immunotherapy, including but not limited to anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents.
• For Part 1 Chemotherapy Combination Cohort only:
  • Any previous treatment with systemic anti cancer immunotherapy in the past 3 months or localized radiotherapy to lung within the past 6 months.
• For Part 2 only:
  • Cohorts A and B: Prior treatment with chemotherapy for metastatic disease is not allowed unless the tumor mutation carries de-novo resistance to EGFR TKI (example, Exon 20 insertions). Cohort C and MET-1: Prior treatment with more than 2 lines of cytotoxic chemotherapy for metastatic disease (maintenance therapy is not included).
• Cohort D:
  • Previous treatment with an EGFR TKI with activity against EGFR Exon 20 insertions (such as poziotinib).
• Cohort E (combination Amivantamab and lazertinib):
  • Any previous treatment in the metastatic setting with other than a first, second, or third generation EGFR TKI
• Participants with untreated brain metastases. Participants with definitively, locally-treated metastases that are clinically stable and asymptomatic for at least 2 weeks and who are off or receiving low-dose corticosteroid treatment (≤ 10 mg prednisone or equivalent) for at least 2 weeks prior to study treatment are eligible. Exception: participants with asymptomatic, untreated brain metastases, each less than 1 cm in diameter, may be eligible for Amivantamab and lazertinib combination therapy in the Part 1 Combination Dose Escalation or Part 2 Combination Expansion Cohort E.
• Participant has a history of malignancy other than the disease under study within 3 years before Screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with or minimal risk of recurrence within a year from Screening).
• Participant has not fully recovered from major surgery or significant traumatic injury prior the first dose of study drug or expects to have major surgery during the study period or within 6 months after the last dose of study drug.

• Has a histologically- or cytologically-confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC] v 8) NSCLC and has not had prior systemic therapy for advanced disease.
• Has confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1- (ROS1-), or B isoform of rapidly accelerated fibrosarcoma- (B-Raf-) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements).
• Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
• Male/female participants who are at least 18 years of age on the day of signing the informed consent.
• Male participants must agree to use contraception during the treatment period and for ≥ 120 days, after the last dose of study treatment and refrain from donating sperm during this period. Male participants with pregnant partners must agree to use a condom.
• Female participants eligible to participate if not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to follow contraceptive guidance during the treatment period and for ≥ 120 days after the last dose of study treatment.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main study without participating in Future Biomedical Research.
• Provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. 
  • Note:  If sending newly cut slides, they should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual).
• Participants must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization.
• Has an Eastern Cooperative  Oncology Group (ECOG) performance status of 0 to 1.
• Has adequate organ function as defined below:
• Hematological
  • Absolute neutrophil count (ANC) ≥1500/μL;
  • Platelets ≥00 000/μL;
  • Hemoglobin ≥.0 g/dL or ≥.6 mmol/L*.
• Renal
  • Creatinine OR Measured or calculated** creatinine clearance (GFR can also be used in place of creatinine or CrCl);
  • ≤1.5 × ULN OR ≥0 mL/min for participant with creatinine levels >1.5 × institutional ULN.
• Hepatic
  • Total bilirubin ≤.5 ×ULN OR direct bilirubin ≤LN for participants with total bilirubin levels >1.5 × ULN;
  • AST (SGOT) and ALT (SGPT) ≤.5 × ULN (≤ × ULN for participants with liver metastases).
• Coagulation
  • International normalized ratio (INR) OR prothrombin time (PT);
  • Activated partial thromboplastin time (aPTT) ≤.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal;
• Specimens must be collected within 10 days prior to the start of study treatment.

* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

** Creatinine clearance (CrCl) should be calculated per institutional standard.

• Has significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability, significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram.
• Prolongation of QTc interval to > 480 milliseconds (ms).
• Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
• Has had an allogenic tissue/solid organ transplant.
• A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment (see Appendix 5). If the urine test cannot be confirmed as negative, a serum pregnancy test will be required.
  • Note: in the event that 24 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study medication.
• Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥ 1 g/24 h will be ineligible.
• Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. Participants who have had major surgery within 3 weeks prior to first dose of study intervention.
  • Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
• Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula, gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
• Radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
•  Has received prior systemic chemotherapy treatment for metastatic/recurrent NSCLC.
  • Note: Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic/recurrent NSCLC.
• Has current NSCLC disease that can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation.
• Is expected to require any other form of systemic or localized antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection).
• Has received prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (e.g., CTLA-4, OX 40, CD137).
• Has received previous treatment with another agent targeting the LAG-3 receptor.
• Has received previous treatment with another agent targeting VEGF or the VEGF receptor.
• Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization.
  • Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
  • Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Has received prior radiotherapy within 2 weeks of start of study treatment or received lung radiation therapy of >30 Gy within 6 months prior to the first dose of study intervention. Participants must have recovered from all radiation-related toxicities to Grade ≤1, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of study treatment.
  • Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

• Subjects must satisfy the following criteria to be enrolled in the study:
  • Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
  • Subject has documented diagnosis of MM and measurable disease
  • Subject has received at least 2 but no greater than 4 prior MM regimens.
  • Subject has received prior treatment with DARA, a proteasome inhibitor and an immunomodulatory compound-containing regimen for at least 2 consecutive cycles.
  • Subject must be refractory to the last treatment regimen. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose of any drug within the regimen) of completing treatment with the last anti-myeloma regimen before study entry.
  • Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen.
  • Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 peripheral neuropathy.

• Subject has nonsecretory multiple myeloma (MM). 
• Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on room air. 
• Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years. 
• Subject has active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome or amyloidosis. 
• Subject with known central nervous system (CNS) involvement with myeloma. 
• Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation. 
• Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal. 
• Subject has a history or presence of clinically relevant CNS pathology. 
• Subject was treated with DARA in combination with POM with or without dex (DP±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DPd as bridging therapy but may receive DVd or IRd as bridging as per Investigator's discretion if randomized to Treatment Arm A. 
• Subject was treated with DP±d as part of their most recent anti-myeloma treatment regimen, cannot receive DPd if randomized to Treatment Arm B but may receive DVd or IRd as per Investigator's discretion. 
• Subject was treated with DARA in combination with BTZ with or without dex (DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd as bridging therapy but may receive DPd or IRd as bridging as per Investigator's discretion if randomized to Treatment Arm A. 
• Subject was treated with DV±d as part of their most recent anti-myeloma treatment regimen, cannot receive DVd if randomized to Treatment Arm B but may receive DPd or IRd as per Investigator's discretion. 
• Subject was treated with IXA in combination with LEN with or without dex (IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd as bridging therapy but may receive DPd or DVd as bridging as per Investigator's discretion if randomized to Treatment Arm A. 

• ≥ 18 years of age and be diagnosed with cancer.
• Provide informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Planned use of one of the defined systemic, antineoplastic therapies.
• Willingness to complete questionnaires with each dose of therapy.
• Plan to receive chemotherapy for the following 3-4 months OR a minimum of 4 cycles of chemotherapy given at intervals of 2 weeks or longer.
• No prior chemotherapy over the previous 3 months.

1. Predisposition to frequent nosebleeds (more than once per month).
2. Verbal baseline nasal dryness, pain, bleeding, or scabbing ≥ 2 on a 10 point scale (from mild=1 to severe=10).
3. Planned receipt of two of the studied agents concurrently (e.g., abraxane and bevacizumab).
4. Planned participation in a placebo-controlled trial.

INCLUSION CRITERIA
•Prior to Step 1 Registration:

• Patients with pathologically proven diagnosis of grade 2-3 (intermediate or high grade) soft tissue sarcoma with size ≥ 5 cm are eligible to enroll if the intention to treat is curative. They must have sufficient tissue to submit to central  laboratory for review as well as for NGS sequencing (see submission requirement). Biopsy should be obtained within 180 days prior to registration.
• Availability of tumor tissue is mandatory for study eligibility. The patient must have consented to provide archived formalin-fixed paraffin-embedded tumor tissue for future central pathology review, NGS sequencing and/or translational research.
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 30 days prior to registration;
  • Imaging of the primary tumor by MRI and/or CT with or without contrast and/or PET/CT within 30 days prior to registration;
  • Staging workup evaluated by chest CT and/or PET/CT showing no distant metastasis within 30 days prior to registration.
• There is a planned definitive surgical resection of the primary tumor.
• Age ≥ 18 years old.
• ECOG or Zubrod performance status of 0-1 within 30 days prior to registration.
• Adequate hematologic function within 30 days prior to registration defined as follows:
  • Absolute neutrophil count ≥ 1500/μL;
  • Platelet count ≥ 100,000/μL;
  • Hemoglobin: ≥ 10 g/dL (transfuse as necessary to raise levels; no transfusions within 7 days of start).
• Adequate renal and hepatic function within 30 days prior to registration defined as follows:
  • Calculated Creatinine Clearance ≥ 60 ml/min (by Cockroft-Gault formula) within 30 days prior to registration;
  • The patient has an adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 x ULN or prothrombin time (PT) ≤1.5 x ULN, and partial thromboplastin time (PTT or aPTT) ≤1.5 x ULN (those receiving anticoagulation therapy except low molecular weight heparin are excluded);
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) appropriate for age (except for patients with Gilbert’s Syndrome, who must have a total bilirubin <3 mg/dL);
  • SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) appropriate for age.
• Females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration.
  • Exceptions: Females not of child-bearing potential due to surgical sterilization (at least 6 weeks following tubal ligation, hysterectomy, or surgical bilateral oophorectomy with or without hysterectomy) confirmed by medical history, or female after menopause:
• A “postmenopausal woman” is a woman meeting either of the following criteria:
  • spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral
  • contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators [SERMs], or chemotherapy);
  • spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level >40 mIU/mL.
• Females of child-bearing potential and males must agree to use highly effective contraceptive precautions during the trial and up to 12 months following the last dose of study treatment. A highly effective method of birth control is defined as one that results in a low failure rate (that is, <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

INCLUSION CRITERIA
•Prior to Step 2 Registration:

• TP53 sequencing by NGS performed by central pathology lab.

EXCLUSION CRITERIA
•Prior to Step 1 Registration:

• Well- differentiated liposarcoma or other low grade STS; Kaposi sarcoma, bone sarcomas, cartilage sarcomas and GIST. 
• Definitive clinical or radiologic evidence of metastatic disease; indeterminate lung nodules less than 8mm are acceptable.
• The patient has history of another primary malignancy, with the exception of:
  •  curatively treated non-melanomatous skin cancer; 
  • curatively treated cervical carcinoma in situ;
  • non-metastatic prostate cancer;
  • other primary non-hematologic malignancies or solid tumor treated with curative intent, no known active disease, and no treatment administered during the last 3 years prior to registration.
• The patient has a serious cardiac condition, such as congestive heart failure; New York Heart Association Class II/ III/IV heart disease; unstable angina pectoris, cardiac stenting within 6 months of enrollment; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatment.
• Females who are pregnant or breastfeeding.
• Prior systemic chemotherapy for the study cancer (sarcoma); note that prior chemotherapy for a different cancer is allowable. However, unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (Grade 2 or 3 toxicities from prior antitumor therapy that are considered irreversible [defined as having been present and stable for > 6 months], such as ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor).
• P rior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
•  Clinically significant bleeding within 4 weeks of screening, current use of warfarin, factor Xa inhibitors, and direct thrombin inhibitors unless these medications can be safely discontinued 14 days prior to AMG-232 administration.
  • Note: Low molecular weight heparin and prophylactic low dose warfarin are permitted. PT/PTT must meet the inclusion criteria. Subjects taking warfarin must have their INR followed closely. History of allergic reactions attributed to  compounds of similar chemical or biologic composition to AMG 232.
• Medication use:
  • All subjects must agree to stop the use of all herbal medicines (e.g., St. John’s wort), and supplements, within the 10 days prior to receiving the first dose of AMG 232, and during the protocol AMG 232 treatment (Weeks 1-5). Subjects may renew the use of the above at week 6. Standard adult multi-vitamin is allowed;
  • All subjects must agree to stop the use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfanide; within the 14 days prior to receiving the first dose of AMG 232 and during protocol AMG 232 treatment (Weeks 1-5). Other medications (such as fentanyl and oxycodone) may be allowed per investigator’s assessment/evaluation;
  • All subjects must agree to stop the use of any known CYP2C8 substrates with a narrow therapeutic window within the 14 days prior to receiving the first dose of AMG 232 and during protocol AMG 232 treatment (Weeks 1-5);
  • All subjects are required to submit a list of medications consumed within 14 days prior to receiving the first dose of AMG232 and during the protocol AMG232 treatment (Weeks 1-5).
• Patients with GI tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,  Crohn’s disease, ulcerative colitis), therefore could affect the absorption of AMG 232 at the discretion of treating physician.
• Patients with active infection requiring IV antibiotics within 2 weeks of registration.
• Patients with known Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B), positive Hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable Hepatitis C virus RNA by a polymerasechain reaction (PCR) assay (indicative of active Hepatitis C – screening is generally done by Hepatitis C Antibody (HepCAb), followed by Hepatitis C virus RNA by PCR if HepCAb is positive).
• Patients known to be positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard.
• PCR-based test HIV testing is not required.
• Treatment with medications known to cause QTc interval prolongation within 7 days of study day 1 is not permitted unless approved by the sponsor. Use of ondansetron is permitted for treatment of nausea and vomiting.

• Age ≥ 18 years.
• Ability to complete questionnaires by themselves or with assistance.
• Paclitaxel at a dose of 80 mg/m^2 given every week for a scheduled course of 12 weeks for treating breast cancer.
• Life expectancy ≥ 6 months.
• ECOG Performance Status (PS) 0, 1.
• Negative pregnancy test (serum or urine) done ≤ 14 days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.

• Previous exposure to paclitaxel (please note that it is acceptable for patients to receive non-neurotoxic chemotherapy, like AC, before or after the weekly paclitaxel and/or to receive concurrent anti-her 2 therapy).
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Previous diagnosis of diabetic or other peripheral neuropathy.
• Current or previous use of fingolimod.
• History of the following preexisting conditions: ischemic heart disease, cardiac arrest, cerebrovascular disease, uncontrolled hypertension, symptomatic bradycardia, macular edema, recurrent syncope, severe untreated sleep apnea, herpes zoster, chronic hepatitis, tuberculosis, systemic fungal infections, skin cancer, or insulin-dependent diabetes.
• Myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure < 6 months prior to registration.
• History or presence of Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
• History of a hypersensitivity reaction to fingolimod or any of the excipients including rash, urticarial, and angioedema upon treatment initiation.
• Baseline QTC interval ≥ 450 ms (on EKG).
• Concurrent use of a class Ia or III antiarrhythmic.
• Drugs with a KNOWN risk of torsades de pointes (Information regarding drug specific risk of QT prolongation can be found at www.crediblemeds.org).
• Concurrent use of beta blockers, calcium channel blockers or digoxin.
• Use of immunosuppressive, or immune-modulating therapies that may have immunosuppressive effects.
• Immunocompromised patients including patients known to be HIV positive.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent.
• Family history of a genetic/familial neuropathy.
• Received a vaccine (inactivated) ≤ 14 days prior to registration.
• Positive varicella zoster IgM titer, consistent with recent exposure.

• Age ≥ 18 years old.
• Pain or symptoms of CIPN of ≥ 3 months duration, for which the patient wants intervention.
  • NOTE: Neurotoxic chemotherapy must have been completed ≥ 3 months (93 days) prior to registration and there must be no further planned neurotoxic chemotherapy for > 2 months after registration.
• Tingling, numbness or pain was at least a four out of ten problem during the week prior to registration, on a 0-10 scale where zero was no problem and ten was the worst possible problem (patient verbal report to clinician utilizing question in Appendix VI).
• ECOG Performance Status (PS) 0, 1 or 2.
• Negative pregnancy test done ≤ 14 days prior to registration, for persons of childbearing potential only.
• Provided written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Life expectancy ≥ 6 months.

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Previous diagnosis of diabetic or other peripheral neuropathy.
• Current or previous use of fingolimod.
• History of the following preexisting conditions: ischemic heart disease, cardiac arrest, cerebrovascular disease, uncontrolled hypertension, symptomatic bradycardia, macular edema, recurrent syncope, severe untreated sleep apnea, Herpes simplex virus (HSV) varicella zoster (VZV), chronic hepatitis, tuberculosis, fungal infections, skin cancer, or diabetes.
• Myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure < 6 months prior to registration.
• History or presence of Mobitz Type II second degree or third degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
• History of hypersensitivity reaction to fingolimod or any of the excipients including rash, urticarial, and angioedema upon treatment initiation.
• Baseline QTc interval ≥ 450 ms (on patient EKG)
• Concurrent use of a class Ia or III antiarrhythmic drug
• Drugs with a known risk of torsades de pointes
• Concurrent use of beta blockers, calcium channel blockers, or digoxin
• Use of immunosuppressive or immune-modulating therapies that may have immunosuppressive effects
• Immunocompromised patients including patients known to be HIV positive.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • or psychiatric illness/social situations that would limit compliance with study requirements.
• Family history of genetic/familial neuropathy.
• Currently receiving another agent to treat CIPN, such as duloxetine, gabapentin or pregabalin, and not willing to be weaned off of these medications prior to therapy initiation.
• History of peripheral neuropathy prior to receiving neurotoxic chemotherapy.
• Received a vaccine (inactivated) ≤ 2 weeks prior to registration.
• Positive varicella zoster IgM titer, consistent with recent exposure.