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

Inclusion Criteria
•Registration:

• Age ≥18 years and ≤ 60 years of age.
• Measurable disease (≥ 1.5 cm) as assessed by 2 dimensional measurement by CT.
• Previously untreated stage I or II non-bulky (defined as a mass measuring < 10 cm in the longest dimension by CT) Classical Hodgkin lymphoma.
• ECOG Performance Status (PS) 0-2. (Form is available on the ACCRU web site https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html)
• Life expectancy ≥3 months.
• Documented negative serologic testing for human immunodeficiency virus (HIV), hepatitis B (unless serologically positive due to prior vaccination), and hepatitis C ≤1 year prior to registration.
• Adequate bone marrow function (without transfusion support >7 days prior to registration) function as demonstrated by:
  • White blood cell ≥ 2,000 /mm3;
  • Hemoglobin ≥ 8.5 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;
  • Platelet count ≥ 75,000/mm3.
• Adequate hepatic and renal function obtained ≤14 days prior to registration as demonstrated by:
  • Alanine and Aspartate aminotransferase (ALT/AST) ≤ 2.5 ﾗ upper limit of normal (ULN);
  • Total serum bilirubin ≤ 1.5 ﾗ ULN (if documented Gilberts syndrome ≤ 3 x ULN);
  • Serum creatinine ≤ 1.5 × ULN or measured calculated creatinine clearance ≥ 40 ml/min for subject with creatinine levels > 1.5 x institutional ULN (per Cockcroft-Gault formula below; see Appendix III
    •Renal Impairment Guidelines).
• Cockcroft-Gault Equation:
  • Creatinine clearance for males = (140
    •age)(weight in kg) | (72)(serum creatinine in mg/dL).
  • Creatinine clearance for females = (140
    •age)(weight in kg)(0.85) | (72)(serum creatinine in mg/dL) .
• Negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to registration in women of child-bearing potential (WOCBP).
• Sexually active female of reproductive capability ie, WOCBP, has agreed to use a medically accepted form of contraception from time of registration to completion of study therapy through 24 weeks (6 months) after last dose of NVB or BV.
  • Note: Females of non-child-bearing potential are those who are postmenopausal for > 1 year or who have had a bilateral tubal ligation or hysterectomy. 
• Male subjects agree to use an adequate method of contraception starting with the first dose of study therapy through 31 weeks after the last dose of study therapy.
• Provide informed written 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.

Exclusion Criteria
•Registration:

• 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.
• Prior therapies including involved field radiation therapy.
• Bulky disease (defined as a nodal mass measuring ≥ 10 cm by CT).
• Known CNS involvement.
• Moderate or severe hepatic insufficiency Child-Pugh score >6 (see Appendix IV
  •Child- Pugh Hepatic Impairment Score).
• Severe renal impairment (i.e., creatinine clearance < 40 mL/min).
• Symptomatic cardiac disease including ventricular dysfunction, left ventricular ejection fraction < 45%, symptomatic coronary artery disease or symptomatic arrhythmias.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy ≤ 7 days prior to registration.
• Known history of active TB (Bacillus Tuberculosis).
• Requires therapy with agents that have a predisposition for hepatoxicity.
• Hypersensitivity to NVB or any of its excipients or to any component of AVD + BV therapy.
• Requires immunosuppressive doses of corticosteroid therapy (>10 mg/day prednisone equivalents) for ≥ 2 weeks prior to registration.
• Active, known, or suspected autoimmune disease that requires systemic weeks prior to registration.
• Active, known, or suspected autoimmune disease that requires systemic treatment (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
  • Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Subjects 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.
• Active infection requiring systemic IV antibiotic therapy.
• History of Steven’s Johnson’s syndrome, toxic epidermal necrolysis syndrome (TENs) or motor neuropathy.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Received a live vaccine ≤30 days prior to registration.
  • Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. Routine vaccinations, including seasonal influenza, must be given ≥ 2 weeks prior to registration.
• History of allergies and adverse drug reaction to study drug components.
• History of another primary malignancy that has not been in remission for at least 3 years.
  • Note: The following are exempt for the 3-year limit: nonmelanoma skin cancer, fully excised melanoma in situ [Stage 0], curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History of progressive PML, known history of pancreatitis, active grade 3 or higher viral, bacterial or fungal infection ≤ 2 weeks prior to registration and documented history of cerebrovascular event (stroke or TIA) ≤6 months prior to registration.

• 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.

Inclusion Criteria

• Histologically confirmed invasive lobular breast cancer, that is hormone receptor-positive and HER2-negative, measuring at least 1 centimeter (cm) radiographically or clinically, clinical stages I-III. Invasive lobular histology will be diagnosed at the enrolling institution for purposes of study participation. Subsequently, invasive lobular histology will be confirmed by central pathology review, but this central review will not be required prior to patient enrollment.
• Prior to initiation of study agents, study participants will be highly encouraged to undergo a baseline research core biopsy of their breast tumor. If this is not possible or the patient refuses, the pre-treatment tumor sample must be obtained from their archival diagnostic core biopsy. If definitive surgery is not performed at day 21-27 after study treatment, a second post-treatment research core biopsy will need to be obtained from their breast tumor. For patients undergoing surgery, the second biopsy will be removed from the breast tumor tissue excised during their operation.
  • Note: In the event that the baseline breast tumor biopsy performed for research purposes does not yield adequate tumor tissue for analysis of the primary and secondary endpoints, tissue will be requested from the patient's archival clinical diagnostic core biopsy if it is available.
• The patient will still remain on study and complete protocol therapy as planned in this unlikely event.
• Participant must be aware of the nature of her malignancy, understand the study requirements and risks and be able and willing to sign a written informed consent document.
• Hormone receptor (HR) status of the invasive component must be documented before trial enrollment. The tumor must be HR-positive. HR will be considered positive if staining is 1% or greater for ER and/or PR. This will be determined at the enrolling institution for purposes of study participation and enrollment onto the trial. Subsequently, HR status will be confirmed by central pathology review, but this central review will not be required prior to enrolling the patient. HER2 status will be determined locally only, based upon current ASCO/CAP guidelines.
• Patients must be female.
• Participants must be fully postmenopausal.
• ECOG performance status of 0, 1 or 2.
• Adequate organ and marrow function as defined by a history and physical exam that rules out comorbidities that would be exclusions to participation in the study (see exclusion criteria) and clinical laboratory parameters as deemed clinically appropriate by the treating physician.
• Prior use of hormone contraceptives and replacement therapy is allowed (e.g., estrogen and/or progestin), but must have been discontinued at least 30 days prior to the study enrollment. Vaginal preparations (e.g., Vagifem® or Estring®) are allowed.
• Participant must be aware of the nature of her malignancy, understand the study requirements and risks and be able and willing to sign a written informed consent document.

Exclusion Criteria

• Prior or concurrent use of hormonal therapy, chemotherapy, radiation therapy, or novel therapy to treat the current breast cancer, including any history of prior irradiation to the ipsilateral breast.
• Additionally, the patient must not have had hormonal therapy for breast cancer treatment or for breast cancer prevention within 2 years prior to study enrollment.
  • Note: Synchronous breast, cancer (including bilateral breast cancer) at separate sites is permissible, provided the patient does not receive medical treatments for breast cancer or radiation therapy to the ipsilateral breast during the 21-day study intervention period.
• Concurrent use of any other investigational agents.
• History of allergic reactions/hypersensitivity attributed to compounds of similar chemical or biologic composition to tamoxifen, anastrozole, or fulvestrant or any of their ingredients.
• History of thromboembolic disease or uterine cancer that is considered a contraindication to tamoxifen.
• Active hepatitis viral infections or a known history of liver disease, especially moderate (Child-Pugh Class B) to severe (Child-Pugh Class C) hepatic impairment.
• Uncontrolled current 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.
• HER-2 positivity.
• Increased Risk of bleeding: including a history of a bleeding diathesis and/or known history of severe thrombocytopenia.
  • NOTE: Anticoagulant use is not a contraindication to fulvestrant, but caution is advised in administration in patients on anticoagulation.
• Patients on anticoagulation who will receive fulvestrant will have PT and aPTT/INR assessed at baseline.

• Age ≥ 18 years old.
• Histological and/or Radiologic confirmation of HCC OR Histologic confirmation of intrahepatic CCA.
• The following tumor characteristics must be met:
  • Unresectable HCC or intrahepatic CCA;
  • Measurable or evaluable disease;
  • All lesions should be treatable by EBRT while meeting normal tissue constraints;
  • Tumor lesions should be accessible using an US guided approach for intratumoral DC injection;
  • Patients are required to have no evidence of extrahepatic tumor (excluding tumor thrombus) by computed tomography (CT) or magnetic resonance imaging (MRI) scan NOTE: Patients who are not candidates for surgical treatment or for ablation with curative intent are allowed.
• Good candidate for standard of care high-dose conformal EBRT in the view of the investigator.
• ECOG Performance Status (PS) 0 or 1.
• The following laboratory values obtained ≤14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥1000/mm3;
  • Absolute lymphocyte count (ALC) ≥500/mm3;
  • Absolute monocyte count (AMC) ≥300/mm3;
  • Platelet count ≥50,000/mm3;
  • Hemoglobin ≥9.0 g/dL;
  • Total bilirubin <3 mg/dL;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 x ULN;
  • Creatinine ≤2 mg/dL;
  • PT/INR ≤1.5 x ULN.
• Negative pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only.
• Ability to provide written consent.
• Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide blood and tissue samples for correlative research purposes.

Exclusion Criteria

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception .
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent that would be considered a treatment for the primary neoplasm.
• Other active malignancy ≤3years prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer.
• Major surgery ≤4 weeks prior to enrollment (other than diagnostic surgery or surgical spacer placement in preparation for radiation treatment).
• History of hypersensitivity or anaphylactoid reactions to pneumococcal vaccine or any component of the formulation, including diphtheria toxoid.
• Active autoimmune disease such as autoimmune hepatitis, Crohn’s disease, rheumatoid arthritis, Sjögrens’ disease, systemic lupus erythematosus, or similar conditions.
• Requires coagulopathy treatment (INR >1.5) or use of anti-platelet agents that cannot be discontinued for the intratumoral injection procedure.
  • NOTE: Heparin for line patency without detectable lab abnormalities in coagulation will be allowed.
• Corticosteroids ≤2 weeks prior to registration, including oral, IV, subcutaneous, or inhaled routes of administration.
  • NOTE: Patients on chronic corticosteroids for adrenal insufficiency or other reasons may enroll if they receive less than 10 mg/day of prednisone (or equivalent).
• History of myocardial infarction ≤6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Child Pugh class B or C cirrhosis of the liver.
• Previously received immune modulating therapies including but not limited to immune checkpoint inhibitors targeting PD-1 PDL-1 CTLA4, etc; or prior dendritic cell therapy.
• Prior liver radiation, including radioembolization.
• BCLC stage D disease (Llovet, Di Bisceglie et al. 2008.

Documentation of Disease

• Histologic Documentation: Well- or moderately-differentiated neuroendocrine tumors of pancreatic and non-pancreatic (i.e. carcinoid) origin by local pathology: 
  • The pathology report must state ONE of the following:
  • well- or moderately-differentiated neuroendocrine tumor;
  • low- or intermediate-grade neuroendocrine tumor; or
  • carcinoid tumor or atypical carcinoid tumor; documentation of histology from a primary or metastatic site is allowed.
  • Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible.
• Stage: Locally advanced/unresectable or metastatic disease.
• Tumor Site: Histological documentation of neuroendocrine tumor of pancreatic, gastrointestinal (GI), lung, or unknown primary site; GI, lung, and unknown primary NETs will enroll in the carcinoid tumor cohort of the study:
  • Functional (associated with a clinical hormone syndrome) or nonfunctional tumors are allowed.
• Radiologic Evaluation: Target lesions must have shown evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria in the 12 months prior to registration; the radiologic images, imaging reports, and clinic notes indicating growth of existing lesions, development of new lesions, or treatment changes must be submitted. 

Measurable Disease 

• Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) scan or magnetic resonance imaging (MRI).
• Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes); non-measurable disease includes disease smaller than these dimensions or lesions considered truly non-measurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung.

Prior Treatment

• Patient must have failed at least one prior systemic therapy that included everolimus; disease progression or treatment intolerance leading to discontinuation is considered treatment failure
  •Prior treatment (except somatostatin analogs) with biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration.
• Prior treatment with somatostatin analogs is allowed, and continuation of treatment with somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months.
• Prior systemic treatment with radionuclide therapy must be completed at least 6 weeks prior to registration. 
• Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies is allowed if measurable disease remains outside of the treated area or if there is documented disease progression in a treated site; prior liver-directed or other ablative treatment must be completed at least 28 days prior to registration. 
• Prior treatment with cabozantinib is not allowed. 
• Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less. 
• Patients must have completed any major surgery at least 12 weeks prior to registration and any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to registration; complete wound healing from major surgery must have occurred at least 28 days prior to registration, and complete wound healing from minor surgery must have occurred at least 10 days prior to registration.

Patient History 

• No class III or IV congestive heart failure (CHF) within 6 months of registration.
• No clinically significant cardiac arrhythmia within 6 months of registration.
• No unstable angina or MI within 6 months of registration.
• No thromboembolic events within 6 months of registration (including [incl.] stroke, transient ischemic attack [TIA], deep vein thrombosis [DVT], & pulmonary embolism [PE]).
• No known history of congenital long QT syndrome. 
• No uncontrolled hypertension within 14 days of registration (defined as systolic blood pressure [SBP] ≥ 150 mmHg and/or diastolic blood pressure [DBP] ≥ 90 mmHg despite optimal medical management).
• No clinically significant GI bleeding within 6 months of registration.
• No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding within 6 months of registration including, but not limited to: active peptic ulcer, known endoluminal metastatic lesion(s) with history of bleeding, inflammatory bowel disease, or other gastrointestinal conditions with increased risk of perforation.
• No GI perforation within 6 months of registration. 
• No known tumor invading the GI tract within 28 days of registration.
• No radiologic or clinical evidence of pancreatitis.
• No known cavitary lung lesions. 
• No known endobronchial lesions involving the main or lobar bronchi and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage; (CT with contrast is recommended to evaluate such lesions).
• No hemoptysis greater than 1/2 teaspoon (2.5 mL) or any other signs of pulmonary hemorrhage within the 3 months prior to registration.
• No known tumor invading or encasing any major blood vessels. 
• No history of non-healing wounds or ulcers within 28 days of registration.
• No history of fracture within 28 days of registration.
• No brain metastases or cranial epidural disease unless adequately treated, stable, and off steroid support for at least 4 weeks prior to registration. 
• No known medical condition causing an inability to swallow oral formulations of agents.
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to cabozantinib/placebo.
• No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ; patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 3 years.

Concomitant Medications 

• Other planned concurrent investigational agents or other tumor directed therapies (chemotherapy, radiation) are not allowed while on this study. 
• Concurrent use of somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months.
• Full dose oral anticoagulation/antiplatelet therapy is not permitted; low dose aspirin =< 81 mg/day is allowed; anticoagulation with therapeutic doses of low molecular weight heparin (LMWH) is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to registration; treatment with warfarin is not allowed; anticoagulation in patients with brain metastases is not permitted.
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed; patients must discontinue the drug at least 14 days prior to registration on the study.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients must discontinue the drug at least 14 days prior to the start of study treatment.

Not pregnant and not nursing

• Women of childbearing potential must have a negative pregnancy test done ≤ 14 days prior to registration.
• 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).
• Eastern Cooperative Oncology Group (ECOG) performance status:
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3;
  • Hemoglobin ≥ 9 g/dL;
  • Platelet count ≥ 100,000/mm^3;
  • Prothrombin time (PT)/ international normalized ratio (INR), partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 3 x ULN
    •Total bilirubin ≤ 1.5 x ULN;
  • Except in the case of Gilbert disease, in which case total bilirubin must be =< 3 x ULN;
  • Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 45 mL/min;
  •  Albumin ≥ 2.8 g/dL;
  • Potassium within normal limits (WNL); 
  • Phosphorus WNL;
  • Calcium WNL; 
  • Magnesium WNL;
  • Urine protein to creatinine (UPC) ratio ≤ 1;
  • QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤ 500 msec;
  • Thyroid-stimulating hormone (TSH) WNL:
    • Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible.

Eligibility last updated 9/28/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Pre-Registration:

• Age ≥ 18 years.
• Measurable disease as defined by RECIST criteria that is:
  • A non-nodal lesion is considered measurable if its longest diameter can be accurately measured as ≥ 1.0 cm with CT scan;
  • CT component of a PET/CT; or
  • MRI and/or A malignant lymph node is considered measurable if its short axis is > 1.5 cm when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).
  • Note: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible.
• Received  ≤ four (4) prior chemotherapy regimens in the metastatic setting.
• Cohort A One of the following must be true:
  • Distant disease progression during administration of combination therapy with taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) for metastatic disease.
    • Note: patients who began treatment with this combination and discontinued taxane-based chemotherapy due to intolerability before distant disease progression are eligible;
  • Distant disease progression during administration or within 180 days of discontinuing combination therapy with taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant disease.
    • Note: Patients who began treatment with this combination and discontinued taxane-based chemotherapy due to intolerability before distant disease progression are eligible. For patients who received taxane based chemotherapy and antiHER2 therapy (trastuzumab or pertuzumab) in the neo-adjuvant setting and underwent surgical resection of primary breast disease: Distant disease progression during or within 180 days of discontinuing anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant setting.
• Cohort B (one of the following must be true):
  • Distant disease progression during administration of combination therapy with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab) for metastatic disease. Permissible endocrine therapies include an aromatase inhibitor or fulvestrant.
    • NOTE: Tamoxifen is not permissible.
  • Distant disease progression during administration of combination therapy with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant setting. Permissible endocrine therapies include an aromatase inhibitor or fulvestrant.
    • NOTE: Tamoxifen is not permissible.
• Willingness to provide mandatory tumor tissue specimens for correlative research.
  • NOTE: If insufficient or no tissue is obtained by the pre-registration biopsy, an archival tissue specimen (preferably from a metastatic site) from procedure performed ≤ 2 years prior to pre-registration must be available to submit for Central Laboratory review prior to registration.
  • Exception: If there is no medically safe site for biopsy, Study Chair (Dr Haddad) may waive this requirement.

Exclusion Criteria
•Pre-Registration:

Cardiac Exclusion Criteria

• Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity/
• Patients with a history of LVEF decline to below 50% during or after prior trastuzumab or other HER2 directed therapy ≤ 6 months prior to preregistration.
• Patients with any class of New York Heart Association (NYHA) CHF or heart failure with preserved ejection fraction (HFPEF).
• Patients with a history of known coronary artery disease or a myocardial infarction within 12 months prior to pre-registration.
• Patients with persistently uncontrolled hypertension (systolic BP > 160 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical therapy.
• Patients with known unstable angina pectoris.
• Patients with a known history of serious cardiac arrhythmias requiring treatment (exception: controlled atrial fibrillation, paroxysmal supraventricular tachycardia).
• Patients with a prolonged QTc interval (≥ 450 ms).
• Leptomeningeal disease or uncontrolled brain metastasis.
  • NOTE: Metastases treated by surgery and/or radiotherapy such that patient is neurologically stable and off steroids ≥ 4 weeks prior to preregistration are eligible.
• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment.
  • EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment.
• Tumors involving spinal cord or heart.
• Visceral crisis or lymphangitic spread.
  • NOTE: Visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease.
• Uncontrolled intercurrent non-cardiac illness including, but not limited to:
  • ongoing or active infection;
  • psychiatric illness/social situations;
  • dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy;
  • or any other conditions that would limit compliance with study requirements.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Prior history of hypersensitivity, drug or radiation-induced, or other immunemediated pneumonitis.
• Patient is unable to swallow oral medications or has impairment of GI function or GI disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
  • Note: Concomitant therapy with proton pump inhibitors and/or H2- receptor antagonists is permissible.
• Patient has a history of clinically significant dry eye (xerophthalmia) or other corneal abnormality, or if a contact lens wearer, does not agree to abstain from contact lens use from baseline through the last TVB-2640 dose.
• Patients with a history of intolerance to trastuzumab (i.e., a grade 3 or 4 infusion reaction) are excluded.
  • Note: Patients with a history of mild infusion reaction to trastuzumab who have previously been successfully re-challenged after an infusion reaction with or without prophylactic medication are allowed.
• Other invasive malignancy ≤ 3 years prior to pre-registration.
  • EXCEPTIONS: Non-melanoma skin cancer, papillary thyroid cancer, or carcinoma-in-situ of the cervix which has been adequately treated.
  • NOTE: If there is a history of prior malignancy, patients must not be receiving other antineoplastic treatment for their cancer and the disease must be inactive/stable.

Inclusion Criteria
•Registration:

• Registration must be completed ≤ 28 days of pre-registration.
• ECOG Performance Status (PS) 0 or 1.
• Disease characteristics.
• Histological confirmation of HER2-positive advanced breast cancer. HER2+ is defined by 2013 ASCO/CAP guidelines.
• For Cohort B only: Histologic confirmation of ERα positive disease (≥ 1% expression).
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3; Platelet count
  • ≥ 100,000/mm^3;
  • Direct bilirubin ≤ 1.5 x ULN;
  • Aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula below:
• Cockcroft-Gault Equation:
• Creatinine clearance for males = (140
  •age)(weight in kg) (72)(serum creatinine in mg/dL).
• Creatinine clearance for females = (140
  •age)(weight in kg)(0.85) (72)(serum creatinine in mg/dL).
• Cardiac ejection fraction (LVEF) ≥ 50% by echocardiogram ≤ 28 days prior to registration.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Negative urine pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Patient and his/her partner agree to use adequate contraception after providing written informed consent through 3 months after the last dose of TVB-2640, as follows:
  • For women: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile or postmenopausal;
  • For men: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile. Men whose sexual partners are of child-bearing potential must agree to use 2 methods of contraception prior to study entry, during the study, and for 3 months after the treatment period.
• Willingness to provide mandatory tumor tissue and/or blood specimens for correlative research.

Exclusion Criteria
•Registration:

• 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.
• Any of the following therapies prior to registration:
  • Chemotherapy ≤ 3 weeks;
  • Immunotherapy ≤ 3 weeks;
  • Biologic therapy ≤3 weeks;
  • Monoclonal antibodies ≤ 3 weeks;
  • Radiation therapy ≤ 2 weeks;
  • CDK 4/6 inhibitors ≤ 4 weeks;
  • mTOR inhibitors ≤ 4 weeks.

• Newly diagnosed and histopathologically confirmed (by central pathology review) potentially resectable soft tissue sarcomas of the extremity and trunk of the following subtypes: liposarcoma (excluding myxoid liposarcoma), leiomyosarcoma and undifferentiated pleomorphic sarcoma
  •An incisional or core biopsy is the preferred method for diagnosis; fine needle aspiration is not acceptable.
• Sites permissible for biopsy include.
• Extremities: upper (including shoulder) and lower (including hip).
• Trunk: body wall.
• Patients must have localized disease with a primary tumor  ≥ 5 cm by magnetic resonance imaging (MRI) or computed tomography (CT) scan.
• Patients must have histologically confirmed grade 2 or 3 tumors by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) sarcoma grading system.
• Patients must have a primary tumor that are determined by multidisciplinary team (medical oncology, orthopedic/surgical oncology, and radiation oncology) to require radiation therapy for optimal management prior to surgical resection.
• Patients must have a sarcoma in the extremity or trunk in location, which is accessible to direct or ultrasound guided injections.
• Karnofsky performance score ≥ 70.
• Absolute neutrophil count (ANC) ≥ 1500/uL.
• Absolute lymphocyte count (ALC) ≥ 800/uL.
• Platelets ≥ 100,000/uL.
• Hemoglobin ≥ 9 g/dL.
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN.
• Calculated creatinine clearance > 70 mL/min/1.73 m^2.
• Patient must have a life expectancy of at least 3 months with appropriate therapy.
• Patients must agree to use contraception during study treatment and for 4 months after the end of treatment.
• 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, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; 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.
• Ability to understand and the willingness to sign a written informed consent document.
• Willingness to provide mandatory tissue and blood samples for correlative studies.

• Patients with localized sarcomas that are not of the extremity or trunk wall (including head/neck, retroperitoneum, visceral organs, peritoneum, pelvis within the confines of the bony pelvis, and tumors arising in bone).
• Patients who have had prior treatment with anti-PD1 or anti-CTLA4 therapy.
• Patients with grade 1 non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) tumors of any size are not eligible.
• Patients with evidence of active bleeding or bleeding diathesis will be excluded (patients with excess of 2.5 mL of hemoptysis are not eligible).
• Patients requiring therapeutic anticoagulation.
• Patients must have had no prior radiotherapy to tumor-involved sites.
• Patients with gross total resection of the primary tumor prior to enrollment are not eligible; patients who have experienced tumor recurrence after gross total tumor resection are not eligible.
• History of serious or non-healing wound, ulcer, or bone fracture.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1).
• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of talimogene laherparepvec (T-VEC) and during the study.
• Previous treatment with talimogene laherparepvec (T-VEC) or any other oncolytic virus. Patients with metastatic disease.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to talimogene laherparepvec (T-VEC) or any of its components.
• History or evidence of active autoimmune disease (e.g., pneumonitis, glomerulonephritis, vasculitis, or other); or history of active autoimmune disease that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) within 2 months of enrollment; (replacement therapy [e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency] is not considered a form of systemic treatment for autoimmune disease).
• Evidence of clinically significant immunosuppression such as Primary immunodeficiency state such as severe combined immunodeficiency disease.
• Concurrent opportunistic infection.
• Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment.
• Active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis).
• Viral infections requiring intermittent or chronic systemic (intravenous or oral) treatment with an anti-herpetic drug, other than intermittent topical use (e.g., acyclovir).
• Other viral infections.
• Known to have acute or chronic active hepatitis B or hepatitis C infection.
• Known to have human immunodeficiency virus (HIV) infection.
• Prior therapy with viral-based tumor vaccine.
• Received live vaccine within 28 days prior to enrollment
  •Patients who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or children under the age of 1 year, during talimogene laherparepvec (T-VEC) treatment and through 30 days after the last dose of talimogene laherparepvec (T-VEC).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who are pregnant, breastfeeding or plan to become pregnant; sexually active patients and their partners must be willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of T-VEC.

• Age ≥ 18 years.
• Histological confirmation of relapsed/refractory B-cell NHL,CD20+.
  • NOTE: Patients with small lymphocytic lymphoma (SLL) are eligible however patients with chronic lymphocytic leukemia (CLL) are not eligible.
  • Waldenström macroglobulinemia patients are not eligible;
  • Aggressive lymphoma patients who are transplant eligible must have undergone a transplant;
  • The biopsy confirming relapse can be up to 24 weeks prior to registration as long as there is no intervening therapy.
• Measurable disease (at least 1 lesion of ≥ 1.5 cm in one diameter) as detected by CT or the CT images of the PET/CT. Skin lesions can be used if the area is greater than or equal to 2cm in at least one diameter and photographed with a ruler.
• ECOG Performance Status (PS) 0, 1, or 2.
• The following laboratory values obtained ≤ 14 days prior to registration.
• Absolute neutrophil count (ANC) ≥ 1500/mm^3.
• Platelet count  ≥  75,000/mm^3.
• Hemoglobin ≥ 8.0g/dL.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or if total bilirubinism.
• > 1.5 x ULN, the direct bilirubin ≤ ULN.
• Alkaline phosphatase ≤ 3 x ULN unless due to directlymphoma involvement, and then ≤ 5 x ULN.
• Aspartate transaminase (AST) 3 x ULN unless due to directlymphoma involvement, and then ≤ 5 x ULN.
• Calculated creatinine clearance must be ≥ 30 ml/min using the Cockcroft-Gault formula below:

• Cockcroft-Gault Equation:

  Creatinine clearance for males =      (140
  •age)(weight in kg)
                                                            (72)(serum creatinine in mg/dL)

  Creatinine clearance for females =  (140
  •age)(weight in kg)(0.85)
                                                           (72)(serum creatinine in mg/dL)

• Life expectancy ≥ 3 months.
• Ability to provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the treatment phase of the study).
• Willing to provide blood samples for correlative research purposes.
• Failed or are intolerant to 2 or more lines of established therapy or for whom no other treatment options are available in the opinion of the investigator.
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Disease-free of prior invasive malignancies for > 5 years prior to registration.
  • Note: Exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.

• 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.
• Active CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells that requires therapy.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Received most recent therapy ≤ 4 weeks prior to registration.
  • NOTE: Use of systemic steroid therapy is allowed pretreatment.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Patients with ≥ 25% of the bone marrow radiated for other diseases.
• Other medical conditions including but not limited to:
  • History of liver disease such as cirrhosis, chronic active hepatitis, chronic persistent hepatitis or hepatitis B or C.
  • Active infection requiring parenteral antibiotics.
  • New York Heart Association class II-IV congestive heart failure (serious cardiac arrhythmia requiring medication).
  • Myocardial infarction or unstable angina ≤ 6 months prior to registration.
  • Congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
  • Clinically significant peripheral vascular disease.
  • History of CNS disease (e.g., primary brain tumor, vascular abnormalities, etc.), clinically significant stroke or TIA ≤ 6 months prior to registration, seizures not controlled with standard medical therapy.
  • Neuropathy ˃ Grade 3
• Administration of strong CYP2C8 or CYP3A4 inhibitors or inducers ≤ 10 days prior to registration.

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

Eligibility last updated 5/25/22. Questions regarding updates should be directed to the study team contact.

• 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 diagnosis of multiple myeloma or related malignancy
• Patients are undergoing standard of care bone marrow aspirates
• Patients (male or female) from any race or ethnicity must be at least 18 years of age at the time of registration.
• Procedure-specific signed informed consent form prior to initiation of any study-related procedures.

• It is the enrolling study physician's discretion to decide if a patient is not fit enough to undergo a bone marrow aspirate.
• Patients who are incarcerated are not eligible to participate.
• Women who are pregnant
• Patients who have had another malignancy within the last five (5) years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix) where there is a possibility to contaminate the bone marrow aspirate.

• Histological confirmation of non-small cell lung cancer
• Forced Expiratory volume in 1 second (FEV1)>1.0 L
• Unresectable stage 2-3 Non-small cell lung cancer (based on CT/positron emission tomography (PET), MRI or CT of brain, and physical exam). 
  • Eligible if recurrence after surgery and now has the equivalent stage 2-3 NSCLC OR had sub totally resected stage 2-3 NSCLC.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
• Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.
• The following laboratory values in specified ranges:
  • White blood cell count (WBC) ≥3.0 x 109/L,
  • Absolute neutrophil count (ANC) ≥1.5 x 109/L,
  • Hgb ≥9g/dl
  • Plts >100 x 109/L
  • Serum creatinine<1.5 times upper limit of normal (ULN)
  • Serum bilirubin <1.5 times upper limit of normal (ULN)
• Provide informed written consent.
• Willing to return to enrolling institution for follow-up for a minimum of 1 year.
• Ability to undergo potentially curative chemotherapy plus radiotherapy

• 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.
• 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.
• Weight loss of >10% in the past 3 months
• Distant metastases (M1 disease)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, lupus, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any investigational agent, that would be considered as a treatment for the primary neoplasm.
• Active second malignancy.
• Other active malignancy ≤3 years prior to registration. EXCEPTIONS:
  • Treated non-melanotic skin cancer;
  • Carcinoma-in-situ of the cervix;
  • Treated Stage 1-2;
  • Gleason 7 or less;
  • Prostate cancer with a stable or undetectable prostate specific antigen (PSA) level;
  • Treated stage 1 breast cancer which is controlled and for which the patient received no thoracic radiotherapy (RT).
• History of myocardial infarction ≤6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Received chemotherapy for lung cancer within 6 months of registration.
• Previous chest radiotherapy that would overlap with the proton field.

• Age 18 - 85 years. Patients under 18 years, should be fully grown (prove of fused growth plates).
• Patients with histological evidence of advanced unresectable and/or metastatic high-gradesoft tissue sarcoma (grade 2
  •3 according to the FNLCC grading system) not amenable to curative treatment with surgery or radiotherapy.
  • The following tumor types are included:
    • Malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma);
    • Myxoid and round cell liposarcoma, pleomorphic liposarcoma or dedifferentiated liposarcoma;
    • Myxofibrosarcoma intermediate and high-grade;
    • Fibrosarcoma;
    • Leiomyosarcoma;
    • Angiosarcoma;
    • Unclassified sarcoma NOS.
  • The following tumor types will not be included:
    • GIST;
    • Mixed mesodermal tumor;
    • Synovial sarcoma;
    • Malignant peripheral nerve sheath tumor;
    • Epithelioid sarcoma;
    • Embryonal rhabdomyosarcoma;
    • Chondrosarcoma;
    • Malignant mesothelioma;
    • Neuroblastoma;
    • Osteosarcoma;
    • Ewing's sarcoma / primitive neuroectodermal tumor;
    • Desmoplastic small round cell tumor;
    • Alveolar soft part sarcoma;
    • Pleomorphic rhabdomyosarcoma;
    • Alveolar rhabdomyosarcoma.
• Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. If only 1 lesion is present at screening, this lesion should not have been irradiated during previous treatments.
• Life expectancy of at least 3 months in the judgment of the investigator.
• ECOG ≤ 2.
• Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible.
• Female patients: negative serum pregnancy test for women of childbearing potential (WOCBP)* within 14 days of starting treatment. WOCBP must agree to use, from the screening to six months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' ClinicalTrial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.
• Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception throughout the study (e.g., condom with spermicidal gel). Double-barrier contraception is required.
  * Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
• Informed consent signed and dated to participate in the study.
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

• Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma.
• Previous treatment with anthracycline-containing chemotherapy.
• Radiotherapy within 4 weeks prior to therapy.
• Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies.
• Absolute neutrophil count (ANC) < 1.5 x 10^9/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
• Chronically impaired renal function as expressed by creatinine clearance < 60 mL/min.
• Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN)
• Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
• History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
• Clinically significant cardiac arrhythmias or requiring permanent medication.
• Abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator. Subjects with current, or a history of QT/QTc prolongation would be excluded. In particular:
  • patients with a marked prolongation of QT/QTc interval (e.g., repeated demonstration of QTc >480 milliseconds using Fredricia's QT correction formula) are excluded;
  • patients with a history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of prolonged QT syndrome) are excluded;
  • patients who require the use of concomitant medications that prolong the QT/QTc interval are excluded.
• Uncontrolled hypertension, despite optimal therapy.
• Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
• Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy.
• Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
• Pregnancy or breast-feeding.
• Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
• Presence of active and uncontrolled infections or other severe concurrent disease which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• Known active or latent tuberculosis (TB).
• Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has been disease-free for at least 2 years.
• Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
• Serious, non-healing wound, ulcer or bone fracture.
• Allergy to study medication or excipients in study medication.
• Concurrent therapy with anticoagulants.
• Concurrent use of other anti-cancer treatments or agents other than study medication.
• Any recent live vaccination within 4 weeks prior to treatment or plan to receive vaccination during the study.

Eligibility last updated 12/10/21. Questions regarding updates should be directed to the study team contact.

Pre-Screening Eligibility Criteria:

• Signed written informed consent to permit tissue analysis.
• 18 years of age or older.
• No medical history that is excluded per the study treatment eligibility criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Eligible for or receiving systemic therapy for inoperable or advanced iCCA.
• Not currently eligible for curative local or surgical therapy.
• To be enrolled in the study, once the FGFR2 genomic aberration status is determined, each prospective patient must meet all of the following inclusion criteria and none of the exclusion criteria.

• Signed written informed consent granted prior to initiation of any study-specific procedures.
• 18 years of age or older.
• Histologically or cytologically confirmed locally advanced, inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-cholangiocarcinoma [cHCC-CCA]).

Substudy 1:

• FGFR2 fusion status based on the following assessments:
  • If central laboratory designated by the Sponsor: Positive FISH test; and/or
  • If non-central laboratory: *
  • Positive FISH or NGS test: patients may be enrolled and may start dosing, but central confirmation is required.**  
  • * Using standard protocols and approved by local IRB/IEC, CLIA, or other similar agency. For enrollment of patients in the EU, assays must be fully CE-marked. ** The patient must not be enrolled if a negative FISH test is obtained from the central laboratory prior to commencing study treatment. Patients without central confirmation of an FGFR2 fusion by the central FISH test will be assessed on a case-by-case basis.
• Negative FISH or NGS test: tissue may be submitted to the central laboratory designated by the Sponsor, and patients may only be enrolled if the central test is positive.

Substudy 2:

• FGFR2 mutations/amplifications without any concurrent FGFR2 translocations based on NGS testing performed or commissioned by the respective study site (see Section 6.8.2 for further details).
  • Note 1: If the FGFR2 mutation/amplification status is derived from plasma-based NGS testing, a tumor block or slides prepared thereof should be submitted for subsequent correlative tissue-based NGS test at a laboratory identified by the Sponsor.
  • Note 2: If the NGS test used cannot identify FGFR2 translocations, a FISH test is mandatory to confirm that none are present.
• Received at least one regimen of prior systemic therapy and then experienced documented radiographic progression (for Substudy 1), and have no satisfactory treatment alternatives (for Substudy 2)
• Measurable disease by RECIST version 1.1 criteria.
• ECOG performance status ≤ 1.
• Adequate organ functions as indicated by the following laboratory values (based on screening visit values from the central laboratory):
  • Hematological
    • Hemoglobin (Hgb) ≥ 9.0 g/dL;
    • Absolute neutrophil count (ANC)  ≥ 1.5 × 10^9/L;
    • Platelet count ≥ 75 × 10^9/L;
    • International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for patients receiving anticoagulant therapy such as warfarin or heparin.
  • Hepatic
    • Total bilirubin ≤ 2 × ULN;
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 ULN (≤ 5 × ULN for patients with liver metastases);
    • Albumin ≥ 2.8 g/dL.
  • Renal
    • Serum creatinine ≤ 1.5 × ULN; or
    • Creatinine clearance of ≥ 30 mL/min as estimated by the Cockcroft-Gault equation.
• Female and male patients of child-producing potential must agree to avoid becoming pregnant or impregnating a partner, respectively, during the study*, and for at least 120 days after the last dose of derazantinib.
• Male patients are considered not to be of child-producing potential if they have azoospermia (whether due to vasectomy or an underlying medical condition). Female patients are considered not to be of child-producing potential if they are:
  • postmenopausal†; or
  • have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; or
  • have a congenital or acquired condition that prevents childbearing.
• Male or female patients of child-producing potential must agree to comply with one of the following until at least 120 days after the last dose of derazantinib:
  • Abstinence from heterosexual activity‡;
  • Using (or having their partner use) a highly effective method of contraception during heterosexual activity.  Highly effective methods of contraception are§:
    • an intrauterine device (IUD);
    • vasectomy of a female patient’s male partner;
    • a contraceptive rod implanted into the skin;
    • combined (estrogen- and progestogen-containing) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral contraceptive pill [estrogen/progestin pill or progestin-only pill] contraceptive skin  patch/implant, vaginal contraceptive ring, or subcutaneous contraceptive injection).
• *From the day of first study medication, or for oral contraception from 14 days before first study medication.
• † Postmenopausal is 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 post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is not sufficient.
• ‡ Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if it is employed during the entire period of risk associated with the study treatment and if it is considered highly effective by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not highly effective methods of contraception.
• § If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as a highly effecive method of contraception for subjects participating at sites in this country/region.

• Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:
  • One chemotherapy or biological (e.g., antibody) cycle interval;
  • Five half-lives of any small-molecule investigational or licensed medicinal product;
  • Two weeks, for any investigational medicinal product with an unknown half-life;
  • Four weeks of curative radiotherapy;
  • Seven days of palliative radiotherapy;
  • 28 days of radiotherapy.
• Major surgery or locoregional therapy within 4 weeks of the first dose of derazantinib.
• Previous treatment with any FGFR inhibitor (e.g., Balversa® [erdafitinib], Pemazyre® [pemigatinib], infigratinib, rogaratinib, futibatinib, lenvatinib, ponatinib, dovitinib, nintedanib, AZD4547, LY2784455).
• Unable or unwilling to swallow the complete daily dose of derazantinib capsules.
• Clinically unstable central nervous system (CNS) metastases (to be eligible, patients must have stable disease  ≥ 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases. well controlled by low-dose steroids, antiepileptics, or other symptom-relieving medications).
• Current evidence of clinically signficant corneal or retinal disorder likely to increase the risk of eye toxicity including, but not limited to, bullous/band keratopathy, keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion, inflammation/ulceration, confirmed by ophthalmologic examination.
• Concurrent uncontrolled or active hepatobiliary disorders, untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, biloma or abscess (to be eligible, the patients have to be treated and disorders/complications should be resolved within 2 weeks prior to the first dose of derazantinib).
• History of significant cardiac disorders:
  • Myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of derazantinib (MI that occurred > 6 months prior to the first dose of derazantinib are permitted);
  • QTcF > 450 msec for men and QTcF > 460 msec for women.
• Serum electrolyte abnormalities defined as follows:
  • Hyperphosphatemia: serum phosphate > institutional ULN;
  • Hyperkalemia: serum potassium > institutional ULN;
  • Hypokalemia: serum potassium < institutional lower limit of normal (LLN);
  • Hypercalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL);
  • Hypocalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL);
  • Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL).
• Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s disease, ulcerative colitis, extensive gastric resection).
• History of 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, and in situ cervical cancer.
• Concurrent uncontrolled illness not related to cancer, including but not limited to:
  • Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements;
  • Known uncontrolled human immunodeficiency virus (HIV) infection.
  • Severe bacterial, fungal, viral, and/or parasitic infections under treatment with therapeutic oral or intravenous (IV) medication at the time of first dose of study drug administration.
• Blood or albumin transfusion within 5 days of the blood draw being used to confirm eligibility.
• Pregnant or breast feeding.
• Known hypsersensitivity to derazantinib, or to any of the study drug excipients (starch, lactose, crospovidone, magnesium stearate).

• 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

• Diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS without invasive breast cancer (date of diagnosis defined as the date of the first pathology report that diagnosed the patient with DCIS) OR: atypia verging on DCIS OR: DCIS + LCIS (mix and/or separate locations in the same breast).
• A patient who has had a lumpectomy or partial mastectomy with margins positive for DCIS (i.e. < 2 mm/ink on tumor) as part of their treatment for a current DCIS diagnosis is also eligible (post-excision bilateral mammogram required at enrollment to establish a new baseline).
• No previous DCIS or invasive breast cancer in ipsilateral breast 5 years prior to current DCIS diagnosis.
• 40 years of age or older at time of DCIS diagnosis.
• ECOG performance status 0 or 1.
• No contraindication for surgery.
• Baseline imaging (must include dimensions):
  • unilateral DCIS:  contralateral normal mammogram ≤ 6 months of registration and ipsilateral breast imaging ≤ 120 days of registration (must include ipsilateral mammogram; can also include ultrasound or breast MRI);
  • bilateral DCIS:  bilateral breast imaging ≤ 120 days of registration (must include bilateral mammogram; can also include ultrasound or breast MRI);
  • DCIS s/p lumpectomy:  post excision mammogram on side of excision ≤ 60 days of registration.
• Pathologic criteria:
  • All grade I DCIS (irrespective of necrosis/comedonecrosis);
  • All grade II DCIS (irrespective of necrosis/comedonecrosis);
  • Absence of invasion or microinvasion;
  • Diagnosis of DCIS confirmed on core needle biopsy, vacuum-assisted biopsy, or surgery ≤ 120 days of registration;
  • ER(+) and/or PR(+) by IHC (≥ 10% staining or Allred score ≥ 4) unless atypia verging on DCIS in which case biomarker criterion does not apply;
  • HER2 0, 1+, or 2+ by IHC if HER2 testing is performed.
• Histology slides reviewed and agreement between two clinical pathologists (not required to be at same institution) that pathology fulfils COMET eligibility criteria. In cases of disagreement between the two pathology reviews about whether or not a case fulfils the eligibility criteria, a third pathology review will be required.
• At least two sites of biopsy for those cases where individual mammographic extent of calcifications exceeds 4 cm, with second biopsy benign or both sites fulfilling pathology eligibility criteria (ER/PR testing required for second biopsy).
• Amenable to follow up examinations.
• Ability to read, understand and evaluate study materials and willingness to sign a written informed consent document.
• Reads and speaks Spanish or English.

• All grade III DCIS.
• Male DCIS.
• Concurrent diagnosis of invasive or microinvasive breast cancer in either breast.
• Documented mass on examination or mass/hypoechoic area on imaging at site of DCIS prior to biopsy yielding diagnosis of DCIS, with exception of: subsequent lumpectomy or partial mastectomy (with positive DCIS margins; i.e., < 2 mm/ink on tumor) followed by a post-surgery MMG; fibroadenoma at a distinct/separate site from site of DCIS; or diagnosis of mass/hypoechoic area as a cyst or a papilloma. In cases of uncertainty about whether the mass was present on physical examination prior to biopsy, the following criteria should be applied: if mammogram noting abnormal findings is diagnostic MMG = symptomatic/if mammogram noting abnormal findings is screening MMG = asymptomatic. If a patient has a mass on imaging that is biopsied (worked-up) and does not show invasive breast cancer, they are eligible. If a patient has a mass on initial MMG that is not seen on subsequent MMG, they are eligible (if initial mass occurred due to additional work-up).
• Any color/bloody nipple discharge (ipsilateral breast).
• Mammographic finding of BIRADS 4 or greater within 6 months prior to registration at site of breast other than that of known DCIS, without pathologic assessment.
• Use of investigational cancer agents within 6 weeks prior to diagnosis of DCIS.
• Any serious and/or unstable pre-existing medical, psychiatric, or other existing condition that would prevent compliance with the trial or consent process.
• Pregnancy. If a woman has been confirmed as pregnant, she will not be eligible to take part in the trial. If she suspects there is a chance that she may be pregnant, a pregnancy test should be undertaken, although a pregnancy test for all women of child-bearing potential is not mandatory. In addition, if a woman becomes pregnant once registered to the trial, she can continue to be followed (endocrine therapy is not a mandatory requirement of the study).
• Documented history of prior tamoxifen, aromatase inhibitor, or raloxifene use in the 6 months prior to registration.
• Current use of exogenous hormones (i.e., oral progesterone).

• PRIOR TO STEP 1 REGISTRATION
• A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial
• The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)
• Patients must provide study-specific informed consent prior to step 1 registration
• PRIOR TO STEP 2 REGISTRATION
• Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration
• Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for analysis of O6-methylguanin-DNA-methyltransferase (MGMT) status
  • Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present
  • Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed
• History/physical examination within 28 days prior to step 2 registration
• The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration
• Documentation of steroid doses within 28 days prior to step 2 registration
• Karnofsky performance status ≥ 70 within 28 days prior to step 2 registration
• Age ≥ 18
• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 10.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
• Bilirubin ≤ 1.5 upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
• Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Recurrent or multifocal malignant gliomas
• Any site of distant disease (for example, drop metastases from the GBM tumor site)
• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide)
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
• Severe, active co-morbidity, defined as follows:
  • Unstable angina at step 2 registration
  • Transmural myocardial infarction within the last 6 months prior to step 2 registration
  • Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  • Serious and inadequately controlled arrhythmia at step 2 registration
  • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
  • Any other severe immunocompromised condition
  • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
  • End-stage renal disease (ie, on dialysis or dialysis has been recommended)
  • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration
• Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia)
• Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.

• 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.

• Age ≥ 18 years old.
• Diagnosis of:
  • Biopsy-proven small lymphocytic lymphoma (SLL); or
  • Diagnosis of chronic lymphocytic leukemia (CLL) with a clonal B-cell population in the peripheral blood with immunophenotyping consistent with CLL as follows:
  • The population of lymphocytes share both B-cell antigens [CD19, CD20 (typically dim expression), or CD23] as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
  • Clonality as evidenced by κ (kappa) or λ (lambda) light chain expression (typically dim immunoglobulin expression) or other genetic method (e.g. IGHV analysis);
  • Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative FISH analysis for t(11;14)(IgH/CCND1).
• Patients must be previously untreated (see note).
• Note: Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL or SLL will be considered prior therapy. Nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments or supplemental vitamins) will not be considered “prior treatment”. Prior corticosteroid therapy for an indication other than CLL/SLL will not be considered “prior treatment."
• All patients will undergo testing for prognostic factors according to the CLL-IPI (testing obtained ≤ 730 days prior to registration).
• Note: If the results for any of the prognostic factors included in the CLL-IPI are unknown including IGVH Mutation status results not being available due to a failed laboratory assay, the patient is not eligible.
• Note:  When determining CLL-IPI, use most recent test results, if more than one result is available.
• Note: Patients with CLL-IPI risk category of High Risk or Very High Risk (total score of  4-10) will be randomized to Arms A or B.
• Note: Patients with CLL-IPI risk category of low risk or intermediate risk (total score of 0-3) will be registered to Arm C.  
• ECOG Performance Status (PS) 0, 1, or 2.
• Provide written informed consent.
• Willing to provide blood and saliva samples for correlative research purposes.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• For high risk and very high risk CLL-IPI (Arms A and B) only.
• The following laboratory values obtained ≤ 30 days prior to randomization:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Hemoglobin ≥ 11.0 g/dL;
  • Aspartate transaminase (AST) ≤ 3 x ULN;
  • Creatinine ≤ 1.5 X ULN;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (or total bilirubin ≤ 3.0 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well-documented Gilbert’s Syndrome);
  • PT, INR, and PTT ≤ 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants.
• Negative serum pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Will provide bone marrow aspirate sample for correlative research purposes.

• Date of CLL/SLL diagnosis ≥ 24 months prior to registration
• Prior exposure to ibrutinib or to a BCR inhibitor (e.g., Btk or PI3 kinase or Syk inhibitors) or a BCL-2 inhibitor (e.g., venetoclax)
• Known CNS lymphoma or leukemia.
• Patients with any of the following indications for chemotherapy:
  • Evidence of progressive marrow failure as manifested by the development of or worsening anemia (≤ 11 g/dL) and/or thrombocytopenia (≤ 100 x 10^9/L) not due to autoimmune disease;
  • Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly;
  • One or more of the following disease-related symptoms:
    • Weight loss ≥ 10% within the previous 6 months;
    • Extreme fatigue attributed to CLL;
    • Fevers ≥ 100.4°F for 2 weeks without evidence of infection;
    • Drenching night sweats without evidence of infection.
• 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.
• Patients known to be HIV positive and currently receiving antiretroviral therapy.
• Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 2 years prior to registration.
• EXCEPTIONS: Non-melanotic skin cancer, carcinoma-in-situ of the cervix, or early stage prostate cancer.
• History of myocardial infarction ≤6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• For high risk and very high risk CLL-IPI (Arms A and B) only, any of the following:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ highly effective contraception.
• Serologic status reflecting active hepatitis B or C infection.
• Note: Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
• History of stroke or intracranial hemorrhage within 6 months before randomization.
• History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug and while on study.
• Requires treatment with a strong CYP3A inducer.
• Requires treatment with proton-pump inhibitors (e.g. omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
• History of confirmed progressive multifocal leukoencephalopathy (PML).
• Received a vaccination with a live vaccine ≤ 28 days prior to randomization.
•  

   

• Age ≥ 18 years old.
• Histological or cytological confirmation of solid tumor malignancy and/or clinical history of known or suspected metastatic disease with an intraparenchymal brain tumor consistent with brain metastasis based on clinical and radiologic findings.
• Clinical indication for surgical resection of one brain metastasis based on neurosurgery recommendation and patient deemed a surgical candidate.
• Clinical indication and plan for stereotactic radiosurgery to all known brain lesions requiring treatment (< 10 metastases).
• ECOG Performance Status (PS) ≤ 2.       
• Provide written informed consent or have a Legally Authorized Representative who is responsible for the care and well-being of the potential study participant, provide consent.     
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) or agreement to complete pre-specified MRI series and follow-up visits according to the study timeline mailing in digital copies of images as well as clinical notes.

• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Prior open neurosurgery for malignancy.
• Known or clinically suspected primary germ cell tumor, small cell carcinoma, or lymphoma.
• History of Whole Brain Radiation Therapy (WBRT).
• Known allergy to gadolinium, pacemaker, or other contraindication such as metal implant that is not safe for MRI.  Patients with MRI-compatible implants including MRI compatible pacemakers are eligible.
• Leptomeningeal metastasis/disease.
• A brain metastasis that is located ≤ 5 mm of the optic chiasm.
• Any brain metastasis > 5cm in size.
• >10 brain metastases.
• Indication for surgical resection of ≥ 2 brain metastases. 
• Indication for long-term (anticipated greater than 4 weeks) 4mg dexamethasone equivalent of steroids or bevacizumab.

Eligibility last updated 5/12/22. Questions regarding updates should be directed to the study team contact.

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