• Diagnosis of acute myeloid leukemia (AML) based on 2017 World Health Organization (WHO) criteria excluding acute promyelocytic leukemia with PML-RARA. 
• No activating mutation in the Fms-like tyrosine kinase-3 (FLT3) defined as a ratio of mutant to wild-type allele >= 0.05 by capillary electrophoresis or a variant allele fraction of >= 5% by next generation sequencing from either bone marrow or peripheral blood. 
• No evidence of CNS involvement of AML.
• No prior chemotherapy for myelodysplastic syndrome (MDS) or AML including hypomethylating agents (e.g., azacitidine and decitabine) or lenalidomide with the following exceptions: 
  • Emergency leukapheresis. 
  • Hydroxyurea.
  • Growth factor/cytokine support.
  • All-trans retinoic acid (ATRA). 
  • Single dose of intrathecal cytarabine and/or methotrexate for patients undergoing lumbar puncture to evaluate for CNS involvement.

• Patients with myeloid sarcoma without bone marrow involvement, acute leukemia of ambiguous lineage or blast transformation of chronic myelogenous leukemia (CML) are not eligible. 

• Age ≥ 18 years old.
• ***Histologically documented Squamous Cell Carcinoma of the oropharynx (AJCC v7** Stage III-IV A,B).
• *Tumor tissue (primary or cervical metastasis) available for human papilloma virus (HPV) and/or p16 (in situ hybridization (ISH), immunohistochemistry (IHC) or genotyping testing).
• If you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing.
• Eastern Cooperative Oncology Group (ECOG) performance status= 0, 1, or 2.
• Negative pregnancy test for women of child bearing potential.
• Concurrent chemotherapy.
• Bilateral neck radiation.

• Previous radiation treatment for head and neck mucosal primary cancers within the past 5 years (i.e., oropharynx, nasopharynx, hypopharynx, larynx, and oral cavity).
• Pregnant or breast-feeding females.
• Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not limited to:
  • Symptomatic congestive heart failure, unstable angina, or cardiac dysrrhythmia not controlled by pacer device;
  • No myocardial infarction within 3 months of registration.
• Distant metastases (AJCC v7** Stage IV C, any T, any N and M1).
• Previous surgical resection or neck dissection for oropharyngeal cancer, administered with therapeutic intent.

*    If you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing.
**  American Joint Committee on Cancer (AJCC) 7th edition.
*** For clinically visible or radiographically diagnosed oropharynx cancer, neck mass biospy/US FNA is acceptable.

• Patients with histologically confirmed intra-hepatic, perihilar or extra-hepatic CCA.
• Patients should not have received more than 2 prior treatment lines with systemic anti-neoplastic therapy (chemotherapy, targeted therapy etc.) for advanced or metastatic CCA. Previous adjuvant therapy, neoadjuvant or combined chemoradiotherapy for early stage disease, are not considered as part of the 2 allowed therapy lines for the purpose of this study.
• The tumor is unresectable and not amenable to curative therapy.
• At least 1 measurable lesion on CT scan per RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy of at least 3 months.
• Age ≥ 18 years.
• Signed, written IRB-approved informed consent.
• A negative pregnancy test (if female).
• Serum sodium within normal limits.
• Acceptable liver and renal function:
  • Bilirubin ≤ 1.5 times upper limit of normal (NCI-CTCAE Grade 2 baseline);
  • AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal (ULN);
  • Serum creatinine ≤ 1.5 X ULN (NCI-CTCAE Grade 1 baseline);
  • Albumin > 3.0 g/dL
• Acceptable hematologic status:
  • Absolute neutrophil count ≥1000 cells/mm^3;
  • Platelet count ≥ 75,000 (plt/mm^3) (NCI-CTCAE Grade 1 baseline);
  • Hemoglobin ≥ 9 g/dL.
  • Acceptable blood sugar control:
    • Fasting glucose value ≤ 160 mg/dL (NCI-CTCAE Grade 1 baseline).
  • Urinalysis: No clinically significant abnormalities.
  • Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 X ULN after correction of nutritional deficiencies that may have contributed to prolonged PT/PTT.
  • For men and women of child-producing potential, willingness to use of effective contraceptive methods during the study. If female (or female partner of male patient), was either not of childbearing potential (defined as postmenopausal for ≥ 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy or hysterectomy]) or practicing one of the following medically acceptable methods of birth control and agreed to continue with the regimen throughout the duration of the study:
    • Oral, implantable or injectable contraceptives for 3 consecutive months before the baseline/randomization visit;
    • Total abstinence from sexual intercourse (≥ 1 complete menstrual cycle before the baseline/randomization visit);
    • Intrauterine device;
    • Double barrier method (condoms, sponge, diaphragm or vaginal ring with spermicidal jellies or cream).

• > 2 previous systemic anti-neoplastic regimens for advanced/metastatic CCA.
• Previously having received ABC294640 or HCQ (or chloroquine) for the treatment of a malignancy.
• New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.
• History of psychosis or anxiety disorders.
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
• Pregnant or nursing women.
  • NOTE: If a woman became pregnant or suspects she is pregnant while participating in this study, she must inform her treating physician immediately.
• Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 28 days prior to study entry. Patients who had received any antineoplastic therapy > 28 days prior to starting treatment with ABC294640 must have recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and Grade 1 neuropathy).
• Unwillingness or inability to comply with procedures required in this protocol.
• Known infection with human immunodeficiency virus.
• Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor.
• Patients who were currently receiving any other investigational agent.
• Patients who were receiving drugs that are:
  • Sensitive substrates, or substrates with a narrow therapeutic range, for CYP2C8, CYP2C9, CYP2C19, CYP3A4 should be avoided, when possible, or used with caution because ABC294640 may either increase or decrease patients’ exposure to these drugs. In addition, P-gp and BCRP sensitive and/or narrow therapeutic range substrates for which safety cannot be readily monitored for should be avoided, when possible, or used with caution for the same reasons.
  • Moderate or strong inhibitors of CYP1A2, CYP3A4 or CYP2D6 or moderate to strong inducers of CYP3A4 and CYP1A2 are prohibited
• Patients who are taking warfarin, apixaban, argatroban or rivaroxaban.
• If the patient is to receive HCQ, pre-existing retinopathy.
• Known history of G-6-PD Deficiency, porphyria or psoriasis.
• History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to HCQ.
• Corrected QT (QTc) interval on electrocardiogram (ECG) > 470 ms for females or > 450 ms for males, calculated using Friedericia’s formula (QTcF)
• In cell culture, ABC294640 inhibited hERG potassium current, with a maximum inhibition of 71%. In dog studies, no ECG abnormalities were noted, nor has QTc prolongation been noted in human studies. However, due to the in vitro hERG results, treatment within seven days, or 5 half-lives, whichever is longer, with any medication that causes QT prolongation prior to initiation of study drug, or intention to use them throughout the study is not recommended. These medications include but not limited to: amiodarone, amitriptyline, azithromycin, citalopram dose greater than 20 mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilide, pimozide, procainamide, quinidine, quinine, quinolone, ranolazine, risperidone, sotalol and tolterodine.

Eligibility last updated 9/29/21. Questions regarding updates should be directed to the study team contact.

• Diagnosed with histologically confirmed adenocarcinoma of the prostate based on core-biopsy within 1 year of study entry from TRUS
• Clinical stages T1c to T2b
• PSA <20
• Gleason score ≤6 if PSA <20 or Gleason score 3 + 4 = 7 or 4 + 3 = 7 if PSA <20
• Must have complete history and physical examination within 45 days of study entry and digital rectal examination of prostate within 180 days of study entry
• Participants who are currently receiving Dutasteride (or have received it within the last 90 days) or Finasteride (or have received it within the last 30 days) must have a PSA of ≤ 10

• Prior surgery (not including TURP), cryosurgery, radiofrequency ablation, chemotherapy or radiation for PCa
• Prior or planned androgen deprivation or bilateral orchiectomy
• Distant metastases, or clinically or pathologically involved lymph nodes confirmed by a CT scan within 365 days of study entry
• Hip prosthesis, inflammatory bowel disease or connective tissue disorder such as active scleroderma or lupus
• History of other malignancies within the past 5 years
• Individuals who have AIDS (CD4 < 200 or an AIDS-defining illness) or are HIV positive and not on HAART therapy are ineligible.
• Major medical or psychiatric illness

• 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).