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

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

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

Physical and Laboratory Test Findings

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

Inclusion Criteria for Eligibility post-surgery

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

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

Exclusion Criteria for Eligibility post-surgery

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

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

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

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

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

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

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

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

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

PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA

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

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

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

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

For dose escalation phase:

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

For dose confirmation phase:

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

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

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

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

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

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

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

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

REGISTRATION TO STEP 1
•ELIGIBILITY CRITERIA:

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

REGISTRATION TO STEP 2
•ELIGIBILITY CRITERIA:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

INCLUSION CRITERIA
•Prior to Step 1 Registration:

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

INCLUSION CRITERIA
•Prior to Step 2 Registration:

• TP53 sequencing by NGS performed by central pathology lab.

EXCLUSION CRITERIA
•Prior to Step 1 Registration:

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

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

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

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

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

• Women ≥ 18 years of age with clinical stage IV ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent.
• Patient must have been treated with an anti-estrogen at any time in their disease history. Combination regimens that include an anti-estrogen and any biologic, or targeted therapy, are permitted (e.g., any CDK inhibitor, everolimus, or any other novel biologics), and are considered to be a single hormonal therapy based regimen.
  • Any number of prior lines of anti-estrogen (i.e., hormonal) therapy is permissible. 
  • One line of prior chemotherapy for advanced/metastatic disease is permissible.
• Histologic documentation of ER strongly+/HER2- breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥1 site(s) of metastatic or locally advanced disease performed as standard of care within the past 4 months for assessment of eligibility for study participation (except as noted below in c/d/e).
  • ER strongly+ status defined as ER staining by immunohistochemistry in ≥ 50% of malignant cell nuclei with an intensity ≥ 2+ on a scale of 0-3+. These criteria are equivalent to an Allred score ≥ 6.
  • HER2-negative status is defined as immunohistochemistry score of 0-1+, or with a FISH ratio of < 2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.
  • Archived tumor specimens: Excess tumor tissue must be available for research purposes. This will include tumor tissue sufficient to make ≥ 10 five-micron sections; more tumor tissue is preferred. Freshly acquired tumor specimens: As part of a clinically indicated biopsy procedure, an additional 1-3 cores or tissue fragments will be obtained by core needle or surgical biopsy for research purposes and FFPE.
  • Patients with bone-only metastatic disease with a history of ER+/HER2- breast cancer are eligible, and bone biopsy is not required, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
  • Patients with non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained are also eligible, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
  • Patient must be a candidate for treatment with 17B-estradiol and an aromatase inhibitor.
  • If the most recent therapy was in the adjuvant setting, the recurrence-free interval (time from initiation of adjuvant anti-estrogen therapy to clinical evidence of disease recurrence) must have been ≥ 2 years. If the most recent therapy was in the advanced/metastatic setting, the progression-free interval must have been ≥ 4 months (except in the case of investigational hormonal therapies).
  • Patient must be post-menopausal based on either a history of an oophorectomy, or ≥ 1 year of amenorrhea. An elevated serum gonadotropin level and estradiol level in the postmenopausal range (as locally defined) can be used to confirm menopausal status in a subject with < 1 year of amenorrhea.
  • Baseline radiographic staging, including specifically either PET/CT, or CT (CAP) and bone scan.
  • Patient must be capable and willing to provide informed written consent for study participation.
  • The following laboratory values must be confirmed for eligibility within 28 days prior to initiation of study therapy:
    • Hematology panel
      • hemoglobin > 9 g/dL;
      • white blood cell (WBC) count (≥ 2,000/uL);
      • platelet count ≥ 75,000/uL.
    • Serum biochemistry/metabolic panel 
      • creatinine ≤ 1.5 x upper limits of normal (ULN);
      • total bilirubin ≤ 1.5 x upper limits of normal (ULN);
      • ALT and AST ≤ 3.0 x upper limits of normal (ULN) For patients with liver metastasis: < 5 x upper limits of normal (ULN).

• Treatment with fulvestrant within 16 weeks prior to study enrollment.
• Any other concurrent systemic anti-cancer treatments, including conventional chemotherapeutic agents and biological agents, during the study period.
  • Anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
• Any investigational cancer therapy in the last 3 weeks.
• Known CNS disease, unless clinically stable for ≥ 3 months.
• History of any of the following:
  • deep venous thrombosis;
  • pulmonary embolism;
  • stroke;
  • acute myocardial infarction;
  • congestive heart failure;
  • previous malignancy not treated with curative intent, or with an estimated recurrence risk ≥ 30%.

• Recently diagnosed with prostate cancer for whom definitive surgical treatment is indicated.

• Not suitable to undergo MRI or receive gadolinium-based contrast agent (severe, untreatable claustrophobia; MRI-incompatible metallic objects or implanted medical devices; renal failure; weight greater than allowable by scanner per institutional standard practice).
• Prior surgical and/or non-surgical treatment for prostate cancer.
• Prior hip replacement or other major pelvic surgery

• Age ≥ 18 years at time of signing Informed Consent Form
• Ability to comply with the study protocol, in the investigator’s judgement
• Pathologically documented Stage II, IIIA, or select IIIB (T3N2 only) NSCLC of squamous or non-squamous histology
• Staging should be based on the 8th edition of the American Joint Committee on Cancer (AJCC) / Union Internationale Contre le Cancer (UICC) NSCLC staging system.
  • – T4 primary NSCLC will be allowed only on the basis of size (tumors > 7 cm). Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, and separate tumor nodules in a different ipsilateral lobe is not permitted.
• Patients with mixed NSCLC histology (squamous and non-squamous) or NSCLC not otherwise specified are eligible.
• Patients may be screened based on clinical stage, but mandatory preoperative documentation of N2 nodal involvement by invasive mediastinal staging; e.g., CT-guided biopsy, endobronchial ultrasound (EBUS), mediastinoscopy, is required for PET-positive N2 nodes. Pre-operative staging of levels 5/6 nodes is optional.
• Solid or subsolid appearance of NSCLC on CT scan with no appearance of purely ground-glass opacity (GGO)
• For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured based on solid component only, exclusive of the GGO component.
• Evaluation by the operating attending surgeon and involved medical oncologist prior to study enrollment to verify study eligibility for R0 resection with curative intent 
• PFTs within 6 months of planned resection and repeated at screening, if clinically indicated, including lung volumes, spirometry, and a diffusion capacity
  • If PFTs were performed before 6 months of planned resection or have never been performed, they must be performed during the screening period.
  • Abnormal PFTs may be further evaluated with quantitative ventilation/perfusion scanning or cardiopulmonary exercise testing.
  • Postoperative percent predicted forced expiratory volume in 1 second (FEV1) and diffusion capacity must be ≥ 40% and/or maximal oxygen consumption (VO2max) should be > 10 mL/kg/min.
• Adequate cardiac function to be eligible for surgical resection with curative intent If clinically indicated, patients with underlying ischemic, valvular, or other significant heart diseases should be evaluated preoperatively by a cardiologist.
• Measurable disease as assessed by the investigator per RECIST v1.1
• Eligibility to receive a platinum-based chemotherapy regimen
• Availability of a representative tumor specimen suitable for determination of PD-L1 status via central testing (results of PD-L1 testing are not required for patient to be randomized into the study)
• A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least a minimum of 3 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report before or within 4 weeks after randomization. Any additional slides beyond the required minimum of 3 slides are strongly encouraged for other exploratory biomarker research. If archival tumor tissue is unavailable, tumor tissue must be obtained from a biopsy performed at screening.
• ECOG Performance Status of 0 or 1
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
  • ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support
  • Lymphocyte count ≥ 0.5 x 109/L (500/µL)
  • Platelet count  ≥ 100 x 109/L (100,000/µL) without transfusion
  • Hemoglobin  ≥ 90 g/L (9.0 g/dL)
    • Patients may be transfused to meet this criterion.
  • AST, ALT, and ALP ≤ 2.5 x upper limit of normal (ULN)
  • Serum bilirubin ≤ 1.5 x ULN with the following exception:
    • Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN
  • Creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gault formula)
    • For patients intended to receive cisplatin: creatinine clearance ≥ 60 mL/min
  • Serum albumin ≥ 25 g/L (2.5 g/dL)
  • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Negative HIV test at screening
• Negative hepatitis B surface antigen (HBsAg) test at screening
• Negative total hepatitis B core antibody (HBcAb) test at screening, or a positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
  • The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
  • The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
  • Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the last dose of atezolizumab, 30 days after the last dose of nab-paclitaxel, or 6 months after the last dose of pemetrexed, gemcitabine, carboplatin, or cisplatin, whichever is later. Women must refrain from donating eggs during this same period.
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not  undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.
  • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
  • With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period for 6 months after the last dose of nab-paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin, whichever is later, to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)  and withdrawal are not acceptable methods of contraception of preventing drug exposure.

• Illness or condition that may interfere with a patient’s capacity to understand, follow, and/or comply with study procedures.
• Any prior therapy for lung cancer, including chemotherapy, or radiotherapy.
• Major surgical procedure, other than for diagnosis, within 28 days prior to initiation of study treatment, or anticipation of need for non-protocol-mandated major surgical procedure during the study.
• Non-squamous NSCLC histology with an activating mutation in the epidermal growth factor receptor (EGFR) or with an anaplastic lymphoma kinase (ALK) fusion oncogene.
  • Patients with non-squamous NSCLC histology that have unknown EGFR and/or ALK status require test results at screening. ALK and/or EGFR may be assessed locally or at a central laboratory (for China, testing will only be performed at a central laboratory);
  • If samples are submitted for central testing, additional tissue, cytology, and/or plasma samples are required.
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
  • Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study;
  • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study;
  • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
    • Rash must cover < 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.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
• Active tuberculosis.
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
• History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
  • Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
• Current treatment with anti-viral therapy for HBV.
• Treatment with investigational therapy within 42 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
  • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study after Medical Monitor approval has been obtained;
  • Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study..
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation.
• Known allergy or hypersensitivity to any component of the chemotherapy regimen the patient will be assigned to.
• For patients intended to receive cisplatin, any significant hearing impairment per the investigator’s clinical judgement.
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after last dose of atezolizumab, 30 days after the last dose of nab-paclitaxel, or 6 months after last dose of pemetrexed, gemcitabine, carboplatin, or cisplatin.
  • Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

• Patients must have inflammatory breast cancer without distant metastases. All biomarker subtype groups (estrogen receptor [ER], progesterone receptor [PR], HER2) are eligible. Inflammatory disease will be defined per American Joint Committee on Cancer (AJCC) 8th edition with documentation by history/exam and pathology at the time of diagnosis. 
• All patients must have completed neoadjuvant chemotherapy prior to mastectomy. The chemotherapy regimen is at the discretion of the treating physician but it is recommended that it include at least 4 cycles of anthracycline and/or taxane-based therapy (plus targeted therapy for patients with HER2+ disease). Response to chemotherapy is not a criterion for eligibility (both complete responders and those with residual disease are eligible). Please note that although pathologic complete response (pCR) is not required or excluded, pCR status must be determined post-surgery prior to randomization.
• All patients must have undergone modified radical mastectomy (with negative margins on ink) with pathologic nodal evaluation (from level I and II axillary lymph node dissection) at least 3 weeks and no more than 12 weeks prior to randomization, unless they receive additional chemotherapy after mastectomy. Patients must not have gross residual tumor or positive microscopic margins after mastectomy. 
• Additional adjuvant chemotherapy after surgery is allowed at the discretion of the treating physician, either completed prior to randomization or planned for after completion of protocol treatment. If adjuvant chemotherapy is administered after mastectomy, the patient must be randomized at least 3 weeks but no more than 12 weeks after the last dose of adjuvant chemotherapy. 
• Patients must not have a history of radiation therapy to the ipsilateral chest wall and/or regional nodes. Prior radiation therapy to other body sites is allowed.
• Patients must not be planning to receive any other investigational agents during radiation therapy. Prior therapy, including prior treatment with olaparib or other PARP inhibitor, is allowed. 
• Patients must not have a known hypersensitivity to olaparib or any of the excipients of the product.
• Patients must not have unresolved or unstable grade 3 or greater toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment. 
• Patients must not be planning to receive strong or moderate CYP3A inhibitors or inducers while on olaparib treatment. Patients receiving strong or moderate CYP3A inhibitors must agree to discontinue use at least 2 weeks prior to receiving olaparib. Patients receiving strong or moderate CYP3A inducers must agree to discontinue use at least 5 weeks prior to receiving olaparib. 
• Patients must not be planning to receive live virus or live bacterial vaccines while receiving olaparib and during the 30 day follow up period.
• Patients must not be planning to receive any additional anti-cancer therapy (chemotherapy, endocrine therapy, immunotherapy, biological therapy or other novel agent) while receiving radiotherapy with or without study medication. If a patient is receiving concurrent anti-HER2 targeted therapies, they must not take these medications during the period of radiotherapy (with or without study drug) while enrolled on the study. 
• Patients must be ≥ 18 years of age.
• Patients must have Zubrod performance status 0-2. 
• Patients must have adequate hematologic function as evidenced by all of the following within 28 days prior to registration:
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (within 28 days prior to registration);
  • Platelet count >= 100,000/mm^3 (within 28 days prior to registration);
  • Hemoglobin >= 9.0 g/dL (after transfusion if required and within 28 days prior to registration).
• Patients must have adequate renal function as evidenced by calculated creatinine clearance >= 51 mL/min by Cockcroft-Gault equation, within 28 days prior to registration.
• Calculated creatinine clearance = [(140
  •age) x wt (kg) x 0.85 (if female)]/[72 x creatinine (mg/dl)].
• Patients must have adequate hepatic function as evidenced by all of the following within 28 days prior to registration:  
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to registration).
  • Patients with documented Gilbert's disease may have bilirubin up to 2.5 mg/dL.
  • Serum glutamic-oxaloacetic transaminase (SGOT) =< 2.5 x ULN (within 28 days prior to registration).
  • Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN (within 28 days prior to registration) .
  • Alkaline phosphatase =< 2.5 x ULN (within 28 days prior to registration). 
• Patients must not have a history of other prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.
• Female patients must be postmenopausal or have a negative urine or serum pregnancy test within 28 days prior to registration. Female patients of childbearing potential and male patients with partners of childbearing potential, who are sexually active, must agree to the use of two highly effective forms of contraception. 
• Patients who are breastfeeding must agree to discontinue breastfeeding before receiving olaparib due to potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib. 
• Patients must not have active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia. 
• Patients must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of the study medication. 
• Patients must not have a history of a resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions (such as unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's formula corrected QT interval [QTcF] prolongation > 500 ms, electrolyte disturbances) or congenital long QCYP3T syndrome. 
• Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML. 
• Patient must not have had major surgery within 2 weeks of starting study treatments and patients must have recovered from any effects of any major surgery. 
• Patients must not have a history of uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan. 
• Patients must not have had previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). 
• Patients must not have had whole blood transfusions in the last 120 days prior to randomization.

• Age ≥ 18 years
• Histological confirmation of non-small cell lung cancer (NSCLC) with advanced disease.
• Prior treatment required:
• Anti-PD1/PD-L1 agent in combination with platinum-based chemotherapy
• NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible.
•  
• ECOG Performance Status (PS) 0 or 1.
• The following laboratory values obtained ≤ 14 days prior to registration:
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelet count ≥ 100,000/mm^3
• Total bilirubin ≤ ULN
• Alanine aminotransferase (ALT/SGPT) and aspartate transaminase (AST/SGOT) ≤ 1.5 × ULN
• Alkaline phosphatase ≤ 2.5 × ULN
• PT/INR/aPTT ≤1.5 × ULN OR if patient is receiving anticoagulant therapy INR or aPTT is within target range of therapy
• •  
• Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula.
• Negative pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only.
• NOTE: If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Willing to use birth control as follows:
• If able to become pregnant: Willing to use birth control during treatment and for 6 months after last dose of docetaxel and/or bintrafusp alfa, whichever is later.
• If able to father a child: Willing to use birth control with partners able to become pregnant during treatment and for 3 months after last dose of docetaxel and/or bintrafusp alfa, whichever is later.
• Provide written informed consent.
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Any of the following prior therapies:
  • Surgery ≤ 4 weeks prior to registration;
  • Chemotherapy ≤ 4 weeks prior to registration;
  • Received single agent anti-PD1/PD-L1 as first line therapy for metastatic disease.
• 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.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • symptomatic congestive heart failure;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 5 years prior to registration.
• EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer.
•  
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
• • Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
  • Evaluable or measurable disease outside the CNS;
• • No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm);
  • No history of intracranial hemorrhage or spinal cord hemorrhage.
• No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted.
• No neurosurgical resection or brain biopsy ≤ 28 days prior to registration.
• Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
  • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study;
  • No stereotactic radiation or whole-brain radiation ≤ 28 days prior to registration;
• • Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks from discontinuation of corticosteroids.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• History or current evidence of bleeding disorder, including bleeding diathesis, i.e., any hemorrhage/bleeding event of CTCAE Grade ≥ 2 in ≤ 28 days prior to registration.
• Taking oral prednisone of ≥ 10 mg daily or equivalent.
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.

Notes:

• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.

Notes:

• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible.
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible.
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations;
• • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%);
  • No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids).
• Known active human immunodeficiency virus (HIV) infection (defined as patients who are not on anti-retroviral treatment and have detectable viral load and CD4+ < 500/ml).
  • Note: HIV-positive patients who are well controlled on anti-retroviral therapy are allowed to enroll.
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
  • Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Severe infections ≤ 4 weeks prior to registration, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• History of peripheral neuropathy ≥ Grade 2.
• Known hypersensitivity to docetaxel or polysorbate 80.

• Patients must have a histopathologically confirmed diagnosis of diffuse large B-cell lymphoma (DBLCL) or primary mediastinal large B-cell lymphoma.
• Patients must have measurable disease, defined as at least one lesion that is ≥ 15 mm (≥ 1.5 cm) in the longest axis on cross-sectional imaging and measurable in two perpendicular dimensions per spiral computed tomography (CT) scan or positron-emission tomography (PET)-CT scan.
• Patients must have disease that is recurrent or refractory to standard therapy; patients must have failed front-line therapy and declined or are not candidates for autologous stem cell transplant (ASCT) or have failed prior ASCT.
• Age ≥ 18 years.  Because no dosing or adverse event data are currently available on the use of copanlisib and nivolumab combination in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. However, if pediatric colleagues and centers are interested in including patients ages 12 to 18 in this trial, this trial then could be available to this group of patients.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Life expectancy of greater than 12 weeks.
• Patients must have normal organ and marrow function as defined below:
  • White blood cell (WBC) ≥ 3000/mm^3;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Hemoglobin > 9.0 g/dL;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL);
  • Aspartate transaminase (AST) ≤ 2.5 x ULN;
  • Serum creatinine ≤ 2.0 mg/dL; OR
  • Calculated creatinine clearance (crcl) ≥ 45 mL/min (if using the Cockcroft-Gault formula):
    • Female CrCl = (140
      •age in years) x weight in kg x 0.85 
                                 72 x serum creatinine in mg/dL
    • Male CrCl = (140
      •age in years) x weight in kg
                                 72 x serum creatinine in mg/dL.
• Negative urine or serum pregnancy test for females of child bearing potential within 7 days prior to registration:
• The effects of copanlisib and nivolumab on the developing human fetus are unknown. For this reason, and because the study drugs used in this trial are known to be teratogenic, females of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 5 months after the last dose of study drug. Males who are the sexual partners of a female of child-bearing potential must use any contraceptive method with a failure rate of less than 1% per year for the duration of study participation and for a period of 7 months after the last dose of study drug. These periods of required use of contraception have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that females of child-bearing potential use contraception for 5 months and males who are the sexual partners of females of child-bearing potential use contraception for 7 months.
• Females must not breastfeed for 1 month after last dose.
• Females of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.
• A female of child-bearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a female over 45 in the absence of other biological or physiological causes. In addition, females under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
• Females who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic males do not require contraception.
• Should a female of child-bearing potential become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

• Any high grade B-cell lymphoma.
• Patients who have had chemotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C), anticancer antibodies within 4 weeks, radio or toxin immunoconjugates within 2 weeks, radiation therapy within 3 weeks or major surgery within 2 weeks prior to entering the study:
  • Palliative (limited-field) radiation therapy is permitted if the patient has additional measurable lesions to assess response of therapy.
• Patients who have not recovered to grade 1 or less from any adverse events due to agents administered more than 4 weeks earlier (excluding alopecia).
• Patients who are receiving any other investigational agents.
• Patients should be excluded if they have had prior treatment with a Pi3 kinase inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• Patients who have received autologous stem cell transplant (ASCT) ≤ 8 weeks prior to the first dose of study drug or no adequate count recovery.
• Patients with a prior history of allogeneic stem cell or solid organ transplantation.
• Patients with evidence of active disease in the central nervous system (CNS) defined as either the presence of active lesions on MRI obtained within 4 weeks of registration or progressive neurological decline.
• Patients with primary CNS lymphoma who develop systemic recurrence following standard therapy may be included as long as no active CNS disease is present at the time or enrollment. Similarly, patients with secondary involvement of the CNS from a systemic lymphoma may be included as long as the CNS disease has been optimally treated and they demonstrate no evidence of active CNS disease.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to copanlisib and/or nivolumab.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• 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.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, non-healing wound or ulcer, or bone fracture, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because copanlisib and nivolumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with copanlisib or nivolumab, breastfeeding should be discontinued for 1 month after last dose if the mother is treated with copanlisib or nivolumab.
• Patients with human immunodeficiency virus (HIV):
• Patients with human immunodeficiency virus (HIV) are eligible for the study provided they meet the other protocol criteria in addition to the following:
  • Undetectable HIV load by standard PCR clinical assay;
  • Absolute CD4 count of ≥200 mm3;
  • Willing to maintain adherence to combination antiretroviral therapy;
  • No history of AIDS defining condition (other than lymphoma or CD4 cell count < 200 mm3);
  • Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma.
• The Patients with evidence of HBV are eligible provided there is minimal hepatic injury and the patient has undetectable HBV on suppressive HBV therapy. Patient must be willing to maintain adherence to HBV therapy.
• Patients with previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic injury are eligible.
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• Patients are permitted to enroll if they have vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event); however, patients with uncontrolled type I or II diabetes mellitus will be excluded; uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) > 8.5%.
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, and gastrointestinal (GI) obstruction which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study.
• Patients with other active malignancy ≤ 3 years prior to registration for which active treatment is required must be excluded; patients with composite lymphomas that have a non-B-cell component must be excluded.
  • EXCEPTIONS: Non-melanotic skin cancers or carcinoma-in-situ of the cervix.
• Copanlisib is primarily metabolized by CYP3A4; therefore, the concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted from 14 days prior to enrollment until the end of the study.
  • Note: Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. APPENDIX B (Patient Drug Information Handout and Wallet Card) should be provided to patients. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Other medications that are prohibited while on copanlisib treatment:
  • Herbal medications/preparations (except for vitamins);
  • Anti-arrhythmic therapy other than beta blockers or digoxin.

• Are ≥ 18 years of age at the time of signing the informed consent.
  • In Japan, if a patient is < 20 years, the written informed consent from his/her parent or guardian will be required in addition to the patient’s written consent.
• Participants must have measurable or non-measurable but evaluable disease assessed by the Investigator. Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).
• 3. Availability of tumor material (< 6 months old) adequate for biomarker analysis is mandatory for all participants and central laboratory confirmation is required. For participants enrolled in the safety run-in, PD-L1 expression will be tested retrospectively by a central laboratory. For participants enrolled in the expansion part of the study, PD-L1 expression must be tested by the central laboratory and results available before randomization. Only results from the central laboratory testing will be used for randomization and if PD-L1 status is non-evaluable, the participant is not eligible for this study. Tumor samples obtained by endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies, and surgical specimens that are < 6 months old and adequate for biomarker analysis are acceptable. Biopsies obtained by fine needle aspiration are not acceptable.
• Participants with tumor harboring an EGFR sensitizing (activating) mutation, ALK translocation, ROS-1 rearrangement are eligible. These tests are not required for enrollment in the study.
• Participants with ongoing post-obstructive pneumonia due to the tumor are eligible.
• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease):
  • When pleural fluid is visible on both the CT scan and on a chest x-ray, a thoracentesis is required to confirm that the pleural fluid is cytologically negative;
  • Participants with exudative pleural effusions are excluded, regardless of cytology;
  • Participants with effusions that are minimal; i.e., are too small to safely tap are eligible.
• Participants must be at least 3 weeks from prior thoracotomy (if performed).
• Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) ≥ 1.2 liters or ≥ 50% of predicted normal volume measured within 3 weeks prior to randomization. If participants do not meet the above criteria, treatment with inhaled steroids and bronchodilators can be initiated if clinically indicated and eligibility can be reassessed after 1-2 weeks.
• ECOG performance status of 0 to 1 at Screening and on the day of first dose.
• Life expectancy ≥ 12 weeks.
• Have adequate organ function as indicated by the following laboratory values:
  • Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL;
  • Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase (AST) level ≤ 3.0 × ULN, an alanine aminotransferase (ALT) level ≤3.0 × ULN and alkaline phosphatase ≤ 2.5 ULN;
  • Adequate renal function defined by creatine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min for participant with Cr > 1.5 × ULN (GFR can also be used).
    • Note: CrCl  should be calculated per institutional standard. If no local guideline is available, CrCl should be calculated using the Cockcroft-Gault Method:
    • CrCl = ((140-age) * weight (kg) * (0.85 for females only)) / (72 * creatinine).
  • Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
  • Male Participants:
    • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention
    • Refrain from donating sperm; PLUS, either:
      • Abstain from intercourse with a WOCBP;
        • OR
      • Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
  • Female Participants:
    • Are not pregnant or breastfeeding, and at least one of the following conditions applies:
      • Not a WOCBP.
        • OR
      • If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
        • Before the first dose of the study intervention(s), if using hormonal contraception:
        • Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses; OR
        • Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay.
        • During the intervention period.
      • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e., after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 4 months after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period.
    • Have a negative pregnancy test, as required by local regulations, on W1D1 before the first dose of study intervention.
    • Additional requirements for pregnancy testing during and after study intervention are in SoA.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
• Can give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

• Participants with mixed small cell with non-small cell lung cancer histology.
• Greater than minimal, exudative, or cytologically positive pleural effusions.
• Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug.
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
• History of organ transplant that requires therapeutic immunosuppression.
• Significant acute or chronic infections including, among others:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in Screening, however participant refuses testing, discuss with Medical Monitor to assess eligibility. (Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in Screening or while on study, a site must consent the participant for HIV testing as per local standard guidance);
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA, or HBV core antibody positive alone with reflex to positive HBV DNA, or positive HCV antibody with reflex to positive HCV RNA) at Baseline. Discuss with the Medical Monitor if history of HBV or HCV  infection is known. If medically indicated, participants infected with HBV must be treated and on a stable dose of antivirals (e.g, entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at study entry and with planned monitoring and management according to appropriate labeling guidance. Participants on active HCV therapy at study entry must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities (must meet criteria above) and with planned monitoring and management according to appropriate labeling guidance. HBV and/or HCV viral titers must be monitored according to SoA in these participants.
  • Participants with active tuberculosis (history of exposure or history of positive tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, active uveitis or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Known clinical history of tuberculosis, lung sarcoidosis and Interstitial Lung Diseases.
• History of another primary malignancy within 3 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ, e.g., cancer of the cervix in situ, superficial bladder cancer. History of other localized malignancies treated with curative intent needs to be discussed with the Medical Monitor.
• Uncontrolled neuropathy Grade 2 or greater regardless of cause.
• Significant hearing loss and participants unwilling to accept potential for further hearing loss (Investigator should consider treating the participant with carboplatin/paclitaxel).
• Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as anti-PD-(L)1, or anti-CTLA-4 antibody.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the cCRT for locally advanced NSCLC is allowed.
• Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), OR is receiving systemic steroid therapy < 3 days prior to the first dose of study intervention or receiving any other form of immunosuppressive medication. Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at low doses (typically ≤ 10 mg of prednisone or equivalent per day). Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy. Corticosteroid use on study as a premedication for IV contrast allergies/reactions (related to scans) is allowed and must be documented. This must be discussed with Medical Monitors for clinical indications in which participants may require a higher dose. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes Type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.  Consult Medical Monitor for other autoimmune diseases.
• Receipt of live attenuated vaccination within 30 days of receiving study drug.
• Use of a prohibited concomitant drug within 4 weeks randomization.
• Known severe hypersensitivity (Grade ≥ 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) to study interventions or any components in their formulations, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma).
• Participation in another clinical study with an investigational product within the last 4 weeks.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• ≥ 10% weight loss within the past month.
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of participant safety or study results.

• Pre- or postmenopausal.  Postmenopausal women are defined as:
  • 60 years of age with no vaginal bleeding over the prior year; or
  • < 60 years with "premature menopause" or "premature ovarian failure” manifest itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards; or
  • surgical menopause with bilateral oophorectomy.
    • Note: Premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy.
• If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of ER+ and HER2− disease as assessed by a local laboratory, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject’s cancer is ER+ and HER2−.
• Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression while on an AI in combination with a CDK4/6 inhibitor for advanced breast cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in the metastatic setting).
• Locally advanced or metastatic breast cancer with measurable (according to RECIST 1.1 and/or non-measurable lesions.
• At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N.  The ctDNA sample collection must be obtained within 90 days prior to randomization to determine eligibility and baseline.
  • Note: a prior genomic test confirming that the subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1 sample must also be collected within 30 days of randomization.
• Subjects who have not received cytotoxic chemotherapy or who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial; and/or no more than one chemotherapy regimen for metastatic breast cancer. Subjects must be free of all chemotherapy acute toxicity excluding alopecia and Grade II peripheral neuropathy before study entry.
• ECOG performance score of 0 or 1.
• Adequate organ function as shown by:
  • absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3;
  • platelet count ≥ 100,000 cells/mm^3;
  • hemoglobin ≥ 9.0 g/dl;
  • ALT and AST levels ≤ 2.5 upper limit of normal (ULN) or < 5 in the presence of visceral metastasis;
  • total serum bilirubin ≤ 0.5 x ULN (≤ 3.0 x ULN for subjects known to have Gilbert Syndrome);
  • alkaline phosphatase level < 2.5 x ULN;
  • creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula;
  • international normalized ratio (INR) and activated partial thromboplastin (aPTT) < 2.0 x ULN.
• Able to swallow tablets.
• Able to understand and voluntarily sign a written informed consent before any screening procedures.

• Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors are excluded unless discontinued due to reasons other than disease progression.
• Presence of brain metastasis.
• Lymphangitic carcinomatosis involving the lung.
• Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator. Radiotherapy within 30 days prior to randomization except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to randomization. Subjects must have recovered from radiotherapy toxicities prior to randomization.
• History of long QTC syndrome or a QTC of > 480 msec.
• History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6 months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment and there is no evidence for active thrombosis. The use of low dose acetylsalicylic acid (ASA) is permitted.
• Any significant co-morbidity that would impact the study or the subject’s safety.
• History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening. Subjects cured of hepatitis C (no viral load) are eligible.
• History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery, or early stage cervical cancer.
• History of vaginal bleeding over the last year unless it is documented that the bleeding was due to non-uterine causes (e.g., vaginal atrophy).
• Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic pressure > 100 mm Hg at Screening.
• History of non-compliance to medical regimens.
• Unwilling or unable to comply with the protocol.
• Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of: 

• Biopsy-proven small lymphocytic lymphoma; OR 
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: 
  • Peripheral blood lymphocyte count of greater than 5 x10^9/L;
  • Immunophenotype consistent with CLL defined as: 
    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression).
  • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g., marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g., marrow aspirate or lymph node biopsy.
• No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL. 
• Has met at least one of the following indications for treatment: 
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L);
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly; 
  • One or more of the following disease-related symptoms: 
    • Weight loss >= 10% within the previous 6 months;
    • Grade 2 or 3 fatigue attributed to CLL;
    • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection;
    • Clinically significant night sweats without evidence of infection.
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months.
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  •Life expectancy of >= 12 months. 
• No deletion of 17p13 on cytogenetic analysis by FISH. 
• Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration).
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration). 
  • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible. 
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.
• No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g., equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. 
  • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer). 
• Able to adhere to the study visit schedule and other protocol requirements.
• No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 
• No radiation therapy =< 4 weeks prior to registration. 
• Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor. 
• Patients must not have any of the following conditions: 
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure; 
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration;
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug; 
  • Cerebral vascular accident or intracranial bleed within the last 6 months
    •Infection with known chronic, active hepatitis C; 
  • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy.
• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Steroid therapy for anti-neoplastic intent;
  • Strong and Moderate CYP3A inhibitors; 
  • Strong and Moderate CYP3A inducers.
• Patients may not be on any other investigational agents.
• Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days. 
• Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 consecutive months. 
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for: 
  • 18 months after the last dose of obinutuzumab; 
  • 90 days after the last dose of ibrutinib; and 
  • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment.
• Patient must be able to swallow capsules and not have the following conditions: 
  • Disease significantly affecting gastrointestinal function;
  • Resection of the stomach or small bowel;
  • Symptomatic inflammatory bowel disease; 
  • Ulcerative colitis; 
  • Partial or complete bowel obstruction. 
• Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug. 
• Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. 
• Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification. 
• Patient must undergo assessment with Timed Up and Go (TUG) test. 
• Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.

Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of: 

• Biopsy-proven small lymphocytic lymphoma; OR 
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: 
  • Peripheral blood lymphocyte count of greater than 5 x10^9/L;
  • Immunophenotype consistent with CLL defined as: 
    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression).
  • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g., marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g., marrow aspirate or lymph node biopsy.
• No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL. 
• Has met at least one of the following indications for treatment: 
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L);
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly; 
  • One or more of the following disease-related symptoms: 
    • Weight loss >= 10% within the previous 6 months;
    • Grade 2 or 3 fatigue attributed to CLL;
    • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection;
    • Clinically significant night sweats without evidence of infection.
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months.
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  •Life expectancy of >= 12 months. 
• No deletion of 17p13 on cytogenetic analysis by FISH. 
• Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration).
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration). 
  • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible. 
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.
• No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g., equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. 
  • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer). 
• Able to adhere to the study visit schedule and other protocol requirements.
• No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 
• No radiation therapy =< 4 weeks prior to registration. 
• Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor. 
• Patients must not have any of the following conditions: 
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure; 
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration;
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug; 
  • Cerebral vascular accident or intracranial bleed within the last 6 months
    •Infection with known chronic, active hepatitis C; 
  • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy.
• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Steroid therapy for anti-neoplastic intent;
  • Strong and Moderate CYP3A inhibitors; 
  • Strong and Moderate CYP3A inducers.
• Patients may not be on any other investigational agents.
• Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days. 
• Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 consecutive months. 
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for: 
  • 18 months after the last dose of obinutuzumab; 
  • 90 days after the last dose of ibrutinib; and 
  • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment.
• Patient must be able to swallow capsules and not have the following conditions: 
  • Disease significantly affecting gastrointestinal function;
  • Resection of the stomach or small bowel;
  • Symptomatic inflammatory bowel disease; 
  • Ulcerative colitis; 
  • Partial or complete bowel obstruction. 
• Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug. 
• Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. 
• Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification. 
• Patient must undergo assessment with Timed Up and Go (TUG) test. 
• Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.

nclusion Criteria: 

• The subject has a histologic or cytologic diagnosis of a variant histology renal cell carcinoma including papillary, chromophobe, Xp.11 translocation, undifferentiated, or unclassified which is treatment naïve or has previously been treated with one systemic treatment line not containing any vascular endothelial growth factor antibody or vascular endothelial growth factor receptor tyrosine kinase inhibitors. The patient may have received treatment with immune checkpoint therapy including nivolumab as a single agent or nivolumab plus ipilimumab in combination. Previous treatment with mammalian target of rapamycin agents such as temsirolimus or everolimus is acceptable.
• Measurable disease per RECIST v1.1 as determined by the investigator. 
• The subject has had an assessment of all known disease sites; e.g., by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib or sunitinib. 
• The subject is ≥ 18 years old on the day of consent.
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Recovery to baseline or ≤ Grade 1 CTAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy;
• The subject has organ and marrow function and laboratory values as follows within 4 days before the first dose of cabozantinib or sunitinib:
  • The ANC ≥ 1500/mm^3 without colony stimulating factor support;
  • White blood cell count ≥ 2500/mm^3 (≥ 2.5 GI/L);
  • Platelets ≥ 100,000/mm^3;
  • Hemoglobin ≥ 9 g/dL; 
  • Bilirubin ≤ 1.5 x the ULN.  For subjects with known Gilbert's disease, bilirubin ≤ 3.0 x ULN;
  • Serum albumin ≥ 2.8 g/dl;
  • Serum creatinine ≤ 2.0 X ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:
  • Males: (140
    •age) x weight (kg)/(serum creatinine [mg/dL] × 72);
  • Females: [(140
    •age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85;
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 X upper limit of normal (ULN). ALP ≤ 5 X ULN with documented bone metastases;
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).
• Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant; i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.

• The subject has a variant histology that includes renal medullary carcinoma or collecting duct renal cell carcinoma. Any clear cell component in the tumor will lead to exclusion.
• Prior treatment with cabozantinib or sunitinib.
• Radiation therapy within 2 weeks. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
• 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 the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment.
• Concomitant anticoagulation with coumarin agents (e.g., warfarin).
• The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 2.0 × the laboratory ULN within 7 days before the 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) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment;
  • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose;
• Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
  • The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction;
  • Abdominal fistula, GI perforation, bowel obstruction, or intraabdominal abscess within 6 months before first dose.
    • Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
• Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose.
• Other clinically significant disorders that would preclude safe study participation.
  • Serious non-healing wound/ulcer/bone fracture.
  • Uncompensated/symptomatic hypothyroidism.
  • Moderate- to- severe hepatic impairment (Child-Pugh B or C).
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 4 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 2 month before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days 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 28 days before first dose of study treatment [add reference for Fridericia formula]. For patients with a bundle branch block the QTcR will be calculated as based on study by Rataharju PM et al. Am J Cardiol 2004;93:1017-1021(see local site documents in ePRTCL). If QTcR is > 500 ms the patient will be eligible for the study.
  • 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.
• Pregnant or lactating females.
• Inability to swallow tablets.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• 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. Patients with Gleason 6 (3+3) prostate cancer with previous treatment or on active surveillance may also be allowed on protocol.
• The subject requires chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort).