• 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).

• Stratum 1 (IDH wild-type): Patients must be ≥ 3 years of age and ≤ 21 years of age at the time of enrollment.  Stratum 1 closed.
• Stratum 2 (IDH mutant): Patients must be ≥ 3 years of age and ≤ 25 years of age at the time of enrollment.
• Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1:
  • Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma;
  • Negative results for H3 K27M by immunohistochemistry (IHC);
  • Negative results for BRAFV600E mutation by next-generation sequencing (NGS).
• Patients must have histological verification of diagnosis.
• Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid (CSF) cytology is not required but may be obtained if clinically indicated prior to study enrollment. If cytology is positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• Pre-operative and post-operative brain magnetic resonance imaging (MRI) with and without contrast must be obtained. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. A spine MRI is not required, but may be obtained if clinically indicated. If the spine MRI is positive, the patient would be considered to have M+ disease (defined as neuraxis dissemination) and would be ineligible.
• Patients must have a performance status of ≥ 50 by Lansky or Karnofsky, corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but are up in a wheelchair will be considered ambulatory for the purposes of assessing the performance score.
• Peripheral absolute neutrophil count (ANC) ≥ 1,000/uL.
• Platelet count ≥ 100,000/uL (transfusion independent). 
• Hemoglobin ≥ 8.0 gm/dL (can be transfused). 
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:
  • 3 to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL);
  • 6 to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL); 
  • 10 to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL);
  • 13 to < 16 years: 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL);
  • ≥ 16 years: 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL).
• Adequate Liver Function defined as:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
  • SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function defined as:
  • Patients with seizure disorder may be enrolled if seizures are wellcontrolled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment).
• Patients with seizure disorder may be enrolled if seizures are well-controlled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment).
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive diagnostic surgery (Day 0). 
• All patients and/or their parents or legal guardians must sign a written informed consent .
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

• Patients with the following histologies: 
  • Diffuse astrocytoma (grade 2);
  • Oligodendrogliomas (any grade);
  • Pleomorphic xanthoastrocytoma (PXA, any grade). 
• Patients with primary tumor location of brainstem or spinal cord.
• Patients with M+ disease (defined as neuraxis dissemination either by imaging or by cytology).
• Patients must not have received any prior tumor-directed therapy including radiation therapy, chemotherapy (tumor-directed therapy), molecularly targeted agents, or immunotherapy for the treatment of HGG other than surgical intervention.
• Lumbar CSF cytology is not required, but may be performed if clinically indicated prior to study enrollment. If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible.
  • Note: False positive cytology can occur within 10 days of surgery.
• Patients with gliomatosis cerebri type 1 or 2. 
• Patients who are not able to receive protocol specified radiation therapy. 
• Patients must not be currently receiving other anti-cancer agents.
• Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD). 
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants. 
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months after the last dose of veliparib.

Eligibility last updated 9/28/21. Questions regarding updates should be directed to the study team contact.

• Histologically confirmed CD30-positive PTCL (most subtypes allowed) or TMF per the revised World Health Organization 2016 classification (Swerdlow, 2016).
  Note: Patients must wait for central results before first dose of study drug.
• Cohorts A and B (PTCL cohorts):
  • measurable by the modified Lugano Classification (Cheson, 2014);
  • measurable disease of ≥1.5 cm diameter by computed tomography (CT), assessed locally for eligibility.
    • Note: Confirmation by fluorodeoxyglucose (FDG) avid disease by positron emission tomography (PET) recommended, if possible.
• Cohort C (TMF cohort):
  • measurable by the Olsen Criteria (Olsen, 2011) including at least 1 cutaneous lymphoma lesion ≥2 cm in diameter, assessed locally for eligibility.

Patients must have relapsed or refractory disease AND the following: 

• Cohorts A and B (PTCL cohorts):
  • patients must have received at least 1 prior line of systemic therapy. For patients with systemic ALCL, patients must have failed or be intolerant to brentuximab vedotin [BV]; Adcetris®.
• Cohort C (TMF cohort):
  • patients must have received at least 1 prior line of systemic therapy; and have exhausted systemic therapies with full approval for their treatment of transformed mycosis fungoides 
• Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≥4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to first dose of study drug.
  Note: patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent to a single cutaneous lesion or single nodal region after discussion with the sponsor.
• Completion of an autologous hematopoietic stem cell transplantation at least 3 months prior to first dose of study drug (if applicable). 
• Resolution of any clinically significant previous therapy-related toxicity to ≤Grade 1 or to baseline if pre-existing condition (exception: patients with all grade alopecia and ≤Grade 2 peripheral neuropathy.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (Appendix B).
• Life expectancy ≥12 weeks.
• Adequate laboratory functional values. Note: transfusions and growth factors allowed during screening; however, transfusion-dependency defined as requiring blood products ≥once per week is not allowed.

• Patients with the following subtypes of lymphoma:
  • T-cell prolymphocytic leukemia;
  • T-cell large granular lymphocytic leukemia;
  • Chronic lymphoproliferative disorder of NK cells;
  • Aggressive NK-cell leukemia;
  • Extranodal NK-/T-cell lymphoma;
  • Indolent T-cell lymphoproliferative disorder of the GI tract.
  • Adult T-cell leukemia/lymphoma (ATLL)
• Current evidence of central nervous system involvement.
• Has had an allogenic tissue hematopoietic cell/solid organ transplant within the last 3 years. Note: Patients who have had a transplant >3 years ago are eligible as long as there are no signs/symptoms of graft versus host disease (GvHD).
• Requirement for chronic systemic immunosuppressive therapy <12 weeks prior to the first dose of study drug for prophylaxis or management of conditions such as GvHD (e.g. mycophenolate, methotrexate, calcineurin inhibitor-based therapy, steroid doses that would require prolonged tapering for discontinuation).
• Major surgery ≤4 weeks prior to first dose of study drug.
• Any active, concurrent, significant illness or disease (other than T-cell lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history, and/or physical examination findings that would preclude the patient from participation in the study such as:
  • active infection requiring systemic therapy ≤10 days before the first dose of study drug
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g. atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug
  • any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
  • active Hepatitis B or Hepatitis C. Antiviral prophylaxis for chronic Hepatitis B virus infection may be used at the discretion of the investigator.
• Diagnosis of Human Immunodeficiency Virus (HIV) i.e. presence of HIV 1/2 antibodies
• Diagnosis of immunodeficiency or requirement for systemic steroid therapy or any other form of immunosuppressive therapy (outside of samples already mentioned in Exclusion Criterion number 4) <7 days prior to the first dose study drug. Topical steroid creams for symptomatic relief for patients in Cohort C (TMF) are exceptions to this rule. Also, the use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor/Medical Monitor.
• Any other malignancy known to be active, with the exception of treated cervical intraepithelial neoplasia and non-melanoma skin cancer.
• General intolerance of any protocol medication or its excipients
• Patient´s inability to appreciate the nature, meaning and consequences of the trial and to formulate his/her own wishes correspondingly.
• Patient is unwilling to comply with the protocol; including the required biopsies and PK sampling.
• Prior treatment with AFM13.

• Age ≥ 18 years old.
• Histological confirmation of advanced biliary tract cancers including cancers originating in the gallbladder who have received at least one line of systemic anticancer therapy. Note: Patients who have either progressed on or are intolerant to the prior therapy can be included in this study.
• Measurable disease as defined by RECIST criteria.
  • 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) of 0 or 1).
• The following laboratory values obtained ≤ 21 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1500/mm3;
  • Platelet count ≥ 100,000/mm3;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
  • spartate transaminase (AST) or alanine transaminase (ALT) ≤ × ULN;
  • Creatinine ≤ 1.5 × ULN.
• Negative pregnancy test done ≤ days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood and tissue specimens for correlative research.

• Any of the following because this study involves an agent that has potential genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception for at least 3 months after the last dose of the study drug.
• 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.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• 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 ≤ 21 days prior to registration.
• Receiving any anticancer therapy for biliary tract cancer ≤ 21 days prior to registration.
• Other active malignancy requiring treatment in ≤ 6 months 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 prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Previous treatment with irinotecan or irinotecan-based chemotherapy for biliary tract cancers.

• Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. 
• Patients must have measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or splenomegaly with spleen >15 cm in craniocaudal dimension. 
• Age ≥ 60 years. 
• No intention to undergo consolidation with high dose chemotherapy and autologous stem cell rescue (Autologous Stem Cell Transplant) in first remission
• ECOG performance status of 0-2. 
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent. 
• Willing to provide mandatory tissue samples (if sufficient tissue available), bone marrow and blood samples for research purposes. 
• Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration: 
  • Absolute Neutrophil Count (ANC) ≥ 1000/mm³;
  • Hemoglobin ≥ 8 g/dL;
  • Platelets ˃75,000/mm³;
  • Creatinine clearance ≥ 40 mL/min, calculated with the use of 24-hour creatinine clearance or by Cockcroft-Gault formula;
  • Total Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) or ≤ 3 x ULN for patients with documented Gilbert's syndrome;
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5 x ULN. 
• All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration. 
• Women must not be pregnant or breastfeeding. Females of childbearing potential who are sexually active with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to study entry, for the duration of study participation, and for 12 months after last dose of therapy. Method of contraception must be documented. 
• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
• Corticosteroids used for other non-lymphomatous conditions will be allowed.
• Corticosteroids no greater than 1 mg/kg prednisone (or equivalent) given for ≤ 14 days will be allowed for treatment of lymphoma related symptoms.

• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma. 
• Patients must have no recent (< 1 year) history of malignancy except for the following:
  • adequately treated non-melanoma skin cancer;
  • adequately treated Stage I melanoma of the skin;
  • in situ cervical cancer;
  • low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation and stable for 6 months. 
• Patients should not have known evidence of central nervous system (CNS) lymphoma. 
• Patients must not have received a prior allogeneic stem cell transplant or solid organ transplant (except for cornea) for any indication. 
• Patients must have no active, uncontrolled infections. 
• Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This is defined as patients with hepatitis B surface antigen (HBsAg) positive. Patients with prior exposure to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND HBsAg negative) are allowed with a protective level hepatitis B surface antibody AND a negative hepatitis B viral load by polymerase-chain reaction (PCR). 
• Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load detectable by PCR. Patients with a negative HCV antibody are assumed to have a negative HCV viral load. Patients with a positive HCV antibody must have a negative hepatitis C viral load by PCR. Prior treatment for an active HCV infection will be allowed as long as the hepatitis C viral load by PCR is negative.
• Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not required in absence of clinical suspicion. 
• Patients must not have evidence of significant, uncontrolled concomitant diseases, including psychiatric diseases, that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient.
• Patients must not have conditions that preclude oral administration or absorption of medications through the GI tract, including but not limited to the inability to swallow pills or malabsorption syndromes. 
• Patients must not have known allergies to both xanthine oxidase inhibitors and rasburicase. 
• Patients must not require the use of warfarin. Blood thinners of other classes are permitted.
• Patient may not receive the following agents within 7 days prior to the first dose of venetoclax: 
  • Strong and moderate CYP3A inhibitors
  • Strong and moderate CYP3A inducers
  • Strong and moderate P-gp inhibitors 
• Patients must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.

• The subject must consent to take precautionary measures to prevent Newcastle Disease Virus (NDV) transmission to humans and birds.
• Subjects must have histologic documentation of advanced solid tumor and received and have progressed, are refractory, or are intolerant to standard therapy for the specific tumor type. All subjects are required to have had at least one prior line of treatment in the recurrent or metastatic setting.
• Subjects must have at least 1 measurable lesion.
• All subjects must consent to provide tumor tissue for correlative studies.
• ECOG performance status of 0 to 1.
• Adequate organ function.
• Use of highly effective contraception (females) or male condom plus spermicide (males).

• Rapidly progressing disease defined as a subject that cannot tolerate a break of at least 8 weeks from systemic anticancer therapy. 
• Primary central nervous system (CNS) disease is excluded.
• Subjects who have received prior immunotherapy will require varying washout times prior to the first dose of MEDI5395.
• Unresolved toxicities from prior anticancer therapy.
• History of severe allergic reactions to any of the study drug components.
• Infectious disease exclusions including tuberculosis, Human immunodeficiency virus (HIV), hepatitis A, B or C, active bacterial, fungal or viral infections plus receipt of live attenuated vaccine prior to first dose of MEDI5395.
• (NOTE: Subjects with hepatitis B/C with undetectable virus load and are on medications may be permitted). 
• Any conditions requiring use of any systemic immunosuppressant including systemic corticosteroids, methotrexate, azathioprine, tumor necrosis factor (TNF) inhibitor, and/or interleukin 6 (IL-6) blockers.
• Active autoimmune disease or chronic inflammatory condition (Exceptions include vitiligo, alopecia, hypothyroidism on stable treatment, diverticulosis, controlled celiac disease and chronic skin conditions not requiring systemic therapy).
• Active acquired immune-deficiency states.
• Subjects who are regularly exposed to poultry or birds.
• Current active hepatitis or biliary disease (except for Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease).
• Clinically significant pulmonary disease and cardiac disease.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

• Participant has documented NF1 mutation or a diagnosis of neurofibromatosis type 1 (NF1) using National Institute of Health (NIH) Consensus Conference criteria inclusive of the presence of a plexiform neurofibroma (PN). 
• Participant has a PN that is causing significant morbidity. 
• Participant has a PN that cannot be completely surgically removed.
• Participant has a target tumor that is amenable to volumetric MRI analysis. 
• Participant is willing to undergo a tumor biopsy pre- and end of treatment if ≥ 18 years of age. 
• Participant has adequate organ and bone marrow function.
• Participant can swallow capsules whole if the capsule dosage form is being utilized. This criterion does not apply if participant is utilizing the dispersible tablet dosage form of study treatment;

• Participant has abnormal liver function or history of liver disease.
• Participant has lymphoma, leukemia or any malignancy within the past 5 years (except for resected basal/squamous skin carcinomas without metastases within 3 years). 
• Participant has breast cancer within 10 years.
• Participant has active optic glioma or other low-grade glioma requiring treatment. 
• Participant has abnormal QT interval corrected or other heart disease within 6 months.
• Participant has a history of retinal pathology, risk factors for retinal vein occlusion or has a history of glaucoma. 
• Participant has known malabsorption syndrome or gastrointestinal conditions that would impair absorption of PD-0325901. 
• Participant has received NF1 PN-targeted therapy within 45 days. 
• Participant has received radiation therapy within 6 months or has received radiation to the orbit at any time. 
• Participant is unable to undergo or tolerate MRI.
• Participant has active bacterial, fungal or viral infection.
• Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year.

• Male and/or female.
• Age ≥ 18 years at the time of screening. For patients aged < 20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Confirmed HCC (by imaging or histopathologically from biopsy specimen).
• No evidence of extrahepatic disease on any available imaging.
• Disease not amenable to curative surgery or transplantation or curative ablation.
• Disease must be amenable to TACE and anticipated to require no more than 4 TACE treatments to treat sites of disease within a ≤ 16-week period (Permitted modalities are DEB-TACE or cTACE (using an emulsion of Lipiodol® and a permitted chemotherapeutic agent as per institutional practice, followed by embolizing agents).
• Child-Pugh score class A to B7.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment 10. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice. HBV antiviral therapy must be initiated prior to randomization and patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients must show evidence HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to starting IP. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomization. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
• Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according to the following mRECIST criteria:
  • Liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans; i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase;
  • Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥ 10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria “a,” “b,” “c,” and “f” may not be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count ≥1000/µL;
  • Platelet count ≥ 75000/µL;
  • Total bilirubin ≤ 2.0 × the upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × ULN;
  • Albumin ≥2.8 g/dL;
  • International normalized ratio ≤1.6;
  • 2+ proteinuria or less urine dipstick reading;
  • Calculated creatinine clearance (CL) ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine CL.
  • Males: Creatinine CL = Weight (kg) × (140
    •Age) (mL/min) 72 × serum creatinine (mg/dL);
  • Females: Creatinine CL = Weight (kg) × (140
    •Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL). 
• Must have a life expectancy of at least 12 weeks.
• Upper Endoscopy to evaluate varices and risk of bleeding is required within 6 months of randomization.
• Body weight >30 kg

• Any history of nephrotic or nephritic syndrome.
• Clinically significant (e.g., active) cardiovascular disease, including:
  • Unstable angina within ≤ 6 months of randomization;
  • New York Heart Association Grade ≥ 2 congestive heart failure;
  • Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG.
• Peripheral vascular disease Grade ≥ 3 (e.g., symptomatic and interfering with activities of daily living requiring repair or revision).
• Significant traumatic injury during 4 weeks prior to randomization.
• Known hereditary predisposition to bleeding or thrombosis; any prior or current evidence of bleeding diathesis.
• Systemic anticoagulation allowed, excluding Vitamin K antagonists.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization 
• Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require wound examinations every 3 weeks.
• History of abdominal fistula or GI perforation, nonhealed gastric ulcer that is refractory to treatment, or active GI bleeding within 6 months prior to enrollment.
• Patients who have had any kind of surgery in the past 28 days (biopsy from any type of surgery within 28 days is not an exclusion criteria. Nor are procedures to treat varices.) 
• Uncontrolled hypertension defined by a systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg, with or without antihypertensive medication. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose:
  • Patients with ascites that has required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months are eligible;
  • Major portal vein thrombosis visible on baseline/eligibility imaging, patients with Vp3 and Vp4 are excluded.
• Patients with infiltrative-type HCC.
• History of allogeneic organ transplantation.
• 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 [eg, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis]). 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 Study Physician;
  • Patients with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection (except for noted HBV or HCV as detailed above), symptomatic congestive heart failure, poorly controlled diabetes mellitus, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence;
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated carcinoma in situ without evidence of disease.
• History of leptomeningeal carcinomatosis.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (positive HIV 1/2 antibodies).
• Patients co-infected with HBV and hepatitis D virus (HDV). (HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA ≥ 10 IU/mL or above the limit of detection per local lab standard ; HDV positive infection is indicated by the presence of anti-HDV antibodies.)
• Any unresolved toxicity National Cancer Institute (NCI) CTCAE v 5.0 Grade ≥ 2 from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• History of allogeneic bone marrow transplant and active chronic graft versus host disease.
• Receipt of anti-PD-1, anti-PD-L1, or anti-CTLA-4 prior to the first dose of IP.
• Receipt of prior TACE, prior bland embolization, or prior radioembolization. Use of TACE or TAE as part of a curative therapy (e.g., in conjuntion with ablation or surgery) can be acceptable if it is used in the lesions where curative therapy was attempted. However, TACE or TAE cannot have been used as sole modalities in prior curative therapy.
• Receipt of prior systemic anticancer therapies for HCC.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 90 days after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of IP. Not engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.
• Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

• Age ≥ 18 years  old.
• Life expectancy of at least 2 months.
• ECOG Performance Status ≤ 2.
• Patients must be able to swallow capsules.
• Adequate hematologic parameters, unless cytopenias are disease caused.
• Adequate renal, liver and cardiac function parameters.

• Patients with GVHD requiring systemic immunosuppressive therapy.
• Uncontrolled leptomeningeal disease, auto-immune hemolytic anemia and uncontrolled and clinical significant disease related metabolic disorde.r 
• Clinically significant intravascular coagulation. 
• Treatment with other investigational drugs within 14 days prior to first study treatment administration.

Inclusion Criteria
•Part 1:

• Patients must be informed about the study and fully consent to participation as demonstrated by signing the written informed consent form (ICF) before any screening procedures.
• Male or female patients 18 years or older at the time of consent.
• Confirmed diagnosis of MM per the revised IMWG diagnostic criteria.
• Patients with RRMM who have failed treatment with, are intolerant to, or are not candidates for available therapies that are known to confer clinical benefit.
• Must meet all of the following criteria for prior therapy:
  • Must be refractory to ≥ 1 proteasome inhibitor (PI), ≥ 1 immunomodulatory drug (IMiD), and ≥ 1 steroid;
  • Must either have received ≥ 3 prior lines of therapy or ≥ 2 prior lines of therapy if 1 line included a combination of PI and IMiD (prior treatment with an anti-CD38 therapy is permitted).
• With measurable disease, defined as ≥ 1 of the following:
  • Serum M-protein ≥ 500 mg/dL (≥ 5 g/L) on serum protein electrophoresis (SPEP);
  • Urine M-protein ≥ 200 mg/24 h on urine protein electrophoresis (UPEP).
  • Serum FLC assay result with an involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) if serum FLC ratio is abnormal.
• Patients with serum M-protein, urine M-protein, or involved immunoglobulin FLC not meeting the measurable disease criteria above will be eligible if they have ≥ 1 of the following:
  • PET imaging with ≥ 1 plasmacytoma lesion with a single diameter of ≥ 2cm;
• • Bone marrow (BM) aspirate/biopsy with plasma cell percentage ≥ 30%
• With Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
• With normal QT interval corrected by the Fridericia method (QTcF) on screening electrocardiogram (ECG)[ QTcF of ≤ 450 millisecond (ms) in males or ≤ 470 ms in females].
• Must meet the following clinical laboratory criteria at entry:
  • Total bilirubin ≤1.5 x the upper limit of the normal range (ULN), except for Gilbert's syndrome (direct bilirubin must be < 2.0 x ULN);
  • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Estimated glomerular filtration rate (eGFR) ≥ 30 (mL/min/1.73 square meter [m^2]), using the modification of diet in renal disease (MDRD) equation;
  • Absolute neutrophil count (ANC) ≥ 1000 per cubic millimeter (/mm^3) (≥ 1.0*10^9 per liter [/L]); ≥ 750/mm^3 (≥ 0.75 x 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Platelet count ≥ 75,000/ mm^3 (≥ 75 x 10^9/L); ≥ 50,000/ mm^3 (≥ 50 X 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Hemoglobin ≥ 7.5 g/dL without transfusion within 7 days before the lab test;
  • Serum albumin ≥ 2.5 g/dL.
• Female patients who:
  • are postmenopausal for at least 1 year prior to screening; OR
  • are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug; OR
  • agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].
• Male patients, even if surgically sterilized (postvasectomy) who:
  • Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug; OR
  • Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods. Female and male condoms should not be used together].

Inclusion Criteria Part 2 (both RRMM and RRNHL patients):

• ECOG performance score of 0 or 1.
• Normal QTcF on screening ECG, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
• Must meet the following clinical laboratory criteria at study entry:
  • Total bilirubin ≤ 1.5 x the ULN, except for Gilbert's syndrome (direct bilirubin must be < 2.0 x ULN);
  • Serum ALT and AST ≤ 2.5 x ULN;
  • eGFR ≥ 30 mL/min/1.73 m^2(MDRD equation);
  • ANC ≥ 1000 mm^3 (≥ 1.0 x 10^9 /L); a count of ≥ 750/mm^3 (≥ 0.75 x 10^9/L) may be acceptable for participant with > 50% of plasma cells in BM;
  • Platelet count ≥ 75,000/ mm63 (≥ 75 x 10^9/L); a value of ≥ 50,000/ mm3(≥ 50 x 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Hemoglobin ≥ 7.5 g/dL without transfusion within 7 days before the lab test;
  • Serum albumin ≥ 2.5 g/dL.
• Female patients who:
  • are postmenopausal for at least 1 year prior to screening; OR
  • are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug; OR
  • agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].
• Male patients, even if surgically sterilized (postvasectomy) who:
  • Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug; OR
  • Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].

Inclusion Criteria Part 2 for RRNHL patients:

• Pathologically confirmed diagnosis of the following NHL subtype based on local pathology report:
  • Mantle cell lymphoma (MCL) - Nodal MCL;
  • Diffuse large B-cell lymphoma (DLBCL), DLBCL- NOS, Plasmablastic lymphoma (PbL), Primary effusion lymphoma (PEL),  Primary effusion lymphoma (PMBL);
  • Follicular lymphoma;
  • Burkitt lymphoma (BL);
  • Peripheral T-cell lymphoma (PTCL) - PTCL-NOS (eligible at MTD/RPTD if biopsy evidence of CD38 positivity), Angioimmunoblastic T-cell lymphoma (AITL);
  • Extranodal NK/T-cell lymphoma (ENKTL)-nasal type.
• RRNHL, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered standard of care (SOC) or are known to confer clinical benefit.
• At least 1 measurable site of disease according to the Lugano classification for lymphoma:
  • A measurable nodal lesion with longest diameter (LDi) greater than 1.5cm; OR
  • A measurable extranodal lesion with LDi greater than 1.0cm.
• Evidence of a CD38 positive tumor. Any of the following are acceptable:
  • Evidence of CD38 expression from most recent biopsy or blood sample [either flow cytometry (FCM) or immunohistochemistry (IHC)]; OR
  • The most recently archived tissue assessed for CD38 expression by IHC; OR
  • Fresh biopsy for CD38 expression assessment by IHC within 35 days of Cycle 1 Day 1; OR
  • Fresh blood sample with circulating NHL cells assessed by FCM within 35 days of Cycle 1 Day 1 (BM biopsy excisional lymph node biopsy, core biopsy of any involved organ are all acceptable methods, find needle aspirate is not. Any level of positive CD38 expression is eligible).

Inclusion Criteria Part 2 for RRMM patients:

• Confirmed diagnosis of MM per IMWG diagnosis criteria:
  • RRMM, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered SOC or are known to confer clinical benefit.
• Must meet the following criteria for prior therapy:
  • Refractory or intolerant to ≥1 PI and ≥ 1 IMiD;
  • Receipt of ≥ 3 prior lines of therapy or ≥ 2 prior lines of therapy if 1 of those lines included a combination of a PI or IMiD (prior treatment with anti-CD38 therapy is permitted except for patients enrolled in the anti-CD38 therapy naïve cohort);
  • Daratumumab RR cohorts: RR to daratumumab at any time during treatment. Patients RR to other anti-CD38 therapies are excluded;
  • Anti-CD38 therapy naïve cohort: must not have received any prior anti CD-38 therapy.
• Measurable disease, defined as ≥ 1 of the following:
  • Serum M-protein ≥ 50 mg/dL (≥ 5 g/L) on SPEP;
  • Urine M-protein ≥ 200 mg/24 hours on UPEP.;
  • Serum FLC assay result with and involved FLC level ≥ 10 mg/dL (≥ 100mg/L), provided the serum FLC ratio is abnormal.
• Serum M-protein, urine M-protein or involved immunoglobulin FLC not meeting measurable disease criteria if at least 1 of the following criteria is met:
  • BM aspirate/biopsy showing plasma cell percentage ≥ 30%;
  • PET imaging showing at least 1 plasmacytoma lesion with a single diameter ≥ 2 cm.

Exclusion Criteria for Part 1 (RRMM patients only):

• With polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or Immunoglobulin M (IgM) myeloma.
• With sensory or motor neuropathy of NCI CTCAE V5 Grade ≥ 3.
• Have received final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:
  • Myeloma-specific therapy, including PIs and IMiDs: 14 days;
  • Anti-CD38 (a) therapy: Isatuximab 90 days; daratumumab 60 days;
  • Corticosteroid therapy for myeloma: 7 days;
  • Radiation therapy for localized bone lesions: 14 days;
  • Major surgery:30 days;
  • Autologous stem cell transplant: 90 days;
  • Investigational therapy: 30 days.
• Have received an allogeneic stem cell transplant or organ transplantation.
• Have not recovered to Grade ≤ 1 or baseline, from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and Grade 2 neuropathy.
• With clinical signs of central nervous system (CNS) involvement of MM.
• With a history of myelodysplastic syndrome or another malignancy other than MM except for the following: any malignancy that has been in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥ 1 year before the start of study therapy.
• With known or suspected light chain amyloidosis of any organ (amyloid on the BM biopsy without other evidence of amyloidosis is acceptable).
• With any of the following cardiovascular conditions:
  • Congestive heart failure (NYHA) class ≥ II or left ventricular ejection fraction (LVEF < 40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening;
  • Resting tachycardia (heart rate of > 100 bpm) at screening;
  • Clinically significant uncontrolled hypertension at screening;
  • Cardiac MRI at screening demonstrates evidence of infiltrative disease of the myocardium.
• With a history of document significant pleural or pericardial effusions within 3 months before the start of treatment, including:
  • Pericarditis (any Grade);
  • Pericardial effusion (Grade ≥ 2);
  • Non-malignant pleural effusion (Grade ≥ 2);
  • Malignant pleural effusion (Grade ≥ 2).
• Patients with a history of noncardiogenic pulmonary edema associated with diffuse peripheral edema and a history of intravascular hypovolemia associated with systemic antineoplastic therapy.
• With chronic or active infection requiring systemic therapy, history of symptomatic viral infection that has not been fully cured.
  • With HIV and an undetectable viral load and CD4+ T-cell (CD4+) counts ≥ 350 cells/mL may be allowed but patient must be taking appropriate opportunistic infection prophylaxis if clinically relevant;
  • With positive HBV serology may be allowed if undetectable viral load, receiving antiviral prophylaxis for potential HBV reactivation per institutional guidelines;
  • With positive HCV serology may be allowed if quantitative PCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
• Have received a live attenuated vaccine within 28 days of first dose of MT-0169.
• With a history of ≥ Grade 2 systemic inflammatory response syndrome (SIRS)/ cytokine release syndrome (CRS) reactions following infusion with any monoclonal antibodies or Chimeric Antigen Receptor (CAR) T therapy.
• With a chronic condition requiring systemic corticosteroids at > 10 mg/day of prednisone or equivalent.
• Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or patients of reproductive potential who are not employing an effective birth control.
• With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
• With known allergy or intolerance to any of the drugs used in the study or excipients in the MT-0169 formulation.
• With a history of hypersensitivity or serious toxic reaction to kanamycin or another aminoglycoside.

Exclusion Criteria for Part 2 NHL patients only:

• With known CNS lymphoma (exception allowed if history of CNS disease and evidence of SD on neuroimaging separated in time by at least 4 weeks and within 4 weeks of Cycle 1 Day 1).   
• Have received a final dose of any of the following treatments/procedures within the following minimum interval before the first dose of MT-0169:
  • Nitrosoureas: 6 weeks;
  • Chemotherapy: 4 weeks;
  • Small molecules (< 0.9 kDa): 5 half-lives or at least 2 weeks:
  • Therapeutic antibodies: 4 weeks;
  • Radio/toxin -immunoconjugates: 12 weeks;
  • Radiation therapy to a target lesion (measurable disease): 4 weeks
  • Radiation therapy to a nontarget lesion (radiation therapy to non-target lesions may be permitted): 2 weeks
  • Investigational chemotherapeutic agents or antibodies: 4 weeks
  • Daratumumab: 60 days
  • Isatuximab: 90 days
  • (MCL) Bruton's tyrosine kinase inhibitors: 2 weeks or 5 half-lives, whichever is longer
  • Major surgery (determined by the principal investigator with the Sponsor): 4 weeks
  • Autologous stem cell transplant: 100 days
  • Allogenic stem cell transplant: 180 days (patients with graft vs host disease > Grade 1 will be excluded).
• With a history of myelodysplastic syndrome or malignancy (other than NHL) except for the following: any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥ 1 year before the start of study therapy.

Exclusion Criteria for Part 2 RRMM patients only:

• With POEMS syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, IgM myeloma.
• Have received a final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:
  • Myeloma-specific therapy, including PIs and IMiDs: 14 days;
  • Anti-CD38 therapy
    •Isatuximab: 90 days;
  • Anti-CD38 therapy
    •Daratumumab: 60 days;
  • Corticosteroid therapy for myeloma: 7 days;
• • Radiation therapy for localized bone lesions: 14 days;
  • Major surgery: 30 days;
  • Autologous stem cell transplant: 90 days;
  • Investigational therapy: 30 days.
• Have received an allogenic stem cell or organ transplant.
• With clinical signs of CNS involvement of MM.
• With a history of myelodysplastic syndrome or another malignancy other than MM except or any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for >1 year before the start of study therapy.
• With known or suspected light chain amyloidosis of any organ (amyloid on BM biopsy without other evidence of amyloidosis is acceptable).

Exclusion Criteria for Part 2 (both RRMM and NHL patients):

• Failed to recover to Grade ≤ 1 or baseline from adverse reactions to prior treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and stable Grade 2 neuropathy.
• With any of the following cardiovascular conditions:
  • Congestive heart failure (NYHA) class ≥ II LVEF < 40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening;
  • Resting tachycardia (heart rate of >100 bpm) at screening;
  • Clinically significant uncontrolled hypertension at screening;
  • Cardiac MRI at screening demonstrating infiltrative disease of the myocardium 12. With a history of documented significant pleural or pericardial effusions, specifically any of the following within 3 months before the start of study treatment:
  • Pericarditis (any grade);
  • Pericardial effusion (Grade ≥ 2);
  • Non-malignant pleural effusion (Grade ≥ 2); OR
  • Malignant pleural effusion (Grade ≥ 3).
• With a history of noncardiogenic pulmonary edema associated with peripheral edema and a history of intravascular hypovolemia associated with antineoplastic therapy.
• With chronic or active infection requiring systemic therapy and a history of symptomatic viral infection that is not fully controlled or cured. The following exceptions apply for those with positive serologies of HIV, HBV, or HCV:
  • With HIV and undetectable viral load and CD4+ T-cell (CD4+) counts ≥ 350 cells/mL may be enrolled, but must be taking appropriate opportunistic infection prophylaxis, if clinically relevant;
  • With positive HBV serology are eligible if they have an undetectable viral load and the patient will receive antiviral prophylaxis for potential HBV reactivation per institutional guidelines;
  • With positive HCV serology are eligible if qPCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
• Have received a live attenuated vaccine within 28 days of the first dose of MT-0169.
• With a history of Grade ≥ 2 SIRS/CRS reactions following infusion with any mAbs or CAR T therapy.
• With a chronic condition requiring systemic corticosteroids ≥ 10 mg/day of prednisone or equivalent.
• With a known allergy or intolerance to any of the drugs in the study or excipients in the MT-0169 formulation.
• Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or male or female patients of reproductive potential who are not employing effective birth control.
• With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
• With a history of hypersensitivity or serious toxic reactions to kanamycin or another aminoglycoside.

• Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic or is surgically unresectable. 
• Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area or in an area subjected to other loco-regional therapy are considered measureable if progression has been clearly demonstrated in the lesion. 
• Documentation of an FGFR1-3 gene mutation or translocation. 
• Objective progression after at least 1 prior therapy and no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit. 
• Eastern Cooperative Oncology Group performance status 0 to 2.
• Baseline archival tumor specimen (if < 12 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis. 
• Willingness to avoid pregnancy or fathering children.

• Prior receipt of a selective FGFR inhibitor in the past 6 months. 
• Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. 
• Cannot be a candidate for potentially curative surgery. 
• Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. 
• Radiation therapy administered within 2 weeks of enrollment/first dose of study treatment.
• Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). 
• Known additional malignancy that is progressing or requires active treatment. 
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues.
• Clinically significant or uncontrolled cardiac disease. 
• Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). 
• Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as elevated transaminases or cirrhosis; chronic HBV/HCV infection with no cirrhosis and no elevated transaminases is allowed). 
• Known HIV infection. 
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half-lives (whichever is longer) before the first dose of study drug/treatment. 
• Women who are pregnant or breastfeeding.

• Signed written informed consent granted prior to initiation of any study-specific procedures. 
• 18 years of age and older.
• For the dose escalation cohorts, relapsed or refractory subjects with a diagnosis of B-cell NHL, CLL/SLL and WM who have received at least two prior systemic therapies . Subjects must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Subjects with low grade lymphoma must be progressing and requiring treatment.. 
• For the expansion cohorts, the following criteria must be met:
  • Cohort A: Relapsed/Refractory (R/R) CLL/SLL subjects with at least 2 prior systemic therapies and previously treated with a covalent BTKi who must have a documented BTK mutation on C481 residue;
  • Cohort B: R/R CLL/SLL subjects who have failed or were intolerant to a BTKi with documentation of the absence of BTK mutation on C481 residue. In this study, intolerance to standard therapy is defined as having experienced a grade 3 or higher adverse event that was caused by the standard therapy and resulted in treatment discontinuation;
  • Cohort C: Richter's transformation subjects who have failed at least one prior therapy;
  • Cohort D: Follicular Lymphoma (FL) subjects who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A;
  • Cohort E: Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior systemic therapies;
  • Cohort F: Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior systemic therapies;
  • Cohort G: High-grade B-cell lymphoma subjects who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations;
  • Cohort H: Waldenström macroglobulinemia (WM) subjects who have failed at least 2 prior systemic therapies.
• Disease status requirement: 
  • For CLL subjects, symptomatic disease that mandates treatment (Hallek et al. 2018); 
  • For B-cell NHL subjects, measurable disease by imaging scan;
  • For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal (ULN). 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
• Good organ function:
  • Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection;
  • Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional ULN in subjects with documented Gilbert's syndrome);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN;
  • Platelet count ≥ 50,000/µL;
  • Absolute neutrophil count (ANC) ≥ 1000/µL;
  • Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
• For men and women of child-bearing potential, willing to use adequate contraception (e.g., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study.
• Female subjects of child-bearing potential must have a negative serum pregnancy test within 14 days of the first day of drug dosing.
• Ability to swallow oral medications without difficulty.

• Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 5 half-lives or four weeks (whichever is shorter) prior to treatment initiation, or oral therapy within 5 half-lives or one week (whichever is shorter) prior to treatment initiation. 
• Transformation of FL to a more aggressive subtype of lymphoma or grade 3b FL.
• Subjects currently being treated with the following drugs:
  • CYP 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin);
  • CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel);
  • CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin);
  • CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine, pimozide);
  • P-gp substrates with a narrow therapeutic index (such as digoxin)
    • Note: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a subject to be eligible for study enrollment. 
• Prior allogeneic bone marrow transplant. 
• Active central nervous system (CNS) involvement. 
• Pregnant or breast-feeding women. 
• Has significant, ongoing co-morbid conditions which would preclude safe delivery of the study drug. 
• Uncontrolled illness including but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, cardiac infarction in the past six months, and psychiatric illness that would limit compliance with study requirements. 
• QTc prolongation (defined as a QTc > 450 msecs) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation. 
• Active human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C infection. 
• Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the subject's safety or interfere with the evaluation of the safety of the study agent.
• History of prior cancer within < 1 year, except for basal cell or squamous cell carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.

• Patients at risk for HCC with either an imaging diagnosis of HCC by ceCT or ceMRI (LI-RADS 5) confirmed by a board-certified abdominal radiologist or biopsy-proven HCC confirmed by a hepatobiliary pathologist.
• No prior treatment for HCC.
• Subjects who may or may not be expected to undergo surgical resection of the hepatic lesion(s) and/or liver transplant.
• Male or female with age greater than 18 years.
• Patients with the capacity to give informed consent and willingness to provide a written consent.

• Subjects requiring emergent surgery for a ruptured/bleeding HCC.
• Bilirubin > 3.0mg/dL, which is a contraindication for Gadoxetate, the MRI contrast agent.
• Pregnant and/or breast-feeding subjects. A negative pregnancy test within 48 hours of the PET scan.
• Subjects with higher than the weight/size limitations of PET/MRI scanner.
• Subjects with contraindication to MRI including:
  • Subjects who have a heart pacemaker;
  • Subjects who have a metallic foreign body (metal sliver) in their eye, or who have an aneurysm clip in their brain;
  • Subjects who have implanted devices with magnets;
  • Subjects who have other implanted electronic devices;
  • Subjects who have deep brain stimulator;
  • Subjects who have vagal nerve stimulator.
  • Subjects with cochlear (ear) or auditory implants.
• Subjects with history of allergic response to radiocontrast media.
• Subjects with known history of claustrophobia.

Newly-Diagnosed

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
• Karnofsky performance status ≥ 60%. performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy.

Recurrent

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.

Newly-Diagnosed

• Received any prior treatment for glioma including:
  • Prior prolifeprospan 20 with carmustine wafer;
  • Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent;
  • Prior radiation treatment for GBM or lower-grade glioma;
  • Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Recurrent

• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy).
• Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

• Adult subjects with large B-cell lymphoma, including Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, Primary mediastinal large B-cell lymphoma (PMBCL), High-grade B-cell lymphoma (HGBL), and Diffuse large B-cell lymphoma (DLBCL) arising from Follicular lymphoma (FL).
• Subjects must have relapsed disease after 2 or more lines of systemic therapy, OR chemorefractory disease defined as the following: No response to first-line therapy, including the following: PD as best response to first therapy, SD as best response after ≥ 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP), with SD duration no longer than 6 months from the last dose of therapy, Note: Subjects who are intolerant to first-line chemotherapy are excluded OR No response to ≥ 2 lines of therapy, including the following: PD as best response to most recent therapy, SD as best response after ≥ 2 cycles of last line of therapy.
• Subjects must have received adequate prior therapy including at a minimum: Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and An anthracycline-containing chemotherapy regimen, Subjects with transformed FL must have chemorefractory disease after transformation to DLBCL.
• At least 1 measurable lesion according to the International Working Group (IWG) Lugano Classification {Cheson 2014}. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
• Magnetic resonance imaging of the brain showing no evidence of CNS lymphoma.
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists).
• Toxicities due to prior therapy must be stable and recovered to Grade ≤ 1 (except for clinically nonsignificant toxicities such as alopecia).
• Age 18 or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Additional Inclusion Criteria may apply.

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) or FL unless disease free for at least 3 years.
• History of Richter’s transformation of chronic lymphocytic leukemia.
• Autologous stem cell transplant (SCT) within 6 weeks of planned axicabtagene ciloleucel infusion.
• History of allogeneic stem cell transplantation.
• Prior CD19 targeted therapy or prior CAR T cell therapy.
• History of PAP.
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management. Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the Kite medical monitor.
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive) infection. A history of hepatitis B or hepatitis C infection is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Additional Exclusion Criteria may apply.

• Are ≥ 18 (or ≥ 20 in Japan and Taiwan or age legally considered to be an adult) years of age at the time of signing the informed consent. In Japan, a participant aged < 20 years of age but ≥ 18 years of age may participate if written informed consent from his/her parent or guardian is provided in addition to the participant’s written informed consent.
• Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC, including intrahepatic CCA, extrahepatic CCA, gallbladder cancer, and ampulla of Vater’s cancer. The histological origin of ampullary carcinomas (intestinal, pancreaticobiliary, or other) will be collected.
• Naïve to chemotherapy, immunotherapy, and interventional radiological treatment (transarterial chemo-embolization, transarterial embolization, transarterial infusion) for locally advanced or metastatic BTC. Participants whose disease has recurred ≥ 6 months after completion of neoadjuvant or adjuvant treatments will be considered eligible.
• Availability of tumor tissue (primary or metastatic) (fresh or archival biopsies) before the first administration of study intervention. Availability of tumor tissue is mandatory except for the safety run-in part. Brush cytology and cell blocks are not acceptable. Tumor tissue (fresh or archival) must be suitable for biomarker assessment as described in the Laboratory Manual.
• At least 1 measurable lesion according to RECIST 1.1. Participants in the safety run-in part do not require a measurable lesion at baseline.
• ECOG PS of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing.
• Life expectancy of ≥ 12 weeks, as judged by the Investigator.
•  Adequate hematological function defined by white blood cell count ≥ 2.0 × 10^9 /L with absolute neutrophil count ≥ 1.5 × 10^9 /L, lymphocyte count ≥ 0.5 × 10^9 /L, platelet count ≥ 100 × 10^9 /L, and hemoglobin (Hgb) ≥ 9 g/dL (participants may have been transfused) at study entry and at Week 1 Day 1 prior to dosing.
  • Previously transfused participants are allowed in the study with a stable Hgb of ≥ 9 g/dL at the time of study entry.
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase level ≤ 3.0 × ULN, and an alanine aminotransferase level ≤ 3.0 × ULN. For participants with liver involvement, aspartate aminotransferase ≤ 5.0 × ULN and alanine aminotransferase ≤ 5.0 × ULN are acceptable.
• Adequate renal function defined by an estimated creatinine clearance (CrCl) > 50 mL/min according to the Cockcroft-Gault formula or by measure of CrCl from 24-hour urine collection.
  • CrCl (mL/min) = (140-age) × weight (kg) / (72 × serum creatinine Cr[jaffe]);
  • If female, × 0.85 ;
  • If creatinine is measured by the enzymatic method, add 0.2 and use as Cr[jaffe] = 0.2 + Cr[enzyme].
• Albumin ≥ 2.8 g/dL.
• Adequate coagulation function defined as prothrombin time or international normalized ratio ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals (e.g., entecavir, tenofovir, or lamivudine; adefovir or interferon is not allowed) at study entry and with planned monitoring and management including baseline HBV DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and management according to appropriate labeling guidance of approved antiviral.
• Are male or female:
  • Male Participants Agree to the following during the intervention period and for at least 4 months after the last dose of study intervention (35 days corresponding to the time needed to eliminate any study interventions; e.g., 5 terminal half-lives plus 90 days for spermatogenic cycle):
    • Refrain from donating sperm PLUS, either:  Abstain from any activity that allows for exposure to ejaculate; OR
    • Use a male condom:  When having sexual intercourse with a woman of childbearing potential 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;
    • When engaging in any activity that allows for exposure to ejaculate.
  • Female participants are not pregnant or breastfeeding and at least 1 of the following conditions applies: Not a woman of childbearing potential; OR
  • If a woman of childbearing potential, agree to 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 study intervention(s), if using hormonal contraception:
    • Has completed at least one 4-week cycle of an oral contraceptive pill and has either had or has begun her menses; OR
    • Has used a depot contraceptive or extended-cycle contraceptive for at least 28 days and has a documented negative pregnancy test using a highly sensitive assay;
    • During the intervention period;
    • After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 65 days (time needed to eliminate any study interventions, eg, 5 terminal half-lives plus 30 days for a menstrual cycle), and as indicated in the respective label (Summary of Product Characteristics [SmPC]) for gemcitabine and cisplatin. Participants have to agree to the following:
      • Women of childbearing potential should refrain from donating eggs from the start of dosing until 2 months after discontinuing study intervention.
      • The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
    • Have a negative serum or highly sensitive urine pregnancy test, as required by local regulations, within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.
    • 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.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and this protocol.

• Previous and/or intercurrent cancers. With the exception of: curatively-treated cancers with no recurrence in > 3 years or early cancers treated with curative intent, including but not limited to cervical carcinoma in situ, superficial, noninvasive bladder cancer, basal cell carcinoma, squamous cell carcinoma in situ, or endoscopically resected gastrointestinal cancers limited in mucosal layer.
• Rapid clinical deterioration not related to malignancy which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures at study entry and at Week 1 Day 1 prior to dosing.
• Participants with symptomatic central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they are judged to have fully recovered from treatment.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• Significant acute or chronic infections including:
  • 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, but the 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 tuberculosis (presence of clinical symptoms, physical or radiographic findings of active tuberculosis).
    • Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage (PTBD). Participants with biliary obstruction should have adequate biliary drainage with no evidence of ongoing infection without antibiotics treatment at the time of enrollment as well as on Cycle 1 Day 1.
    • Active bacterial, fungal, or viral infection (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 prior to dosing.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
  • Participants with type 1 diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. 
  • Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg of prednisone or equivalent per day.
  • Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is acceptable.
• History of, or concurrent, interstitial lung disease.
• Known history of hypersensitivity reactions to bintrafusp alfa or its products or known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification ≥ Class II), or serious cardiac arrhythmia.
• Other severe, acute, or chronic medical conditions, including immune colitis, inflammatory bowel disease, immune pneumonitis, or psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for study intervention are also excluded.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Participants who are candidates for liver transplantation and who can receive the transplantation within a medically acceptable period.
• Concurrent treatment with nonpermitted drugs. Participants who have completed prior adjuvant therapy > 6 months prior to randomization are eligible.
• Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints), including but not limited to anti-PD-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, or anti-4-1BB antibody is not allowed, inclusive of localized administration of such agents.
• Prior therapy with any antibody/drug targeting TGFβ/TGFβ receptor.
• Radiation within 28 days other than focal palliative bone-directed radiotherapy.
• Systemic therapy with immunosuppressive agents within 7 days before the start of study intervention; or use of any investigational drug within 28 days before the start of study intervention.
• Live vaccine administration within 4 weeks of study intervention administration.
• Unable to tolerate CT or magnetic resonance imaging (MRI) in the opinion of the Investigator and/or allergy to contrast material.

Other Exclusions:

• Major surgery within 28 days before the start of study intervention (excluding prior diagnostic biopsy and stenting/PTBD for the purpose of releasing biliary tract obstruction).
• Pregnancy or breastfeeding.
• Known alcohol or drug abuse.
• Legal incapacity or limited legal capacity.

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab).
  • NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis.
• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase.
• Tumor block or a minimum of 5 unstained slides.
• Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
• Measureable disease by RECIST version 1.1.
• Post-menopausal defined as:
  • Age ≥ 55 years and 1 year or more of amenorrhea;
  •  Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL;
  • Surgical menopause with bilateral oophorectomy.
• ECOG performance status 0, 1 or 2.
• Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record. 
• Adequate organ function within 14 days of study enrollment defined as: 
• Hematology:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³;
  • Platelets ≥ 100,000/mm³;
  • Hemoglobin ≥ 8 g/dL.
• Biochemistry: 
  • Total Bilirubin within normal institutional limits.
  • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
  • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min.
• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e., peripheral neuropathy) is permitted. 
• A minimum time period must elapse between the end of a previous treatment and start of study therapy: 
  • 1 week from the completion of radiation therapy for brain metastases;
  • 4 weeks from the completion of chemotherapy or any experimental therapy;
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury).
• Voluntary written consent before any research related procedures or therapy.

• Known active CNS disease.
• If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery.
• Patients should be neurologically stable and requiring ≤ 10mg oral prednisone equivalence of steroids per day.
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2.
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity.
• Inability or unwilling to swallow study drug.
• Any gastrointestinal condition causing malabsorption or obstruction (e.g., celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e., black cohosh).
• Known hypersensitivity to exemestane or its excipients.
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment.
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval.
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane.

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab).
  • NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis.
• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase.
• Tumor block or a minimum of 5 unstained slides.
• Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
• Measureable disease by RECIST version 1.1.
• Post-menopausal defined as:
  • Age ≥ 55 years and 1 year or more of amenorrhea;
  •  Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL;
  • Surgical menopause with bilateral oophorectomy.
• ECOG performance status 0, 1 or 2.
• Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record. 
• Adequate organ function within 14 days of study enrollment defined as: 
• Hematology:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³;
  • Platelets ≥ 100,000/mm³;
  • Hemoglobin ≥ 8 g/dL.
• Biochemistry: 
  • Total Bilirubin within normal institutional limits.
  • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
  • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min.
• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e., peripheral neuropathy) is permitted. 
• A minimum time period must elapse between the end of a previous treatment and start of study therapy: 
  • 1 week from the completion of radiation therapy for brain metastases;
  • 4 weeks from the completion of chemotherapy or any experimental therapy;
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury).
• Voluntary written consent before any research related procedures or therapy.

• Known active CNS disease.
• If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery.
• Patients should be neurologically stable and requiring ≤ 10mg oral prednisone equivalence of steroids per day.
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2.
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity.
• Inability or unwilling to swallow study drug.
• Any gastrointestinal condition causing malabsorption or obstruction (e.g., celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e., black cohosh).
• Known hypersensitivity to exemestane or its excipients.
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment.
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval.
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane.

• Have active, relapsed or refractory AML. Active, relapsed or refractory AML is defined as any one of the following:
  • primary induction failure (PIF) after 2 or more cycles of therapy; or
  • first early relapse after a remission duration of fewer than 6 months; or
  • relapse refractory to salvage combination therapy; or
  • second or subsequent relapse (Schmid, 2006).
• Have documented CD45 expression by leukemic cells via flow cytometry (a “blast gate” on CD45 vs. side scatter analysis consist.nt with AML);
• Be ≥ 55 years of age.
• Have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea is allowed).
• Have a calculated creatinine clearance (Cockroft-Gault equation) > 50 mL/min.
• Have adequate hepatic function (direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), defined as ≤ 2 times the upper limit of normal [ULN]).
• Have a Karnofsky score ≥ 70.
• Have an expected survival of > 60 days.
• Have a central venous catheter line in place prior to study treatment administration.
• Have 8/8 allele-level, related or unrelated, HSC donor matching at human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and DRB1 with a donor who is medically cleared.
• Syngeneic donors that meet these criteria are allowed.
• Women of childbearing potential, be surgically sterile or agree to practice abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal, or combination oral contraceptive) through 1-year post transplant; Males who are sexually active with women of childbearing potential must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from time of screening through 12 weeks after last dose of study drug.
• Be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written Informed Consent.

Exclusion Criteria: 

• Have circulating HAMA noted on initial screening.
• Have received prior radiation to maximally tolerated levels to any critical normal organ.
• Have active leukemic central nervous system (CNS) involvement, as defined by any leukemic blasts detected in the cerebrospinal fluid (CSF) by morphology or flow cytometry and/or any chloromas detected by CNS imaging.
• Have previously received a HCT (includes both allogeneic and autologous HCT).
• Clinically significant cardiac disease (NYHA Class III or IV); clinically significant arrhythmia; i.e., ventricular tachycardia, ventricular fibrillation, or “Torsade de Pointes”. Myocardial infarction with uncontrolled angina within 6 months, congestive heart failure, or clinically significant cardiomyopathy.
• Have abnormal QTcF (> 450 milliseconds) after electrolytes have been corrected (at least two different ECG readings and at least 15 minutes between readings). Subjects with paced rhythm or prolonged QTcF may be exempt from this exclusion if considered eligible for transplant per treating physician clinical judgment, with optional cardiology consultation.
• Have current or prior positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C. Subjects who have positive HBV test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti- hepatitis B core protein (HBc) and positive antibody to the HBsAg (anti-HBs) are not excluded; Subjects who have positive hepatitis test results with adequate organ function as defined in the protocol are not excluded.
• Have active serious infection uncontrolled by antibiotics or antifungals.
• Have acute promyelocytic leukemia and the associated cytogenetic translocation t(15;17).
• Have active malignancy within 2 years of entry. Active malignancy is defined as those malignancies requiring treatment with anti-cancer therapy or in the event of indolent malignancies, having measurable disease.  Exceptions to this exclusion include:
  • myelodysplastic syndrome;
  • treated non-melanoma skin cancer;
  • completely resected Stage 0 or 1 melanoma no less than 1 year from resection;
  • carcinoma in situ or cervical intraepithelial neoplasia;
  • successfully treated organ-confined prostate cancer with no evidence of progressive disease based on prostate specific antigen (PSA) levels and are not on active therapy;
• Have a perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation.
• Currently receiving any other active investigational agents.