Phase 1a Escalation (Completed and now Closed)

• Histologically documented, advanced lymphoma after the failure of at least 2 prior therapies with at least one site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis). Additionally, subjects with NHL (indolent and aggressive B-cell lymphomas) should have failed CD20-targeted therapy.
• Adequate hematologic status (in the absence of transfusion and growth factor support for at least 28 days), defined as:
  • absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
  • platelets ≥ 75 x 109/L;
  • hemoglobin ≥ 10 g/dL.

Phase 1b Expansion (Selected Cohorts Currently Open for Parts 2 and 3)

• Advanced measurable malignancy documented by histology, cytology, flow cytometry, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) methodology in one of the following categories:
  • (closed) Small cell lung cancer (SCLC) (measurable disease by the Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.1).
  • Histologically documented, advanced lymphoma after the failure of at least 2 prior systemic therapies with at least one site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis). Additionally, subjects with CD20-positive NHL (indolent and aggressive B-cell lymphomas) should have failed CD20-targeted therapy:
    • Indolent B-cell lymphoma;
    • Aggressive B-cell lymphoma;
    • Classic Hodgkin lymphoma.
      • Patients with cHL should have failed at least one checkpoint inhibitor therapy before enrolling to the nivolumab combination cohort.　
    • Peripheral T-cell lymphoma ([PTCL] as defined by mature T- and NK-cell neoplasms per WHO and CTCL), having failed at least 1 prior systemic therapy. Subjects with PTCL must have at least 1 site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis).
    • CTCL (both MF and SS):
      • Failed at least 2 prior systemic therapies for CTCL. Systemic therapy does not include local radiation therapy or topical agents;
      • Malignancy is measurable per global CTCL criteria (Olsen, 2011);
      • History of histologically-documented diagnosis of CTCL stage IIB to IVB (Olsen, 2011).
    • (closed) B-cell or T-cell acute lymphoblastic leukemia (ALL):
      • First or greater bone marrow relapse from complete remission; or
      • Any bone marrow relapse after allogeneic transplant; or
      • Absence of complete remission after 2 induction attempts employing standard regimens; or
      • Ph+ B-ALL if subjects are intolerant to or ineligible to receive tyrosine kinase inhibitor therapy or have progressed after at least one line of this therapy.
    • (closed) CLL: subjects should have failed at least 2 prior therapies, including CD20-targeted therapy.
    • (closed) Multiple myeloma (MM): subjects should have failed at least 3 prior therapies, including an immunomodulatory drug (IMID) and proteasome inhibitor-based therapy and have measurable disease as defined as 1 or more of the following:
      • serum M-protein > 0.5g/dl; and/or
      • urine M-protein > 200 mg/24 hours; and/or
      • in subjects who do not meet these criteria, serum free light chains (FLC) > 100 mg/L (involved light chain) and abnormal ratio (FLC kappa/FLC lambda);
      • biopsy-proven plasmacytoma.
    • (closed) AML, with the exception of AML M3 using the French American British (FAB) classification (i.e., acute promyelocytic leukemia [APL]).
    • (closed) MDS of WHO classifications RAEB-1 (refractory anemia with excess blasts) and RAEB-2.
    • (closed) BCR/ABL1-negative myeloproliferative neoplasm (MPN) or myeloproliferative/myelodysplastic overlap neoplasm (MPN/MDS) per the revised 2016 WHO criteria, including:
      • chronic phase (CP) (defined as peripheral blood and bone marrow <10% blasts) primary myelofibrosis or post-essential;
        • if the diagnosis is Myelofibrosis-CP, must have Dynamic International Prognostic Scoring System (DIPSS) intermediate-2/high risk disease (Passamonti et al., 2010) and either be: 1) intolerant/resistant to ruxolitinib or 2) ineligible for ruxolitinib therapy, as determined by the treating Investigator.
      • accelerated phase/blast phase MPN (MPN-AP/BP) (defined as either a peripheral blood or bone marrow with ≥10% blasts);
        • if the diagnosis is MPN-AP/BP, must have progressive/resistant disease after treatment with a DNA methyl transferase 1 (DNMT1) inhibitor therapy (e.g. azacitidine or decitabine), as determined by the treating Investigator.
      • chronic myelomonocytic leukemia (CMML) -1 or 2 characterized by:
        • > 1x109/L monocytes and 2-19% blasts in peripheral blood or Auer rods; and
        • dysplasia in ≥1hematopoietic line and 5-19% marrow blasts or Auer rods.
      • (closed) Subjects with MPN or MPN/MDS must not be eligible to proceed with hematopoietic stem cell transplantation (HSCT) and must have:
        • for MPN, an indication to treat with cytoreductive drugs (e.g. hydroxyurea, anagrelide, interferon, ruxolutinib, etc.), according to the judgment of the treating physician;
        • for MPN, documentation of inadequate response or intolerance to first line therapy, which includes at least one cytoreductive drug (e.g. hydroxyurea, anagrelide, interferon, ruxolutinib, etc.);
        • for CMML, documentation of inadequate response or intolerance to first line therapy, which includes at least one hypomethylating agent.
• Hematologic status as follows (transfusions not permissible to achieve these levels within 14 days prior to the first dosing of study drug):
  • o ANC ≥1 x 109/L (not applicable to subjects with AML, ALL, MDS, or MPN/MDS);
  • o platelets ≥75 x 109/L (≥0 x 109/L if the patient has bone marrow involvement);
  • o hemoglobin ≥9 g/dL.

Phase 1b Expansion (Dose Optimization Part 4)

• Histologically confirmed diagnosis of CTCL (both Mycosis Fungoides and Sezary Syndrome):
  • Failed at least 2 prior systemic therapies for CTCL (systemic therapy does not include local radiation therapy or topical agents);
  • Malignancy is measurable per global CTCL criteria (Olsen, 2011);
  • History of histologically-documented diagnosis of CTCL stage IB to IVB (Olsen, 2011).
• Hematologic status as follows (transfusions not permissible to achieve these levels within 14 days prior to the first dosing of study drug):
  • ANC ≥ 1 x 109/L;
  • platelets ≥ 75 x 109/L;
  • hemoglobin ≥ 9 g/dL.

Both Phases

• Male or female 18 years of age or older.
• Availability of fresh or archived tumor tissue for immunohistochemical studies. Archival tissue may be used provided it was obtained subsequent to the last prior anti-cancer therapy. For subjects with SS, peripheral blood is acceptable.
• Relapsed or refractory disease that has previously progressed on, or is currently progressing on standard anticancer therapy or for whom no other approved conventional therapy exists.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Adequate coagulation function, defined as:
  • International Normalized Ratio (INR) < 1.5 x the upper limit of normal (ULN) for that laboratory;
  • partial thromboplastin time < 1.5 x ULN;
  • subjects receiving anticoagulation therapy must be on a stable dose with monitoring studies within therapeutic range per local institutional standards
• Adequate hepatic function, defined as:
  • total bilirubin < 1.5 x ULN unless considered due to Gilbert’s disease;
  • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 1.5 x ULN or < 3 x ULN with documented liver metastases.
• Adequate renal function, defined as estimated serum creatinine clearance > 30 mL/minute calculated using the Cockcroft-Gault equation.
• Recovery from the toxicities of previous anticancer drugs or radiotherapy to Grade 0 or 1 (or to baseline grade if condition was pre-existing).
• Commitment from male and female subjects of reproductive potential to use, from the time of screening through 60 days after the last dose of TTI-621, either:
  • one highly effective method of contraception, including hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants), intrauterine device (IUD) or intrauterine system (IUS), vasectomy, or tubal ligation; OR
  • at least 2 effective methods of contraception, including male condom, female condom, cervical cap, diaphragm, or contraceptive sponge; OR
  • abstain from sex during study participation and for 60 days after the last dose of TTI-621.

Both Phases

• (AML cohort closed) AML M3 by FAB classification (APL).
• Known, current central nervous system disease involvement or untreated brain metastases.
• Investigational agent or any anticancer drug within 14 days prior to planned start of treatment (with the exception of hydroxyurea in subjects with MPN, MPN/MDS, ALL or AML).
• Allogeneic transplant within 30 days prior to the planned start of treatment or subjects with active graft-vs-host disease with the exception of Grade 1 skin involvement.
• Prior anti-CD47 therapy, with the exception of prior TTI-621 therapy delivered intratumorally only.
• Major surgery within 28 days prior to planned start of treatment.
• Use of irreversible antiplatelet/anticoagulant agents within 7 days prior to planned start of treatment (except subjects with thrombocytosis where low dose aspirin is being used to reduce the risk of thrombosis); use of low dose aspirin (≤81 mg/day) and selected, reversible anticoagulants are permitted (low molecular weight heparin, heparin, warfarin and dabigatran).
• History of hemolytic anemia or bleeding diathesis.
• Uncontrolled infection requiring systemic antibiotics/antivirals/antifungals.
• Chronic use of systemic corticosteroids of more than 20 mg per day of prednisone or equivalent; enrollment of post-transplant subjects who are on corticosteroids for graft-vs-host disease prophylaxis requires approval of the Medical Monitor. CTCL patients who are on a stable dose of medium or low potency topical corticosteroids for at least 4 weeks prior to study entry may continue its use on study at the same dose.
• Known hypersensitivity to any component of study drug.
• Positive serum pregnancy test in females of child-bearing potential or current breastfeeding.
• Significant cardiovascular disease such as symptomatic congestive heart failure (New York Heart Association Class III or IV), symptomatic coronary artery disease, myocardial infarction within the last 6 months, unstable arrhythmia requiring treatment, unstable angina, or prolonged QTc interval > 480 milliseconds (Grade 2 or higher) (QTc interval calculation at the discretion of the Investigator).
• Active hepatitis B or C or a history of HIV infection.
• Other significant medical condition unrelated to the primary malignancy that would compromise subject’s safety or ability to comply with protocol requirements.
• Inability for the subject to complete protocol requirements, such as geographic considerations, psychiatric disorders, or other compliance concerns.
• Prior Grade 4 rituximab infusion-related reaction (rituximab combination arm only).
• Active autoimmune disease or history of autoimmune disease that might recur (nivolumab combination arm only); subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.

• POEMS syndrome requiring therapy, previously treated or untreated
• Plasma vascular endothelial growth factor (VEGF) > 2 x upper limit of normal (ULN)
• Presence of a plasma cell clone (any of the following):
  • Monoclonal protein in the serum or urine
  • Measurable light chains by free light chain assay
  • Measurable plasmacytoma
  • Monoclonal plasma cells in bone marrow
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2, or 3
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Platelet count (PLT) ≥ 75,000/uL
• Total bilirubin ≤ 2.0 mg/dL unless due to known Gilbert's disease
  • NOTE: If total bilirubin is > 2 mg/dL, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed
• Alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 x upper limit of normal (ULN)
• Creatinine clearance ≥ 30 mL/min/1.73 m^2 (as determined by Cockcroft-Gault equation)
• Negative serum pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only
  • NOTE: Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
• Birth control
  • Female patients of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
    • NOTE: Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male patients must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
    • NOTE: Abstinence is acceptable (for either males or females) if this is the established and preferred method of contraception for the subject
• Willing to adhere to the guidelines of the Revlimid REMS (formerly known as RevAssist) program
  • NOTE: The counseling must be documented
• Provide written informed consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Note: During the active monitoring phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
• No contraindication to be on a minimum of 81 mg aspirin a day (or other anticoagulant therapy as prescribed) for thromboembolism prophylaxis
• Willing to provide mandatory blood and bone marrow samples for research purposes
• Ability to complete questionnaire(s) by themselves or with assistance

• Recent prior chemotherapy:
  • Newly diagnosed patients (regardless of group); any prior chemotherapy for POEMS with the following exceptions:
    • Prior immunomodulators like azathioprine, cyclosporin, and/or corticosteroids are not exclusionary therapies if used for prior diagnosis of chronic inflammatory demyelinating polyneuropathy
    • Prior chemotherapy directed at a "myeloproliferative neoplasm" like hydroxyurea is not exclusionary
  • Previously treated patients (group 2)
    • Alkylators (e.g. melphalan, cyclophosphamide) ≤ 28 days prior to registration
    • Anthracyclines ≤ 28 days prior to registration
    • High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide), or proteosome inhibitors (e.g. ixazomib or bortezomib) ≤ 28 days prior to registration
• Requirement for concomitant high dose corticosteroids
  • EXCEPTION: Patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for adrenal insufficiency, rheumatoid arthritis, etc
• Receiving any other investigational agent, which would be considered as a treatment for the primary neoplasm
• Participation in other clinical trials, including those with other investigational agents not included in this trial, ≤ 30 days prior to registration and throughout the duration of this trial
• Prior refractoriness to proteasome inhibitor or immunomodulatory drugs (IMiD)
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• Other active malignancy ≤ 3 years prior to registration
  • EXCEPTIONS: Non-melanotic skin cancer, ductal carcinoma in-situ, 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
• 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, e.g. uncontrolled infection (infection requiring systemic antibiotic therapy or other serious infection ≤ 14 days prior to registration); or uncompensated heart or lung disease
• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
• Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort ≤ 14 days prior to registration
• History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Radiotherapy ≤ 14 days prior to registration
• Major surgery ≤ 14 days prior to registration
• Failure to fully recover (i.e. ≤ grade 1 adverse event [AE]) from the reversible effects of prior chemotherapy
• Known allergy to any of the study medications, their analogs, or excipients in the various formulations of any agent
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of the study drugs including difficulty swallowing
• Ongoing or active systemic infection or active hepatitis B or C virus infection

• Patients must have constitutional trisomy 21 (Down syndrome) or trisomy 21 mosaicism (by karyotype or fluorescence in situ hybridization [FISH])
• Patients with previously untreated de novo AML who meet the criteria for AML with ≥ 20% bone marrow blasts as set out in the World Health Organization (WHO) Myeloid Neoplasm classification
• Patients with cytopenias and/or bone marrow blasts who do not meet the criteria for the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20% marrow blasts are eligible if they meet the criteria for a diagnosis of myelodysplastic syndrome (MDS)
• Patients with a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention), who:
  • Are > 8 weeks since resolution of transient myeloproliferative disease (TMD) with ≥ 5% blasts, OR
  • Patients sho have an increasing blast count (≥ 5%) in serial bone marrow aspirates performed at least 4 weeks apart
• Children who have previously received chemotherapy, radiation therapy or any anti-leukemic therapy are not eligible for this protocol, with the exception of cytarabine for the treatment of TMD
• There are no minimal organ function requirements for enrollment on this study
  • Note: Previous cardiac repair with sufficient cardiac function is not an exclusion criteria
• Each patient's 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 subjects research must be met

• Patients with promyelocytic leukemia (French-American-British [FAB] M3)
• Prior therapy
  • Patients ≤ 30 days from the last dose of cytarabine used for treatment

• Histologically proven advanced MPM of biphasic or sarcomatoid histology. Biphasic MPM is defined using the World Health Organization's international histological classification of tumors as containing an epithelial and a sarcomatoid component with each component comprising at least 10% of the tumor
• Naïve to prior chemotherapy or immunotherapy (i.e., this is a first-line systemic therapy study).
• MPM tumor sample for determination of ASS1 status. ASS1-deficiency is not required for study entry at study start, but tumor sample for ASS1 status is required. This study will employ an adaptive biomarker-driven design with an interim analysis to be conducted at the end of the phase 2 portion. The interim analysis will evaluate the treatment effect of ADI PEG 20 in combination with pemetrexed and cisplatin on overall survival (OS) in the overall population (biphasic and sarcomatoid histology patients) and pre-defined subpopulation of biomarker-positive patients (ASS1-deficient subpopulation). Thus, ASS1 deficiency may be required for the phase 3 portion of the study, pending the interim analysis. ASS1-deficiency, demonstrated on tissue specimen (cytospin samples are not acceptable), will be defined in the laboratory manual. If archived tissue is not sufficient or not available, then tissue must be obtained by biopsy.
• Measurable disease as assessed by modified RECIST for MPM for thoracic disease and RECIST 1.1 for extra-thoracic disease.
• ECOG performance status of 0
  •1.
• Predicted life expectancy of at least 12 weeks.

• Radiotherapy (except for palliative reasons) the previous two weeks before.
• Ongoing toxic manifestations of previous treatments.
• Symptomatic brain or spinal cord metastases (patients must be stable for > 1 month post radiotherapy or surgery).
• Major thoracic or abdominal surgery from which the patient has not yet recovered.
• Serious infection requiring treatment with intravenous antibiotics at the time of study entrance, or an infection requiring intravenous therapy within 7 days prior.
• Known to be serologically positive for human immunodeficiency virus (HIV). Testing to determine possible infection status is not required.

Patients must meet all of the following inclusion criteria to be eligible for participation in this study:

• The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
• Age ≥ 18 years.
• Surgical or biopsy-proven diagnosis of WHO grade 3 AA.
• Received EBRT and temozolomide chemotherapy prior to first tumor progression or recurrence of WHO Grade 3 AA.
• First AA tumor progression or recurrence ≤ 6 months prior to randomization based on MRI using T2 hyperintensity, Gd-contrast enhancement, or both. To avoid enrollment of patients with glioblastoma, patients with Gd-contrast enhancing tumors will be eligible if there is no necrosis seen on MRI and any one of the following criteria is true:
  • Gd-contrast lesion margins are not clearly defined;
  • Gd-contrast lesions are only measurable in one dimension;
  • Gd-contrast lesion has two perpendicular diameters less than 10mm [1];
  • Gd-contrast lesion has two perpendicular diameters greater than 10 mm but less than 20 mm and lesion does not demonstrate central necrosis;
  • Recent histopathological confirmation of WHO grade 3 AA.
• Completion of EBRT ≥ 6 months prior to randomization.
• Stained, unstained slides or tumor tissue block(s) are available from their most recent tumor surgery are available for central histological confirmation.
• A patient whose AA tumor has progressed or recurred and has had another surgical resection prior to randomization will be eligible if a) pathology review confirms AA, and b) post-surgical MRI demonstrates measurable tumor on T2 FLAIR.
• If taking corticosteroids, must be on a stable or decreasing dose for at least 5 days prior to the screening MRI.
• Karnofsky Performance Status (KPS) score of ≥ 70.
• Off anticancer therapy for at least 4 weeks and recovered from any significant treatment-related toxicities to Grade ≤ 1 prior to randomization.
• Adequate recovery from any major surgery is required; at least 4 weeks must have elapsed from the time of any major surgery and must have recovered from all surgery-related toxicities to Grade ≤ 1 prior to randomization.
• Adequate hematologic function (ANC ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 10.5 gm/dL) within 14 days prior to randomization.
• Total bilirubin ≤ 1.5x upper limit of normal (ULN) within 14 days prior to randomization.
• Hepatic transaminases (AST and ALT) ≤ 2x ULN within 14 days prior to randomization.
• Adequate renal function (serum creatinine ≤ 1.5x ULN) within 14 days prior to randomization.
• Life expectancy ≥ 6 months.
• Female patients of childbearing potential must agree to utilize acceptable contraceptive methods from screening throughout the duration of the study period, and for 30 days following the last dose of study drug. Abstinence is an acceptable method of contraception. Otherwise, consistent and current use of 1 of the following methods of birth control is accepted: oral contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), tubal sterilization, Essure micro-insert system, or vasectomy in the male partner. Female patients must also refrain from egg donation and in vitro fertilization during treatment and until at least 30 days from the last dose of study drug.
• Male patients must agree to abstain from sexual intercourse or use an acceptable contraceptive method (e.g. condoms) from screening throughout the duration of the study period, and for 90 days following the last dose of study drug. Male patients must also refrain from sperm donation during treatment and until at least 90 days from the last dose of study drug.

Patients who meet any of the following exclusion criteria are not eligible for study participation:

• MRI defining progression is consistent with a diagnosis of glioblastoma or radiation necrosis.
• Patients who are considered to be refractory to EBRT and temozolomide but who have not progressed.
• Prior systemic therapy for recurrence of AA.
• Presence of extracranial or leptomeningeal disease.
• Prior lomustine use.
• History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 2 years prior to the first dose of study drug. Patients with non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia and organ-confined prostate cancer deemed by the Investigator to be at low risk of recurrence are not excluded.
• Active infection or serious intercurrent medical illness.
• Known to be HIV positive or to have an AIDS-related illness, active Hepatitis B Virus (HBV), or active Hepatitis C Virus (HCV).
• Poorly controlled seizures.
• Unable to undergo an MRI with contrast.
• Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class III or IV congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
• Malabsorption syndrome, history of resection of the stomach or small bowel, active ulcerative colitis or Crohn’s disease, or partial or complete bowel obstruction or other conditions that would be expected to alter the absorption or PK of study drugs.
• Receipt of any other anticancer therapy while receiving protocol-defined therapy.
• Concurrent use of any other investigational agent during the study or within 30 days prior to randomization.
• Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study.
• Pregnant or breastfeeding.

• Confirmed acute index (original venous thrombotic) event: lower extremity or upper extremity (jugular, innominate, subclavian, axillary, brachial) DVT, PE, splanchnic (hepatic, portal, splenic, mesenteric, renal, gonadal), or cerebral vein thrombosis for which the patient has received >= 180 days (but =< 365 days) of anticoagulant therapy prior to registration; the date, imaging modality, and location of index event will be required; the date of initiation and specific type of anticoagulants used will also be required
• Active cancer defined as metastatic disease and/or any evidence of cancer on cross-sectional or positron emission tomography (PET) imaging, cancer related surgery, chemotherapy or radiation therapy within the past 6 months Note: non-melanoma skin cancer does not meet the cancer requirement
• Life expectancy >= 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
• Hemoglobin >= 8 g/dL
• Platelet count >= 50,000/mm^3
• Alanine aminotransferase (ALT) or aspartate transaminase (AST) =< 3 x upper limit of normal (ULN)
• Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft-Gault formula
• Negative serum or urine pregnancy test done =< 7 days prior to registration, for women of childbearing potential only; Note: a woman of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal; menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes
• Ability to provide informed written consent
• Willing to undergo monthly follow-up assessment, either in person at the enrolling institution or by telephone

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
    • Note: women of child bearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 33 days after finishing the last dose
    • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 93 days after finishing the last dose
    • Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements; however they must still undergo pregnancy testing as described in this section

Note: investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception; at a minimum, subjects must agree to the use of one method of highly effective contraception as listed below:

• Male condoms with spermicide
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner
• Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception
• Intrauterine device (IUDs), such as ParaGard
• Tubal ligation
• Vasectomy.
• Complete abstinence
  • Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs; acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence
    • Active major bleeding
    • Severe hypersensitivity reaction to apixaban (e.g., anaphylactic reactions)
    • Current use of strong CYP3A4 inducers or inhibitors NOTE: patients may be eligible if they transition to an alternative agent or are able to stop CYP3A4 inducer or inhibitor
    • Current use of thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor) that will be continued on study
    • Severe liver disease (known cirrhosis Childs Pugh class B or C), or active hepatitis
    • Documented venous thromboembolism while on therapeutic anticoagulation ("anticoagulation failure")
    • Mechanical heart valve
    • Documented hemorrhagic tendencies (e.g., hemophilia)
    • Bacterial endocarditis
    • Any of the following conditions:
• Intracranial bleeding =< 6 months prior to randomization
• Intraocular bleeding =< 6 months prior to randomization
• Gastrointestinal bleeding and/or endoscopically proven ulcer =< 6 months prior to randomization
• Head trauma or major trauma =< 1 month prior to randomization
• Neurosurgery =< 2 weeks prior to randomization
• Major surgery =< 1 week prior to randomization
• Gross hematuria at the time of randomization

• Have histologically and/or cytologically documented adenocarcinoma of the colon or rectum, which is metastatic and/or unresectable
• Unless otherwise contraindicated, subjects must have received and failed regimens containing the following agents: fluoropyrimidines (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF mAb (bevacizumab, ramucirumab, or ziv-aflibercept), and an anti-PD-(L)1 therapy (nivolumab or pembrolizumab) if the tumor has dMMR proteins or is MSI-H.
• Have progression of unresectable or mCRC after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.
• Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS testing including KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146), and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146).
• Subjects must be willing and able to provide the most recently available tissue blocks (or slides, with Medical Monitor’s approval), obtained prior to treatment initiation, to a sponsor-designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor lesion is required.
• Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Amendments (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory, meeting at least one of the following criteria: a. HER2+ overexpression (3+ immunohistochemistry [IHC]) by an FDA-approved or Conformité Européenne (CE)-marked HER2 IHC test following the package insert’s interpretational manual for breast cancer b. HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked HER2 in situ hybridization assay (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) following the package insert’s interpretational manual for breast cancer c. HER2 (ERBB2) amplification by CLIA-certified or ISO-accredited Next Generation Sequencing (NGS) sequencing assay.
• Age ≥ 18 years at time of consent.
• Have radiographically measurable disease assessable by RECIST 1.1, with at least one site of disease that is measurable and that has not been previously irradiated; or, if the subject has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2.
• Life expectancy greater than 3 months, in the opinion of the investigator.
• Have adequate hematological, hepatic, renal, coagulation, and cardiac function as defined below, obtained ≤ 7 days prior to the first study treatment:
  • Absolute neutrophil count (ANC) ≥ 1.0 × 103 /µL;
  • Platelet count ≥ 75 × 103 /µL;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤1.5 × upper limit of normal (ULN). Subjects with known history of Gilbert’s Syndrome and normal direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are eligible;
  • AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastases are present);
  • Calculated creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula;
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless on medication known to alter INR and/or aPTT;
  • Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan documented ≤ 28 days prior to study treatment.
• For subjects of childbearing potential, the following stipulations apply:
  • Must have a negative serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of study treatment. A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation;
  • Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study drug administration;
  • Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of study drug administration;
  • May choose to practice complete abstinence, if consistent with the subject’s preferred lifestyle, as an acceptable form of contraception;
  • If sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control, as defined in APPENDIX C starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.
• For subjects who can father children, the following stipulations apply:
  • Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 7 months after the final study drug administration;
  • If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control, as defined in APPENDIX C, starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug;
  • If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.
• Subject must provide signed informed consent that has been approved by an institutional review board/independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the subject’s disease.
• Subject must be willing and able to comply with study procedures.

• Have previously been treated with anti-HER2 targeting therapy 2. Have received treatment with any systemic anticancer therapy (including hormonal and biologic therapy), non-central nervous system (CNS) radiation, or experimental agent ≤3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial.
• Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
  • Alopecia and neuropathy, which must have resolved to ≤ Grade 2;
  • Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely;
  • Anemia, which must have resolved to ≤ Grade 2;
  • Decreased ANC, which must have resolved to ≤ Grade 2 4.
• Have clinically significant cardiopulmonary disease such as:
  • Ventricular arrhythmia requiring therapy;
  • Symptomatic hypertension or uncontrolled asymptomatic hypertension, as determined by the investigator
  • Any history of symptomatic CHF, left ventricular systolic dysfunction or decrease in ejection fraction;
  • Severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen therapy;
  • Presence of ≥ Grade 2 corrected QT interval (QTc) prolongation on screening electrocardiogram (ECG).
• Have known myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to first dose of study treatment.
• Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days prior to enrollment (≤ 56 days for hepatectomy, open thoracotomy, or major neurosurgery) or anticipation of need for major surgical procedure during the course of the study.
• Serious, non-healing wound, ulcer, or bone fracture.
• Known to be positive for hepatitis B by surface antigen expression.
• Known to have active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
• Known to be positive for human immunodeficiency virus (HIV).
• Subjects who are pregnant, breastfeeding, or planning a pregnancy.
• Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
• Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment.
• Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures.
• History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥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).
• Subjects with known active CNS metastasis (irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days).
• Have a hypersensitivity to tucatinib or any of its excipients, to trastuzumab or any of its excipients, or to murine proteins.

• Participants must have histologically confirmed invasive breast cancer. All histologic subtypes are eligible.
• Patients must have known ER, PR, and HER2 status defined as triple-negative breast cancer (TNBC), defined as:
  • --ER and PR <10% by immunohistochemistry, and HER2-negative ( as per ASCO/CAP guidelines, defined as IHC 0 or 1+, or FISH ratio <2.0 or HER2 copy number <6.0).
• Patients must have the clinical diagnosis of inflammatory breast cancer involving an intact breast.
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ruxolitinib in participants <18 years of age, children are excluded from this study.
• ECOG performance status 0 or 1.
• Participants must have normal organ and marrow function as defined below:
  • Leukocytes ≥ 3,000/mm3;
  • Absolute neutrophil count ≥ 1,500/mm3;
  • Platelets ≥ 100,000/mm3;
  • Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN);
  • AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal;
  • Creatinine ≤1.5 x institutional upper limit of normal OR creatinine clearance > 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.
• Patients must be without evidence of visceral or bone involvement with metastatic cancer on physical exam or any diagnostic study. Extensive nodal involvement is allowed.
• Both men and women are allowed.
• The effects of ruxolitinib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry until completion of chemotherapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.
• LVEF > 50% calculated by echocardiogram (ECHO) or MUGA
• Patients may have bilateral breast cancer so long as one breast meets criteria for inflammatory breast cancer, and neither breast cancer has received prior therapy

• Participants may not be receiving any other investigational agents.
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib.
• Participants receiving any medications or substances that are potent inhibitors of CYP3A4, including grapefruit juice are ineligible. Participants receiving fluconazole are also ineligible. (Please refer to Appendix B for the full list of potent inhibitors and washout periods).
• Chronic corticosteroid use in excess of the equivalent of prednisone 10 mg once daily.
• 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.
• Pregnant women are excluded from this study because paclitaxel, doxorubicin, and cyclophosphamide have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study. These potential risks may also apply to other agents used in this study.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Known HIV-positive individuals on combination antiretroviral therapy are eligible so long as they meet all other criteria. Known HIV-positive individuals who are not on combination antiretroviral therapy are not eligible because these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Clinically significant malabsorption syndrome.
• Patients may not have received paclitaxel, doxorubicin, or cyclophosphamide as anti-neoplastic therapy.
• Patients with prior radiation to the affected breast.

Core

• Signed written informed consent.
• Age ≥ 18 years old.
• Histologically or cytologically confirmed solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
• Docetaxel monotherapy is a reasonable treatment in the judgement of the Investigator.
• Able to swallow oral medication as an intact dosage form.
• Adequate hematologic status as demonstrated by not requiring transfusion support or granulocyte-colony stimulating factor (G-CSF) to maintain an absolute neutrophil count (ANC) ≥ 1500 cells/mm^3, platelet count ≥ 100 x 10^9/L, or hemoglobin (Hgb) ≥ 9 g/dL.
• Adequate liver function as demonstrated by a total bilirubin of < upper limit of normal (ULN), aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × ULN, alkaline phosphatase (ALP) ≤ 2.5 x ULN or < 5 x ULN if bone metastases are present, and normal serum albumin.
• Adequate renal function as demonstrated by serum creatinine ≤ 1.5 x ULN or creatinine clearance>60 mL/min as calculated by the Cockroft and Gault formula.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Life expectancy of at least 3 months.
• Willing to fast for 6 hours before and 2 hours after Oradoxel administration.
• Sexually active male subjects including men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) must agree to use a condom with spermicide and to not donate sperm from the time of screening until 6 months after the last dose of study drug.

Core

• Currently taking a prohibited concomitant medication, other than a premedication, that are/is:
  • Strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin or St. John's Wort) of CYP3A45 (within 2 weeks prior to the start of dosing in the study);
  • Strong P-gp inhibitors or inducers.  Subjects who are taking such medications but who are otherwise eligible may be enrolled if they discontinue the medication ≥ 1 week before dosing and remain off that medication through the end of PK sampling after the administration of the second study treatment;
  • An oral medication with a narrow therapeutic index known to be a P-gp substrate within 24 hours prior to start of dosing in the study.
• Unresolved toxicity from prior chemotherapy (subjects must be recovered to ≤ Grade 1 toxicity from previous anticancer treatments or previous investigational products.
• Planning to receive other medical, surgical, or radiological cancer treatments during the course of this study.
• Received investigational agents within 14 days or 5 half-lives prior to the first study dosing day, whichever is longer.
• Require therapeutic use of anticoagulants.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant myocardial infarction within the last 6 months, unstable angina pectoris, clinically significant cardiac arrhythmia, bleeding disorder, chronic pulmonary disease requiring oxygen, or psychiatric illness/social situations that would limit compliance with study requirements.
• Major surgery to the upper gastrointestinal (GI) tract, or have a history of GI disease or other medical condition that, in the opinion of the Investigator, may interfere with oral drug absorption.
• A known history of allergy to docetaxel, Cremophor or polysorbate 80 (Tween 80).
• Evidence of fluid retention at screening (including, for example, peripheral edema, pleural effusion, or ascites on physical or radiological examination) or history of severe capillary leak syndrome.
• Any other condition which the Investigator believes would make participation in the study not acceptable.

Module 1

In addition to the Core Inclusion Criteria listed above, subjects with solid malignancies other than mCRPC must meet the following criteria to be included in Module 1:

• Subjects have measurable disease as per RECIST v1.1 criteria or evaluable disease.
• Women of non-child bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause (ie, no menstrual bleeding for more than 12 months in a woman aged ≥ 45 years), OR women of childbearing potential who test negative for pregnancy at time of enrollment based on serum pregnancy test must be using a highly effective method of contraception from the time of Screening until 6 months following the last dose of study drug.
  • Note: Highly effective methods of contraception that result in a low failure rate (i.e., <1% per year) when used consistently and correctly include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence.
    True abstinence, when in line with the preferred and usual lifestyle of the subject, is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of study participation and for 6 months post- Oradoxel administration. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation method) and withdrawal are not acceptable methods of contraception.

Module 1

• There are no exclusion criteria in addition to the Core Exclusion Criteria listed above.

Module 2

• In addition to the Core Inclusion Criteria listed above, subjects with mCRPC must meet the following criteria to be included in Module 2:
  • Subjects have measurable or evaluable mCRPC as per modified RECIST 1.1 based on PCWG3 criteria;
  • Subjects have a minimum PSA of 2.0 ng/mL.

Module 2

• In addition to the Core Exclusion Criteria listed above, subjects who meet the following criterion will be excluded from the study:
  • Subjects who have had prior treatment with taxanes.

• Feasibility Phase: Patients must be < 21 years of age at the time of enrollment
• Efficacy Phase: Patients must be < 40 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification, are eligible to enroll on the study based upon stage, group, and age, as below
• RMS types included under embryonal rhabdomyosarcoma (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2013 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant); classification of alveolar rhabdomyosarcoma (ARMS) in the 2013 WHO classification is the same as in the ICR and includes classic and solid variants
  • ERMS
    • Stage 1, group III (non-orbit)
    • Stage 3, group I/II
    • Stage 2/3, group III
    • Stage 4, group IV, < 10 years old
  • ARMS:
    • Stages 1-3, groups I-III
• Specimen Submission: Patients must have sufficient tissue available for the required biology studies
• Lansky performance status score ≥ 50 for patients ≤ 16 years of age; Karnofsky performance status score ≥ 50 for patients > 16 years of age
• Peripheral absolute neutrophil count (ANC) ≥ 750/uL
• Platelet count ≥ 75,000/uL
• 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:
  • 1 month to < 6 months old: 0.4 mg/dl (male), 0.4 mg/dl (female)
  • 6 months to < 1 year old: 0.5 mg/dl (male), 0.5 mg/dl (female)
  • 1 to < 2 years old: 0.6 mg/dl (male), 0.6 mg/dl (female)
  • 2 to < 6 years old: 0.8 mg/dl (male), 0.8 mg/dl (female)
  • 6 to < 10 years old: 1 mg/dl (male), 1 mg/dl (female)
  • 10 to < 13 years old: 1.2 mg/dl (male), 1.2 mg/dl (female)
  • 13 to < 16 years old: 1.5 mg/dl (male), 1.4 mg/dl (female)
  • ≥ 16 years old: 1.7 mg/dl (male), 1.4 mg/dl (female)
  • Patients with an elevated serum creatinine due to obstructive hydronephrosis secondary to tumor are still eligible; however, patients with urinary tract obstruction by tumor must have unimpeded urinary flow established via diversion (ie. percutaneous nephrostomies or ureteric stents) of the urinary tract
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
• 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
• FOXO1 Fusion Status:
  • All patients will undergo institutional pathology review and FOXO1 fusion determination; FOXO1 status results must be available by week 3 (day 21) of therapy; patients will be eligible to remain on protocol therapy based upon stage, group, and age:
    • FOXO1 fusion negative:
      • Stage 1, group III (non-orbit)
      • Stage 3, group I/II
      • Stage 2/3, group III
      • Stage 4, group IV, < 10 years old
    • FOXO1 fusion positive:
      • Stage 1-3, group I-III Note: FOXO1 fusion status must be performed at local institutions
• Patients with institutional histologic classification of ARMS but FOXO1 fusion negative with the following stage and group can remain on study but will receive VAC/VA therapy on Regimen C instead of the previously assigned treatment regimen; patient consent is required to transfer to Regimen C
  • Stage 1, group I/II
  • Stage 1, group III (orbit)
  • Stage 2, group I/II

• Patients who have previously received TORI, another mTOR inhibitor, or any other investigational agent
• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy prior to this enrollment
• Patients with uncontrolled hyperglycemia
• Patients with uncontrolled hyperlipidemia
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for at least 3 months after treatment is completed if sexually active with reproductive potential
• Female patients who are pregnant are not eligible; Note: a pregnancy test is required for female patients of childbearing potential prior to study entry
• Lactating females who plan to breastfeed their infants are not eligible

• Diagnosis of malignant disease of any stage (Stage I through Stage IV).
• No prior history of chemotherapy for any malignancy
• Scheduled to receive intravenous HEC (Highly Emetogenic Chemotherapy) (either cisplatin-containing regimen or doxorubicin and cyclophosphamide [AC]).
  • Cisplatin, given on a single day, at a dose of ≥ 70 mg/m2, with or without other chemotherapy agent(s); or 
  • Doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2).
• No nausea or vomiting ≤ 24 hours prior to registration.
• Negative pregnancy test (serum or urine) done ≤ 7 days prior to registration, for women of childbearing potential only. A female of childbearing potential is a sexually mature female who:
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• No known diagnosis of dementia. Patients with stable treated brain metastases are eligible to participate.
• No known history of CNS disease (e.g., seizure disorder).
• No treatment with another antipsychotic agent such as olanzapine, risperidone, quetiapine, clozapine, phenothiazine or butyrophenone ≤ 30 days prior to registration.
• No chronic phenothiazine administration as an antipsychotic agent (patients may receive prochloperazine and other phenothiazines as rescue anti-emetic therapy but not within 24 hours prior to registration).
• No use of amifostine within 7 days prior to registration.
• No radiotherapy within 7 days prior to registration or planned for one week after the current dose of chemotherapy.
• No use of quinolone antibiotic therapy within 7 days prior to registration.
• No chronic alcoholism (as determined by the investigator).
• No known hypersensitivity to olanzapine.
• No known uncontrolled cardiac arrhythmia, no known uncontrolled congestive heart failure, or no acute myocardial infarction within the previous six months.
• No history of uncontrolled diabetes mellitus, i.e., no diabetic ketoacidosis; within 6 months prior to registration. Patients are eligible if they have controlled diabetes on diet, oral agents, and/or insulin.
• Age ≥ 18 years old
• ECOG Performance Status 0, 1 or 2.
• Patients must be able to read and comprehend English. Local translation, including verbal translation of PROs is not permitted.
• Required Initial Laboratory Values ≤120 days prior to registration Serum Creatinine ≤ 2.0 mg/dL .
• AST or ALT ≤ 3 x upper limit of normal (ULN).

• Any non-compliance with Inclusion Criteria above.

• Patients must have a histopathologically confirmed diagnosis of an aggressive B-cell non-Hodgkin lymphoma that is recurrent or refractory to standard therapy.
• For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma belonging to one of the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms (Swerdlow et al., 2016).
• For the purposes of stratification, diagnoses are grouped into 2 categories:
• Category A
  • Burkitt lymphoma;
  • Burkitt-like lymphoma with 11q aberration;
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements;
  • High-grade B-cell lymphoma, NOS.
• Category B
  • Diffuse large B-cell lymphoma (DLBCL), NOS;
  • Diffuse large B-cell lymphoma (DLBCL), NOS; Germinal center B-cell type;
  • Diffuse large B-cell lymphoma (DLBCL), NOS; Activated B-cell type;
  • Large B-cell lymphoma with IRF4 rearrangement;
  • T-cell/histiocyte-rich large B-cell lymphoma;
  • Primary DLBCL of the central nervous system (CNS);
  • Primary cutaneous DLBCL, leg type;
  • EBV+ DLBCL, NOS;
  • EBV+ mucocutaneous ulcer;
  • DLBCL associated with chronic inflammation;
  • Lymphomatoid granulomatosis;
  • Primary mediastinal (thymic) large B-cell lymphoma;
  • Intravascular large B-cell lymphoma;
  • ALK+ large B-cell lymphoma ;
  • Plasmablastic lymphoma;
  • Primary effusion lymphoma;
  • HHV-8+ DLBCL, NOS;
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin 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 measureable in two perpendicular dimensions per computed tomography (spiral CT), PET-CT or MRI.
• Patients must have disease that has relapsed after or is refractory to at least 2 lines of standard therapy; the remaining standard treatment options are unlikely to be effective in the opinion of the treating physician, or patient is felt to be ineligible for such therapies or the patient refuses such therapies; patients who have undergone autologous stem cell transplant are eligible as long as they meet all other criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
• Life expectancy of greater than 12 weeks
• White blood cell (WBC) ≥ 2000/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 (aspartate aminotransferase [AST]) ≤ 2.5 x ULN. 
• Calculated creatinine clearance (CrCl) ≥ 50 mL/min (if using the Cockcroft-Gault formula). 
• Negative urine or serum pregnancy test result for females of child bearing potential; 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 23 weeks 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 31 weeks 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 half-lives plus 30 days and males who are the sexual partners of females of child-bearing potential use contraception for 5 half-lives plus 90 days.
• Females must not be breast-feeding. 
• 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.

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or at least 5 half-lives, whichever is longer, prior to entering the study. 
• Palliative (limited-field) radiation therapy is permitted, if all of the following criteria are met. 
• Repeat imaging demonstrates no new sites of bone metastases. 
• The lesion being considered for palliative radiation is not a target lesion. 
• 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 an 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) =< 12 weeks prior to the first dose of study drug. 
• 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 CDX-1127 (varlilumab) and/or nivolumab.
• History of severe hypersensitivity reaction to any monoclonal antibody. 
• 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. 
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with CDX-1127 (varlilumab) or nivolumab .
• 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 polymerase chain reaction (PCR) clinical assay; 
  • Absolute CD4 count of >= 200 mm^3;
  • Willing to maintain adherence to combination antiretroviral therapy; 
  • No history of acquired immunodeficiency syndrome (AIDS) defining condition (other than lymphoma or CD4 cell count < 200 mm^3); 
  • Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma:
    • Patients with evidence of hepatitis B virus (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, Sjogren'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 I 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). 
• 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, gastrointestinal (GI) obstruction and abdominal carcinomatosis 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 cancer or carcinoma-in-situ of the cervix.

Inclusion Criteria
•Pre-Registration:

• Smoking history of ≥ 30 pack‐years AND either current smoker (still smoking or quit < 1 year prior to pre‐registration) OR former smoker (quit 1‐15 years prior to pre‐registration).
  • Note: Pack years is determined by multiplying the number of packs smoked per day by the number of years smoked.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Computed tomography (CT) scan of the chest done ≤ 6 months prior to pre‐registration showing either negative findings (no nodules) or solid or part‐solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung‐Reporting and Data Systems [RADs] version 1.0).
• Willingness to employ adequate contraception, if applicable; Note: women of child‐bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

Inclusion Criteria
•Registration:

• Leukocytes (white blood cell [WBC]) ≥ 3,000/microliter.
• Neutrophils (absolute neutrophil count [ANC]) ≥ 1,500/microliter.
• Platelets ≥ 100,000/microliter.
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) Note: Higher total bilirubin levels (≤ 3 mg/dL) can be allowed if due to known benign liver condition; i.e. Gilbert''s.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 1.5 x institutional upper limit of normal (ULN).
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 1.5 x institutional upper limit of normal (ULN).
• Creatinine ≤ institutional upper limit of normal (ULN).

Exclusion Criteria
•Pre-Registration:

• History of any malignancy; exceptions: non‐melanoma skin cancer or carcinoma in situ (CIS) of the cervix.
• Known hepatitis B or C.
• Receiving any other investigational agents.
• Any prior investigational immune therapy, such as for lung cancer prevention or treatment or for CIS of the cervix.
• Use of oral or systemic steroids or other systemic anti‐immune therapy ≤ 90 days prior to pre-registration.
  • Note: Use of inhaled/nasal steroids and local steroid injections for pain control are not exclusionary.
• Known human immunodeficiency virus (HIV).
• Known autoimmune disease.
• Known non‐alcoholic steatohepatitis (NASH) or non‐alcoholic fatty liver disease (NAFLD).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MUC1/Poly‐ICLC
  •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.

Exclusion Criteria
•Registration:

•  Any positive antinuclear antibody (ANA) titer above 1:160, even in an asymptomatic individual.
  • Note: Weakly positive ANA defined as ANA titers up to 1:160 maximum (≤ 1:160) will be acceptable in an asymptomatic individual who is otherwise eligible for the study.
• Pregnant or breast feeding.
  • Note: Pregnant women are excluded from this study because the MUC1/Poly-ICLC vaccine may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with MUC1/Poly-ICLC vaccine, breastfeeding should be discontinued if the mother is treated with the vaccine

• Age ≥ 18 years old
• Histological confirmation of melanoma of any mucosal site including (but not limited to) anus/rectum, vulvar/vaginal, sinonasal.
  • NOTE: Melanomas of cutaneous origin and/or ocular origin are ineligible.
• R0 or R1 resection of primary melanoma tumor (no gross disease can be left behind, but microscopically positive margins are acceptable).
• Surgery within ≤ 90 days of registration.
• ECOG Performance Status (PS) ≤ 1.
• The following laboratory values obtained ≤ 14 days prior to registration:
• Hematological
  • Absolute Neutrophil Count (ANC) ≥ 1500/mm^;3
  • Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused);
  • Platelet (Plt) 100,000/mm^3.
• Renal
  • Serum Creatinine ≤ 1.5 x ULN.
• Hepatic
  • Alkaline Phosphatase (Alk Phos) ≤ 1.5 x upper limit of normal (ULN);
  • Total and Direct Bilirubin ≤ 1.5 × (ULN);
  • Aspartate aminotransferase (AST) ≤ 1.5 × ULN.
• Negative pregnancy test done within 7 days prior to registration, for women of childbearing potential only.
  • NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Written informed consent and HIPAA authorization for release of personal health information prior to registration.
  • NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Willing to return to enrolling institution for follow-up.
• Willing to provide archival tissue prior to C1D1 if available and blood samples for correlative research purposes

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and subjects known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Subjects 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.
• Other active malignancy ≤ 3 years prior to registration.
  • EXCEPTIONS: Malignancies with a very low (< 5%) risk of recurrence such as non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Active autoimmune disease -including but not limited to:
  • Subjects with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease;
  • Subjects with a history of symptomatic autoimmune disease requiring systemic treatment within the past 2 years with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs:
  • rheumatoid arthritis;
  • systemic progressive sclerosis (scleroderma);
  • systemic lupus erythematosus;
  • psoriasis;
  • autoimmune vasculitis (e.g., Wegener’s Granulomatosis);
  • CNS or motor neuropathy considered of autoimmune origin (e.g., GuillainBarre Syndrome and Myasthenia Gravis, multiple sclerosis).
    • EXCEPTION: autoimmune conditions that are only requiring replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Any radiation within 2 weeks prior to study initiation. Neoadjuvant and adjuvant radiation are allowed, but must be completed > 2 weeks prior to registration.
• Any prior systemic therapy for melanoma (chemotherapy, immunotherapy, targeted therapy).
• Women of childbearing potential (WOCBP) must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent until 5 months after the last dose of study drug. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Examples include: intrauterine device (IUD), vasectomy of a female subject’s male partner, contraceptive rod implanted into the skin, or use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive.

*Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• NOTE: Male subjects are not required to utilize contraception. The study regimen is not genotoxic and systemic concentrations sufficient to produce a risk of fetal toxicity are not expected in WOCBP partners from exposure to a male participant’s seminal fluid.
• Pregnant or breastfeeding.
  • NOTE: breast milk cannot be stored for future use while the mother is being treated on study.

• Participants must have histologically confirmed intracranial glioblastoma or gliosarcoma following maximum surgical resection. Tumors primarily localized in the infratentorial compartment will be excluded.
• Participants may have had prior surgery for glioblastoma or gliosarcoma but no systemic or radiation therapy.
• Age ≥ 18 years.
• Karnofsky performance status ≥60
• Participants must have normal organ and marrow function as defined below:
  • Leukocytes ≥3,000/mL
  • Absolute neutrophil count ≥1,500/mL
  • Platelets ≥100,000/mL
  • Hemoglobin ≥ 9g/dl
  • Total bilirubin within normal institutional limits (except for participant's with Gilbert's disease)
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
  • Creatinine ≤ institutional upper limit of normal OR
  • Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
  • Potassium within normal institutional range, or correctable with supplements
  • Serum amylase ≤ 1.5 x institutional upper limit of normal
  • Serum lipase ≤ 1.5 x institutional upper limit of normal
  • INR < 2.0
  • PTT ≤ institutional upper limit of normal, unless receiving therapeutic low molecular weight heparin
• Must be able to swallow pills.
• Participants must plan to begin radiation therapy 14-42 days after surgical resection.
• Immunohistochemically negative for IDH1 R132H mutation.
• Evidence that the tumor MGMT promoter is unmethylated by standard of care assays.
• Genotyping data available or in process (data must be available at time of initial registration if randomization probabilities differ across biomarker subgroups as determined by the DFCI Coordinating Center) to assign biomarker subgroups through whole exome sequencing, whole genome copy number analysis, or a combination as described in Section 9.1.
• MRI with gadolinium should be obtained within 21 days prior to beginning treatment. Patients without measurable disease are eligible. Participants must be able to undergo MRIs (CTs are not allowed for response assessment on study).
• The effects of the experimental agents used in this study on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (women who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation unless otherwise specified in sub-study that the participant is randomized to. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• For women of child bearing potential (women who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) a negative serum pregnancy test must be documented prior to initial registration.
• Ability to understand and the willingness to sign a written informed consent document.

• Participants will not be eligible if the original diagnosis was a lower grade glioma and a subsequent histologic diagnosis revealed glioblastoma.
• Planned major surgery.
• Participants who are receiving any other investigational agents.
• Participants who have had any prior cranial radiotherapy.
• Planned use of Optune™.
• History of a different malignancy, unless (a) have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, and/or (b) malignancy was cervical cancer in situ, superficial bladder cancer or basal cell or squamous cell carcinoma of the skin, and malignancy has been treated. Patients who meet the above listed criteria and are only on preventative treatment will be deemed eligible.
• History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician.
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
• Known history of congenital QT prolongation or Torsade de pointes (TdP).
• Complete left bundle branch or bifascicular block.

  --QTc interval > 450 ms for men or > 470 ms for women.

• Persistent or history of clinically meaningful ventricular arrhythmias or atrial fibrillation.
• Unstable pectoris or myocardial infarction ≤ 3 months prior to starting study treatment.
• Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg).
• Other clinically significant heart disease such as congestive heart failure requiring treatment.
• Uncontrolled diabetes mellitus, or subjects with either of the following:
• Fasting blood glucose (FBG defined as fasting for at least 8 hours) ≥ 200 mg/dL (7.0 mmol/L), or
• HbA1c ≥ 8%
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease, pancreatitis, chronic pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations.
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNS [qualitative] is detected).
• Known acute or chronic pancreatitis.
• Participants with active diarrhea ≥ CTCAE grade 2 despite medical management.
• Active infection requiring antibiotics.
• Pregnant or breastfeeding.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection). Participants with unresolved diarrhea ≥ CTCAE grade 2 will be excluded as previously indicated.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the experimental agents or other agents used in study.
• Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate. Participant must be off any EIAEDs for at least 7 days prior to planned start of study treatment. A list of EIAED and other inducers of CYP3A4 is provided. Among non-EIAED, caution is recommended with use of valproic acid due to potential for drug interaction.
• Participants taking a drug known to be strong inhibitors or inducers of isoenzyme CYP3A. Participant must be off CYP3A inhibitors and inducers for at least 7 days prior to planned start of study treatment. NOTE: participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to planned start of study treatment and during the entire study treatment period due to potential CYP3A4 interaction.
• Current use of herbal preparations/medications, including but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 7 days prior to planned start of study treatment.
• Current use of warfarin sodium or any other coumadin-derivative anticoagulant. Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior to planned start of study treatment. Low molecular weight heparin and factor Xa inhibitors are allowed.

ELIGIBILITY CRITERIA FOR PREREGISTRATION (STEP 0): 

• Preoperative biopsy for confirmation of renal cell carcinoma (RCC) must be performed within four (4) months prior to randomization. 
• If biopsy was performed as part of patients standard care, and will not be performed during step 0 proceed directly to randomization.

ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): 

• Patients with newly diagnosed higher risk RCC of any histology including sarcomatoid or (if preoperative biopsy was uninformative)
  •"unknown" histology; RCC must have been confirmed by biopsy within 4 months prior to randomization; if the biopsy clearly demonstrated a benign condition or a different type of cancer, the patient is not eligible to be randomized
  •Clinical stage >= T2NxM0 or TanyN+ disease for which radical or partial nephrectomy is planned.
• Patients must have no clinical or radiological evidence of distant metastases (M0.) 
• No concurrent or prior systemic or local anti-cancer therapy for RCC is permitted; examples of these prohibited therapies include: 
  • Radical or partial nephrectomy for prior RCC;
  • Metastectomy for RCC; 
  • Radiation therapy to the renal bed or any distant metastatic sites; 
  • Antineoplastic systemic therapies for RCC: i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents for treatment of RCC; 
  • Prior treatment with an anti-programmed cell death 1 (PD-1), anti-programmed cell death-ligand 1 (PD-L1), anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 
• Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1. 
• Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study 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: 
  • Has not undergone a hysterectomy or bilateral oophorectomy; or 
  • Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and effective methods of contraception, as described in the informed consent form (ICF), or to abstain from sexual intercourse for the duration of their participation in the study; women of childbearing potential should use adequate methods to avoid pregnancy for 23 weeks after the last dose of nivolumab; sexually active males should use adequate methods to avoid pregnancy for 31 weeks after the last dose of nivolumab.
• Patient must have no prior history of RCC that was resected with curative intent within the past 5 years.
• Patients must not have other current malignancies: 
  • 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 3 years prior to the time of registration and they are not receiving any current treatment;
  • Prior or current prostate cancer is excluded;
    • A history of superficial Ta urothelial cancer is permitted (not being currently treated) but T1 or greater disease is excluded.
• No active known or suspected autoimmune disease; the following are permitted: patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune or non-autoimmune condition requiring hormone replacement, asymptomatic hypothyroidism not requiring treatment, psoriasis not requiring systemic treatment, or conditions not expected to recur.
• No ongoing condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications; no treatment with other immunosuppressive agents within 14 days prior to the first dose of study drug; topical, ocular, intra-articular, intranasal, inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.; a brief (less than 3 weeks) course of corticosteroids (any amount) for prophylaxis (for example: contrast dye allergy) or for treatment of non-autoimmune conditions (for example: delayed-type hypersensitivity reaction caused by a contact allergen) is permitted if > 14 days since last dose.'
• No uncontrolled adrenal insufficiency.
• No known chronic active liver disease or evidence of acute or chronic hepatitis B virus (HBV) or hepatitis C (HCV).
• Patients must not have a serious intercurrent illness, including ongoing or active infection requiring parental antibiotics.
• No known evidence of human immunodeficiency virus (HIV) infection.
• No known medical condition (e.g. a condition associated with uncontrolled diarrhea such as ulcerative colitis or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or interfere with the interpretation of safety results.
• No major surgery within 28 days prior to randomization.
• Patients currently enrolled in other clinical trials testing a therapeutic intervention.
• Patients must have the following baseline laboratory values within 4 weeks of randomization:
  • White blood cells >= 2000/uL, within 4 weeks of randomization.
  • Absolute granulocyte count (AGC) >= 1,500/mm^3, within 4 weeks of randomization.
  • Platelet count >= 100,000/mm^3, within 4 weeks of randomization.
  • Hemoglobin >= 9.0 g/dL, within 4 weeks of randomization.
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 40 mL/min, within 4 weeks of randomization.
  • Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 x ULN), within 4 weeks of randomization.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN, within 4 weeks of randomization.
• No history of severe hypersensitivity to a monoclonal antibody.
• Signed, dated informed consent.

• None.

Inclusion Criteria
•Pre Registration:

• Patients must have histologically or cytologically confirmed malignant pleural mesothelioma.
• Patient is willing to submit a tissue sample to test for expression of mesothelin.
  • Note: Tissue sample for mesothelin assay may have been collected prior to, during or after receipt of the frontline chemotherapy; patients will not be required to submit another tissue sample after receipt of the chemotherapy.
• Patients must have received platinum based chemotherapy.

Inclusion Criteria - Registration (Phase 2 Only):

• Patient has measurable disease per RECIST 1.1 for non-pleural disease or modified RECIST 1.1 (mRECIST) for pleural disease. Note: For pleural disease, this is defined as at least one lesion that can be accurately measured perpendicular to the chest wall or mediastinum that is ≥ 10 mm (≥ 1 cm). For extra pleural disease, measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 10 mm (≥ 1 cm) for non-nodal lesions and ≥ 15 mm (≥ 1.5 cm) for nodal lesions with spiral CT scan, MRI, or calipers by clinical exam as per RECIST 1.1.
• Tissue submitted for testing at pre-registration shows moderate or stronger mesothelin expression in ≥ 30% of the tumor cells.

For Phase 1 and 2

• Patients must have received platinum-based therapy with or without bevacizumab.
• Patients age ≥ 18 years old.
  • Note: Because MPM primarily affects older adults and no dosing or adverse event data are currently available on the use of anetumab ravtansine and MK-3475 (pembrolizumab) in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status < 2 (Karnofsky ≥ 70%).
• Patients must have normal organ and marrow function as defined below:
  • leukocytes ≥ 3,000/mcL;
  • absolute neutrophil count ≥ 1,500/mcL;
  • platelets ≥ 100,000/mcL;
  • total bilirubin Within normal institutional limits;
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal (ULN).
  • creatinine Within normal institutional limits OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN AND partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, unless patient is on stable dose of anti-coagulation therapy in which case patients will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the Investigator’s discretion.
• Negative serum pregnancy test for females of child bearing potential.
• Note: Females are considered to not be of child bearing potential if any of the following apply:
  • Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
  • Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
• Has a congenital or acquired condition that prevents childbearing.
• Negative serum pregnancy test for females of child bearing potential.
  • Note: Females are considered to not be of child bearing potential if any of the following apply:
    • Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
    • Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
    • Has a congenital or acquired condition that prevents childbearing.
• Patient agrees to use one of the following acceptable methods of contraception prior to study entry, during study participation, and for at least six months after receiving the last dose of study treatment.
• Acceptable methods of contraception are:
  • Single method (1 of the following is acceptable):
    • abstinence, if consistently employed as the patient’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and Institutional Review Boards (IRBs);
    • intrauterine device (IUD);
    • vasectomy of a female patient’s male partner;
    • contraceptive rod implanted into the skin.
  • Combination method (requires use of 2 of the following):
    • diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide);
    • cervical cap with spermicide (nulliparous women only);
    • contraceptive sponge (nulliparous women only);
    • male condom or female condom (cannot be used together);
    • hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection.
• Ability to understand and the willingness to sign a written informed consent document, unless patient is of impaired decision making capacity in which case patient may be eligible if they have a Legal Authorized representative or caretaker available.

• Patients who have received any monoclonal antibody therapy within 4 weeks prior to entering the study.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1).
  • Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
  • Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patients who are receiving any other investigational agents.
• Patients with known brain metastases with progressive neurologic dysfunction, requirement of steroids and lack of improvement on head imaging obtained prior to consent to this clinical trial should be excluded because of their poor prognosis and because they would confound the evaluation of neurologic and other adverse events.
• Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
• Patients with carcinomatosis meningitis should also be excluded.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to anetumab ravtansine or MK-3475 (pembrolizumab).
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4, including herbal preparation containing CYP3A4 inducers (e.g., St. John’s Wort), grapefruit and grapefruit juice (CYP3A4 inhibitor), within 2 weeks before the start of study treatment.
• Patients are prohibited from receiving the following therapies during the screening and treatment phases (including retreatment for post-complete response relapse) of this trial:
  • Antineoplastic systemic chemotherapy or biological therapy;
  • Immunotherapy not specified in this protocol;
  • Chemotherapy not specified in this protocol;
  • Investigational agents other than anetumab ravtansine and MK-3475 (pembrolizumab);
  • Radiation therapy;
    • Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be considered on an exceptional case by case basis after consultation with CTEP. The patient must have clear measurable disease outside the radiated field. Administration of palliative radiation therapy will be considered clinical progression for the purposes of determining PFS.
  • Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Chalmette–Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  • Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the study PI and CTEP.
• 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.
• Women who are pregnant or breastfeeding.
  • Note: Pregnant women are excluded from this study because anetumab ravtansine and MK-3475 (pembrolizumab) 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 anetumab ravtansine and MK-3475 (pembrolizumab), breastfeeding should be discontinued if the mother is treated with anetumab ravtansine or MK-3475 (pembrolizumab).
• HIV-positive patients who do not meet all of the following and/or are on HIV medications considered to be strong inhibitors or inducers of CYP3A4:
  • Undetectable HIV viral load by standard clinical assay within 6 months of registration;
  • Willing to adhere to antiretroviral therapy that has minimal overlapping toxicity or pharmacokinetic interactions with protocol therapy;
  • No AIDS-defining events other within the past 12 months;
  • Near normal life expectancy if not for the presence of the cancer.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Patients who are known to have a history of or a finding of corneal epitheliopathy at pre-study are excluded because anetumab ravtansine may worsen this condition and reduce vision.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Receipt of transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to study treatment.
• Patient with active interstitial lung disease (ILD)/pneumonitis or a prior history of ILD/pneumonitis requiring treatment with steroids.
• Patient has received prior treatment with PD-1, PD-L1 or PD-L2 inhibitor.

1. Age ≥18 years
2. Histologically confirmed diagnosis, according to the World Health Organization (WHO, 2008) classification, of: DLBCL NOS, THRLBCL, EBV-positive DLBCL, composite lymphoma with a DLBCL component with a DLBCL relapse subsequent to DLBCL treatment, disease transformed from an earlier diagnosis of low grade lymphoma (i.e. an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with a DLBCL relapse subsequent to DLBCL treatment.
3. Fresh tumour tissue for central pathology review must be provided as an adjunct to participation in this study. Should it not be possible to obtain a fresh tumour tissue sample, archival paraffin embedded tumour tissue acquired ≤3 years prior to screening for this protocol must be available for this purpose.
4. Patients must have:
   1. Relapsed or refractory DLBCL
   2. At least one bidimensionally measurable disease site. The lesion must have a greatest transverse diameter of ≥1.5 cm and greatest perpendicular diameter of ≥1.0 cm at baseline. The lesion must be positive on PET scan
   3. Received at least one, but no more than three previous systemic therapy lines for the treatment of DLBCL. At least one previous therapy line must have included a CD20-targeted.
   4. ECOG 0 to 2
5. Patients after failure of ASCT or patients considered in the opinion of the investigator currently not eligible for HDC with subsequent ASCT.
6. Patients must meet the following laboratory criteria at Screening:
   1. ANC ≥1.5 × 109/L (unless secondary to bone marrow involvement by DLBCL)
   2. PLTs ≥90 × 109/L (unless secondary to bone marrow involvement by DLBCL) and absence of active bleeding
   3. Total serum bilirubin ≤2.5 × ULN unless secondary to Gilbert's syndrome (or pattern consistent with Gilbert's) or documented liver involvement by lymphoma. Patients with Gilbert's syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤5 x ULN
   4. ALT, AST and AP ≤3 × ULN or <5 × ULN in cases of documented liver involvement by lymphoma
   5. Serum creatinine ≤2.0 x ULN or creatinine clearance must be ≥40 mL/min calculated using a standard Cockcroft-Gault formula (Cockroft & Gault, 1976)
7. For a female of childbearing potential (FCBP), a negative pregnancy test must be confirmed before enrolment. An FCBP must commit to take highly effective contraceptive precautions without interruption during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later. An FCBP must refrain from breastfeeding and donating blood or oocytes during the course of the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later. Restrictions concerning blood donations apply as well to females who are not of childbearing potential.
8. Males must use an effective barrier method of contraception without interruption during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later, if the patient is sexually active with an FCBP. Males must refrain from donating blood or sperm during study participation and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later.
9. In the opinion of the investigator, the patients must:
   1. Be able to comply with all study-related procedures, medication use, and evaluations
   2. Be able to understand and give informed consent
   3. Not be considered to be potentially unreliable and/or not cooperative.

1. Patients who have: any other histological type of lymphoma including, e.g., primary mediastinal (thymic) large B-cell lymphoma (PMBL) or Burkitt's lymphoma, primary refractory DLBCL, patients with known "double/triple hit" DLBCL genetics, CNS lymphoma involvement in present or past medical history
2. Patients who had a major surgery less than 30 days prior to Day 1 dosing
3. Patients who have, within 14 days prior to Day 1 dosing:
   1. Not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy
   2. Received live vaccines
   3. Required parenteral antimicrobial therapy for active, intercurrent systemic infections
4. Patients who:
   1. In the opinion of the investigator, have not recovered sufficiently from the adverse toxic effects of prior therapies, major surgeries or significant traumatic injuries
   2. Were previously treated with CD19-targeted therapy or BEN
   3. Have a history of previous severe allergic reactions to compounds of similar biological or chemical composition to MOR00208, RTX, murine proteins or BEN, or the excipients contained in the study drug formulations
   4. Have undergone ASCT within a period of ≤3 months prior to signing the informed consent form. Patients who have a more distant history of ASCT must exhibit full haematological recovery before enrolment into the study.
   5. Have undergone previous allogeneic stem cell transplantation
   6. Concurrently use other anticancer or experimental treatments
5. Prior history of malignancies other than DLBCL, unless the patient has been free of the disease for ≥3 years prior to Screening. Exceptions to the ≥3-year time limit include history of the following:
   1. Basal cell carcinoma of the skin
   2. Squamous cell carcinoma of the skin
   3. Carcinoma in situ of the cervix, breast and bladder
         f) Incidental histological finding of prostate cancer (Tumour/Node/Metastasis [TNM] stage of T1a or T1b)
6. Patients with:
   1. Positive hepatitis B and/or C serology
   2. Known seropositivity for or history of active viral infection with HIV
   3. Evidence of active, severe uncontrolled systemic infections or sepsis
   4. A history or evidence of severely immunocompromised state
   5. A history or evidence of severe hepatic impairment (total serum bilirubin > 3 mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma
   6. A history or evidence of clinically significant cardiovascular, cerebrovascular, CNS and/or other disease that, in the investigator's opinion, would preclude participation in the study or compromise the patient's ability to give informed consent

Patients presenting with an incipient clinical diagnosis for FSGS/MCD or MN or pediatric participants not previously biopsied, with a clinical diagnosis for FSGS/MCD or MN meeting the following inclusion criteria:

• Documented urinary protein excretion ≥500 mg/24 hours or spot protein: creatinine ratio equivalent at the time of diagnosis or within 3 months of the screening/eligibility visit.
• Scheduled renal biopsy

• Prior solid organ transplant
• A clinical diagnosis of glomerulopathy without diagnostic renal biopsy
• Clinical, serological or histological evidence of systemic lupus erythematosus (SLE) as defined by the ARA criteria. Patients with membranous in combination with SLE will be excluded because this entity is well defined within the International Society of Nephrology/Renal Pathology Society categories of lupus nephritis, and frequently overlaps with other classification categories of SLE nephritis (68)
• Clinical or histological evidence of other renal diseases (Alport, Nail Patella, Diabetic Nephropathy, IgA-nephritis, monoclonal gammopathy (multiple myelomas), genito-urinary malformations with vesico-urethral reflux or renal dysplasia)
• Known systemic disease diagnosis at time of enrollment with a life expectancy less than 6 months
• Unwillingness or inability to give a comprehensive informed consent
• Unwillingness to comply with study procedures and visit schedule
• Institutionalized individuals (e.g., prisoners)

• Age birth-100 years, male or female, any race/ethnicity
• Potential participant shall have a confirmed diagnosis of a mitochondrial disease or a suspected diagnosis based on a review of clinical history by a Mitochondrial Disease Biobank working group member using the clinical criteria listed in the table below
• Selected participants shall have at least two documented conditions contained within the minor clinical criteria
  • Minor Criteria
    • Symptoms compatible with a mitochondrial defect
    • Smaller numbers of RRF or widespread electron microscopy abnormalities of mitochondria
    • Antibody-based demonstration of an mito defect or residual activity of an mito complex 20%–30% in a tissue, 30%–40% in a cell line, or 30%–40% in >2 tissues
    • Fibroblast ATP synthesis rates 2–3 SD below mean, or fibroblasts unable to grow in galactose media
    • Nuclear or mtDNA mutation of probable pathogenicity
    • One or more metabolic indicators of impaired metabolic function
• OR one condition in the major criteria with evidence of a condition in the minor criteria, will be considered for inclusion of a participant of appropriate age
  • Major Criteria
    • Multi-systemic symptoms characteristic of mito disorder
    • Progressive clinical course with episodes of exacerbation
    • A family history strongly indicative of an mtDNA mutation
    • Exclusion of other metabolic or non-metabolic disorders
    • >2% ragged red fibers (RRF) in skeletal muscle
    • Cytochrome c oxidase negative fibers (>2-5%) or residual activity of a mito complex <20% in a tissue; <30% in a cell line, or <30% in >2 tissues
    • Fibroblast ATP synthesis rates >3 SD below mean
    • Nuclear or mtDNA mutation of undisputed pathogenicity
• 1st-degree relatives of affected participants (described above) are also invited to participate in the project.
• In addition, samples from participants with one of the following mitochondrial disease diagnosis will be included:
  • Alpers’ progressive sclerosing poliodystrophy 
  • Barth syndrome 
  • CPEO 
  • Dominant optic atrophy
  • Friedriech’s Ataxia
  • Hereditary paraganglioma 
  • Hereditary spastic paraplegia 
  • Kearns-Sayre syndrome Leber hereditary optic neuroretinopathy
  • Leigh and Leigh-like Syndrome 
  • MELAS 
  • MERRF
  • NARP 
  • Pearson syndrome 
  • Wolfram syndrome 
  • Mitochondrial fatty acid oxidation disorder 
  • Urea cycle defect

• Unwilling to provide informed consent
• Unwilling to consent to providing biospecimens to be stored in the biobank for an indefinite amount of time and to be used in future research studies of as yet unknown design
• Does not have a diagnosis of mitochondrial disease or clinical symptoms that are indicative of a potential mitochondrial disease as determined by a chart review by at least one Individualized Medine Biobank for Mitochondrial Disease working-group member

• Be ≥ 18 years of age
• Have been admitted to hospital
• Have a signed informed consent by participant or surrogate/representative
• Have a local diagnosis (confirmed or suspected) of influenza, or of a targeted non-influenza viral respiratory infection*, resulting in (or extending a previous) hospitalization
  • A list of targeted non-influenza respiratory viruses is maintained on the INSIGHT website.

• Current imprisonment, or compulsory detention (involuntary incarceration) for treat of a psychiatric or physical illness.

Inclusion Criteria  

• Age 18 to 85 years old.
• Equal number of males and females.
• Participants recruited to three experimental groups:
  • Class I-II heart failure patients;
  • Class III-IV heart failure patients;
  • Age, BMI and sex matched healthy control subjects.

Exclusion Criteria  

• Pacemaker dependent.
• If they currently smoke.
• If they are allergic to the CT contrast material.
• If participating in an aim of the study in which an esophageal balloon catheter will be used, subjects will be excluded if:
  • They are allergic to latex; or
  • If they have a history of nose bleeds.                      

Group IA

• Patients with open elbow procedures or trauma which have resulted in arthrofibrosis of the elbow joint  

Group IB

• Patients with normal motion  

Group IIA 

• Patients with established shoulder contractures limiting ADL’s 

Group IIB

• Normal patients 

Group IIIA 

• Patients with knee arthrofibrosis after TKA  

Group IIIB

• Patients without contracture after TKA

• Age less than 18 years
• History of infection in operative extremity
• History of malignancy in operative extremity
• Presence of a condition

Subject Population:

• Heart failure patients and healthy subjects

• Ages 18-90

• Age less than 18

• Age 18-40 years
• No chronic medical conditions other than seasonal or environmental allergies
• On no prescription medications other than second generation antihistamines (Cetirizine, Fexofenadine, Desloratadine, Loratadine, etc), oral contraceptive pills, or intrauterine devices.
• BMI 18.5-35 kg/m2
• Both normotensive and prehypertensive people are eligible and will be studied
• Not a current smoker or tobacco user
• Not pregnant or breast feeding and not intending to become pregnant or breast feed

• The investigators will exclude subjects who have any medical or psychiatric disorders
• History of anxiety or depression, and those taking any medications other than non-sedating antihistamines or oral contraceptives.
• Those found to have depression on a depression screening tool (BDI-II) will be excluded. Current smokers will be excluded.
• All female subjects will undergoing a screening pregnancy test and excluded if positive.
• Subjects found to have significant sleep disorders will be excluded.

• Age ≥ 7 years.
• Biopsy confirmed newly diagnosed or recurrent WHO Grade II or Grade III malignant glioma.
• CT simulation, 18F-DOPA PET imaging, and standard of care pre-RT MRI scans to be performed at Mayo Clinic Rochester.
• Provide informed written consent.

• Patients diagnosed with WHO grade IV malignant glioma.
• Patients previously treated with radiation therapy.
• Unable to undergo MRI scans with contrast (e.g., cardiac pacemaker, defibrillator, kidney failure).
• Unable to undergo an 18F-DOPA PET scan (e.g., Parkinson’s Disease, taking anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from discontinuance of dopamine agonists.  Other potentially interfering drugs consist of: amoxapine, amphetamine, benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, paroxetine, citalopram, and sertraline).
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.

• Age 18-40 years
• BMI of 18.5-30 kg/m²
• Not a current smoker or tobacco user
• No chronic medical or psychiatric disorders
• On no prescription medications other than second generation antihistamines (cetirizine, fexofenadine, desloratadine, loratadine, etc), oral contraceptive pills, or intrauterine devices
• History of normal sleep patterns, defined as nocturnal sleep duration of 6.5-8 hours per night without regular daytime naps

• The investigators will exclude subjects who have any medical or psychiatric disorders
• History of anxiety or depression
• Those taking any medications other than non-sedating antihistamines or oral contraceptives will be excluded
• Those found to have depression on a depression screening tool (BDI-II) will be excluded
• Current smokers will be excluded
• All female subjects will undergoing a screening pregnancy test and excluded if positive
• Subjects found to have significant sleep disorders will be excluded

Women should meet at least one of the following criteria:

• Abnormal uterine bleeding
• Postmenopausal bleeding
• Thickened endometrial stripe
• Hereditary predisposition to endometrial cancer (e.g. HNPCC)
• Women referred for endometrial biopsy to evaluate suspicion or high risk of endometrial cancer

• Prior hysterectomy
• Pregnant women (There will be a verbal screen by the clinic nurse and the physician about a potential pregnancy and a pregnancy test may be conducted if there is any doubt)
• Prior pelvic radiation

• Elevated serum IgG4 or a clinical or histopathologic diagnosis of IgG4-RD in adult patients

• None

Inclusion Criteria Heart Failure Patients:

• History of Heart Failure with preserved ejection fraction or with reduced ejection fraction
• No history of dangerous arrhythmias
• Body Mass Index less than or equal to 35 kg/m
• Current non-smokers with less than 15 pack year history
• Non-pregnant women
• Individuals who are able to exercise without orthopedic limitations
• All patients will be managed by their primary care physician or cardiologist prior to enrollment to ensure inclusion and exclusion criteria have been satisfied and participation in exercise testing is safe.

Inclusion Criteria Control Participants:

• Will be matched for age, gender, height and weight and will have no history of cardiovascular related abnormalities.
• Body Mass Index less than 35 kg/m
• Current non-smokers with less than 15 pack year history
• Non-pregnant women
• Individuals who are able to exercise without orthopedic limitations