Current sites credentialed: SJMH (AA, Brighton, Canton, Chelsea), GenHur, LVHN, Sparrow, St. John, Macomb, SJMO, Livonia, Saginaw,

SJMH - not participating in diffuse weighted MRI sub-study 

Eligibility Criteria

- Patients must be age ≥ 18 years.

- Patients must have histologically confirmed T1N1-3M0 or T2-3N0-2M0 esophageal or gastroesophageal junctional adenocarcinoma (Siewert I and II).

- Patients must have an ECOG Performance Status 0-1.

- Patents must be deemed a surgical candidate by a thoracic surgeon, surgical oncologist, or surgeon who is qualified to perform an esophagectomy.

- Patients must have normal organ and marrow function as definded below within less than or equal to 14 days prior to randomization:

- Absolute neutrophil count ≥ 1,500/mcL 

- Platelets ≥ 100,000/mcL 

- Total bilirubin ≤ institutional upper limit of normal (ULN).

-AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional 

- Serum creatinine ≤ 1.5 X institutional ULN 

- Hgb ≥ 9 g/dL 

- Leukocytes ≥ 3,000/mm3 

- Patients may not have received prior chemotherapy or radiation therapy for management for this malignancy.

- Patients may not have received prior immunotherapy for management of this malignancy or for any other past malignancy.

- Patients must have no contraindication to receiving either carboplatin or paclitaxel chemotherapy.

- Patients must have no contraindication to receiving radiation therapy  

-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, GuillainBarre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue disease, 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). - Patient must NOT have previous or concurrent malignancy. Exceptions are made for patients who meet any of the following conditions: 

· Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or breast cancer in situ OR

· Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years.

OR

· Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years.

· Date of last evidence of disease:

- Patients must not have a condition requiring systemic treatment with either corticosteroids (>10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses ≤ 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.

- Adequate cardiac function including EKG and echocardiogram for any patient with a history of CHF or at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs.

- For patients with evidence of CHF, MI, cardiomyopathy, or myositis, cardiac evaluation including lab tests and cardiology consultations including EKG, CPK, troponin, and echocardiogram.

- Patients must not have a positive test result for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection. Testing should be conducted to determine eligibility. 

-Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) must have no detectable viral load on a stable antiviral regimen.

- Patients must not be receiving any other investigational agents.

-Patients with an uncontrolled intercurrent illness such as 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 will be excluded.

- Women must not be pregnant or breast-feeding due to potential harm to the fetus from carboplatin, paclitaxel, or nivolumab. All females of childbearing potential must have a blood test or urine study done within 2 weeks prior to registration to rule out pregnancy. Those enrolled on Arm B with nivolumab must agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of starting nivolumab to rule out pregnancy. 

-A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at east 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one month (female patients) or one week (male patients) prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP). 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.

- If patient says ‘Yes’ to “I choose to take part in the imaging study and will have the diffusion weighted MRI scans”: patients must be able to tolerate MRI scans: 

-No history of untreatable claustrophobia.

- No MR incompatible implants/devices or metallic foreign bodies.

- Weight compatible with limits imposed by the MRI scanner table.  

Eligibility Criteria: Step 2

-Patient registration must not exceed 12 weeks from time of esophagectomy.

- Patients must have a post-operative ECOG performance status of 0- 2. 

-Patients must have normal organ and marrow function as definded below within less than or equal to 14 days prior to randomization:

-Absolute neutrophil count ≥ 1,500/mcL 

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ institutional upper limit of normal (ULN). 

- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional ULN 

- Serum creatinine ≤ 1.5 X institutional ULN 

- Patients must be disease free following esophagectomy as is demonstrated by having no evidence of disease on a post-surgical CT scan. Patients must also have a negative surgical margin (R0 resection).  

Patients must not have an active, known or suspected autoimmune disease or a condition requiring treatment with steroids or immunosuppressive agents. 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.

- Patients must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive medications with 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.

- Patients must not be receiving any other investigational agents.

- Patients with an uncontrolled intercurrent illness such as 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 will be excluded. 

-Women must not be pregnant or breast-feeding due to potential harm to the fetus from nivolumab or ipilimumab. All females of childbearing potential must have a blood test or urine study done (minimum sensitivity 25 IU/L or equivalent units of HCG) within 2 weeks prior to registration to rule out pregnancy. All patients must also agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of starting nivolumab to rule out pregnancy. Those enrolled on Arm D with ipilimumab must agree to have pregnancy tests within 72 hours of each ipilimumab administration to rule out pregnancy. 

- Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one month (female patients) or one week (male patients) prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP). 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.  

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton), St. Mary's Livonia, Genesys, Hurley, LVHN, Sparrow, St. John, Macomb, Holy Cross, Saginaw

Eligibility Criteria:

• Patient must have inoperable, recurrent, or metastatic disease (tumor resectability should be assessed by a local surgeon or a multidisciplinary team) not amenable to curative therapy.
• Patient must have histological or cytological confirmation of anal squamous cell carcinoma (includes basaloid and cloacogenic lesions) from the primary tumor or a newly diagnosed recurrent/metastatic lesion.
• Patient must be = 18 years of age.
• Patient must have ECOG Performance Status = 0-1.
• Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and based on radiologic assessment performed <4 weeks prior to randomization.
• Patient receiving palliative (limited-field) radiation therapy is allowed, as long as the lesion treated for palliation is not a target lesion.
• Patients with brain metastasis are eligible if patient is asymptomatic and if treatment ended > 3 months prior to randomization. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression within 4 weeks prior to randomization.

• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
• All females of childbearing potential must have a blood test or urine study with a minimum sensitivity of 25 IU/L or equivalent units of BCG, within 14 days prior to randomization to rule out pregnancy.
• A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Female of child bearing potential? ______ (Yes or No)

Date of blood test or urine study: ___________

• Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or to abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP.
• Patient must have adequate organ and marrow function as defined below , obtained < 14 days prior to randomization:

Leukocytes = 3,000/mcL

Leukocytes:__________ Date of Test:__________

Absolute neutrophil count = 1,500/mcL

ANC:__________ Date of Test:__________

Platelets = 100,000/mcL

Platelet:__________ Date of Test:__________

Hemoglobin (Hb) = 9 g/dL for males and = 9 g/dL for females

Hgb:__________ Date of Test:__________

Total bilirubin = 1.5 X institutional upper limit of normal (ULN)

Bilirubin:__________ Institutional ULN:_________

Date of Test:__________

AST(SGOT) /ALT(SGPT) = 5 × institutional ULNALT:_______

Institutional ULN:_________

Date of Test:_______

AST:_______Institutional ULN:_________

Date of Test:_______

Creatinine = 1.5 X institutional ULN

OR

Creatinine clearance (CrCl) =50 mL/min (if using the Cockcroft-Gault formula below):

• Female CrCl = (140 - age in years) x weight in kg x 0.85

• • 72 x serum creatinine in mg/dL

• Male CrCl = (140 - age in years) x weight in kg x 1.00

• • 72 x serum creatinine in mg/dL

• Human immunodeficiency virus (HIV)-infected patients on effective Anti-Retroviral Therapy (ART) with undetectable viral load are eligible
• All HIV+ patients should be under the care of an Infectious Diseases specialist. If a relationship with an Infectious Diseases specialist is not established, an Infectious Disease specialist should be consulted. Records of all viral counts and peripheral T-cell counts should be documented in order to follow these values over the course of treatment.
• All patients must be willing to undergo testing for HIV testing if not tested within the past 12 months.
•  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients with known history or current symptoms of cardiac disease, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients with a history of CHF or who are at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs must be willing to undergo evaluation of cardiac function including EKG and ECHO as clinically indicated.
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.
• Patient must not have had previous use of systemic chemotherapy or other investigational drugs for the treatment of inoperable recurrent or metastatic anal cancer (Previous use of radiotherapy or chemoradiotherapy in this setting is not an exclusion criterion if: 1) non-irradiated target tumor lesions are present at randomization for the purpose of tumor response assessment or 2) in the absence of non-irradiated target tumor lesions, progression of the irradiated tumor lesions according to the RECIST criteria version 1.1 is documented). Patient must not have current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
• Patient must not have had prior immunotherapy.
• Patient must not have a history of known hypersensitivity reaction to any platinum or taxane-based chemotherapy or monoclonal antibody.
• Patient must not have active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater). 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 SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patients with any of these are ineligible because of the risk of recurrence or exacerbation of disease.
• Patient must not have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of randomization. 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.
• Patient must not have had major surgery performed = 28 days prior to randomization.
• Patient must not have a history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
• Patient must not have a serious active infection requiring IV antibiotics at time of randomization.
• Patient must not have other primary malignancy within the last 3 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer, or any other cancer from which the patient has been disease-free for at least 3 years.
• Patient must not have known peripheral neuropathy > grade 1 at the time of randomization (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
• Patients must agree to not receive live vaccines while on this study.

Eligibility Criteria:

- Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided radiation therapy is completed at least 2 weeks prior to registration and adjuvant therapy was administered more than 6 months prior to registration. Patients with the following histology are excluded: Acinar cell; Adenosquamous carcinoma.

- Patient must be = 70 years of age.

- Patient must have an ECOG Performance status 0-2

- Patient is an English speaker with the ability to understand and complete the informed consent and questionnaires

- Patient must have adequate organ and marrow function as defined below, with results obtained within 4 weeks prior to registration:

 - Leukocytes = 3,000/mcL

 - Absolute neutrophil count = 1,500/mcL

 - Platelets = 100,000/mcL

 -

Total bilirubin = institutional upper limit of normal (ULN)

 - AST(SGOT)/ALT(SGPT) = 2.5 × institutional ULN

 - Creatinine = institutional ULN and glomerular filtration rate (GFR) = 40 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.

-Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this protocol. HIV (+) patients who are on ritonavir or/and cobicistat-based regimen must be switched to alternative ART.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Male patients must agree not to father children while on study.

-Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this protocol, patients should be class 2B or better.

-Patient must have measurable disease as defined in Section 6.1.2 and scans must be done within 4 weeks prior to registration.

-Patients classified to have mild-moderate abnormalities in any of the domains evaluated in the screening geriatric assessment (as outlined in the table in Section 10.1) and are classified as "vulnerable" are eligible.

Patients classified without any abnormalities ("fit") or with severe cognitive/functional impairment or high co-morbidity score ("frail") on the screening geriatric assessment are ineligible.

- Patient must agree not to take any medications or substances that are strong inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan treatment arm should avoid drugs that are UGT1A1 inhibitors.

**DTL is required for this study- Physicians must sign the toxicity grids

Current sites credentialed: SJMH (AA, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys

Eligibility Criteria:

Eligibility Criteria for Step 0 (Pre-Registration)

- Patient must be ≥18 years of age on day of consent.

- Patient must have an ECOG Performance Status of 0-2.

- Patient must have a diagnosis of pancreatic cancer and have successfully undergone a curative intent surgical resection and must have no evidence of recurrent disease as determined by the investigator.

NOTE: This includes patients with adenocarcinoma, acinar carcinoma, squamous cell carcinoma adenosquamous and variants thereof. Patients with neuroendocrine tumors are excluded from enrolling.

- Patient must be planning to receive, be receiving or be within 8 weeks of having completed at least three combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy.Patients may have had up to 6 months of perioperative systemic therapy as deemed appropriate by their primary treating medical team (patients can have received radiation or chemoradiation in addition to this 6 month course).  

- Patient must have a known pathogenic or likely pathogenic germline or somatic mutation in BRCA1, BRCA2, or PALB2, as determined by a Clinical Laboratory Improvement Amendments (CLIA) certified or equivalently-accredited laboratory. Mutations must be considered pathogenic or likely pathogenic by a reference database such as ClinVar or OncoKb.org.

Eligibility Criteria for Step 1 (Randomization)

- Patient must have met the eligibility criteria outlined in Section 3.1.

- Patient must have undergone at least 3 combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy. Patients may have had up to 6 months of perioperative systemic therapy as deemed appropriate by their primary treating medical team (patients can have received radiation or chemoradiation in addition to this 6 months course).

- Central expert reviewer must have determined the patient eligible for randomization after review of local genetic testing reports.

- If mutation in BRCA1, BRCA2 or PALB2 was identified in tumor tissue and the patient has not previously undergone germline testing, the patient must agree to undergo germline testing.

- Patient must have no evidence of recurrent or metastatic pancreatic cancer at the time of randomization as documented by baseline scans obtained ≤ 4 weeks prior to randomization.

- Patient must not have previously had evidence of progressive pancreatic cancer while receiving platinum-based therapy

- Patient must be ≥ 21 days (three weeks) from their last treatment (including chemotherapy or radiotherapy) but ≤ 56 days (eight weeks) from their last treatment. Patients who have received neoadjuvant and/or adjuvant radiotherapy are eligible.

- Patient must have recovered from any adverse events due to prior anti-cancer therapy (i.e., have no residual toxicities > Grade 1 with the exception of alopecia and/or neuropathy).

- Patient must not be receiving any other investigational agents at the time of randomization and while on protocol treatment.

- Patient must not have any history of allergic reactions attributed to compounds of similar chemical or biological composition to olaparib. 

- Patient must not have any personal history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.

- Patient must not have any uncontrolled gastrointestinal disorder that would, in the opinion of the investigator, interfere with the ingestion or absorption of olaparib.

- Patient must not be pregnant or breast-feeding due the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.  

-All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point,

2) has not undergone a hysterectomy or bilateral oophorectomy; or

3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 

 - Patients of childbearing potential and sexually active patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or abstaining from sexual intercourse for the duration of their participation in the study and for 1 month after the last dose of protocol treatment for female patients and for 3 months after the last dose of protocol treatment for male patients. Patients must also not donate sperm while on protocol treatment and for 3 months after the last dose of protocol treatment. Patients must also not breast-feed while on protocol treatment and for 3 months after the last dose of protocol treatment.

- Patient must have adequate organ and marrow function as defined below: (labs must be obtained ≤ 14 days prior to randomization):

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

- Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤ 2.5 X ULN of the direct bilirubin

- Patient with Gilbert’s syndrome?

- AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN

- Creatinine ≤ 1.5 institutional ULN OR calculated Cockcroft Gault creatinine clearance > 50 mL/min/1.73 m2 .

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Patient must not have resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTc prolongation >500 ms, electrolyte disturbances, etc.) or have congenital long QT syndrome.

- Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir is prohibited. See Section 8.1.13 for more details.

- Patients who are being actively treated for an ongoing concurrent malignancy are ineligible, with the exception of those receiving adjuvant hormone therapies and those receiving topical therapies for skin cancers.

- Patient must not have, in the opinion of the investigator, any other concurrent medical condition that would prevent the patient from complying with the study procedures. 

-Patient must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.

- Patient must have the ability to understand and the willingness to sign a written informed consent document, or have legally authorized representative provide authorization to participate.

- Patient must not have had major surgery within 2 weeks prior to randomization and patients must have recovered from any effects of any major surgery.  

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: TH SJMH (Ann Arbor, Canton, Chelsea, Brighton), Livonia, Genesys, Hurley 

Eligibility Criteria:

3.1.1 Patient must be ≥ 18 years of age.

3.1.2 Patient must have histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma that is MSIH/dMMR (microsatellite instability-high/mismatch repair deficient) as determined by one of three methods:

3.1.2.1 Deficient DNA Mismatch Repair Protein (MMR) Expression Status: MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR. dMMR may be determined either locally or by site-selected reference lab by CLIA-certified assay. NOTE: Loss of MLH1 and PMS2 commonly occur together.

3.1.2.2 Polymerase chain reaction (PCR) determined microsatellite instability. 

3.1.2.3 MSI-H tumor status determined by next-generation sequencing.

3.1.3 Patient must have previously untreated localized gastric, or Siewert type II or III GEJ (gastroesophageal junction) adenocarcinoma. Tumors must be staged as T2 or greater primary lesion or be any T stage with the presence of positive locoregional lymph nodes- N+ (clinical nodes) without evidence of metastatic disease.

-Siewert Type II tumors: tumors located between 1 cm proximal and 2 cm distal to the GEJ. ?

-Siewert Type III tumors: tumors located between 2 and 5 cm distal to GEJ. 3.1.4 Patient must be amenable to surgical resection with therapeutic intent.

3.1.5 Patient must have an ECOG Performance Status 0-2.

3.1.6 Patient must demonstrate adequate organ and marrow function as defined below (these labs must be obtained ≤ 14 days prior to randomization): (Refer to most recent Protocol)

3.1.7 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

3.1.8 Patient must have no contraindications to receive one of the chemotherapy regimens: FLOT or mFOLFOX / CAPOX. 3.1.9 Patient must not have had prior potentially curative surgery for carcinoma of the stomach/GEJ.

3.1.10 Patient must not receive any other standard anti-cancer therapy or experimental agent concurrently with the study drugs.

3.1.11 Patient must have recovered from clinically significant adverse events of their most recent therapy/intervention prior to randomization.

3.1.12 Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. 3.1.13 Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

3.1.14 Patient must have chest/abdomen/pelvis CT completed within 4 weeks prior to randomization. 3.1.15 Patient may not have received prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PDL-1, anti-PDL-2, anti-CTLA4 monoclonal antibody).

3.1.16 Patient must not have received any live vaccines within 30 days prior to randomization and while participating in the study. Live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any nonlive vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist® are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events.

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH (Ann Arbor, Brighton, Canton, Chelsea), Sparrow, Saginaw, Livonia, LVHN, Holy Cross, St. John, Macomb, SJMO

Eligibility Criteria:

Eligibility for Step 1:

• Age = 18 years
• ECOG performance status of 0 or 1.
•  Patients must have oropharynx cancer that is p16-positive by immunohistochemistry with smoking status:

  =10 pack-years, stage T1-2N2-N3 or T3-4N0-3

  OR

  <10 pack-years, stage T4N0-N3 or T1-3N2-3. 

•  Patients must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.  
•  Patients with a history of allergic reactions attributed to platinumbased chemotherapy agents are excluded.
•  Patients must not have had prior systemic therapy or radiation treatment for p16 positive OPSCC.
•  Patients must not have received previous irradiation for head and neck tumor, skull base, or brain tumors.
•  Patients must not receive investigational agents within 4 weeks of enrollment or at any time while on study.
• Patients with evidence of distant metastases or leptomeningeal disease (LMD) are excluded.

• Patients with uncontrolled inter-current illnesses which in the opinion of the investigator will interfere with the ability to undergo therapy including chemotherapy are excluded.

• Baseline organ and marrow parameters (must be obtained = 2 weeks prior to randomization).

• ANC = 1500/mm3 ANC

• Hgb = 8.0 g/dL Hgb

• Platelet count = 100,000/mm3

• Creatinine clearance of = 60 ml/min.

- Baseline liver function parameters (must be obtained = 2 weeks prior to randomization)

• Total bilirubin within 1.5 times the normal limits

• SGOT (AST) or SGPT (ALT) within 2.0 times the normal limits AND Alkaline Phosphatase within 1.5 times the normal limits

- Women must not be pregnant or breast-feeding

- Patients must have measurable disease as defined in Section 6.1.

- Patients must have tumor measurements with CT of neck and CT of chest (or CT of neck  and FDG PET/CT if standard of care) within 4 weeks prior to Step 1 randomization.

Eligibility Criteria for Step 2:

• Patients must have progression per RECIST criteria AND tissueproven progression on Arm B treatment within 12 months after completion of radiation therapy.
• ECOG performance status of 0 or 1.
•  Patients must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.
• Patients must not have received non-protocol anti-cancer therapy after completion of radiation and chemotherapy.
• Baseline organ and marrow parameters (must be obtained = 2 weeks prior to registration).

-  ANC = 1500/mm3

-  Hgb = 8.0 g/dL

-  Platelet count = 100,000/mm3

-  Creatinine clearance of = 60 ml/min.

•  Baseline liver function parameters (must be obtained = 2 weeks prior to registration):

-  Total bilirubin within 1.5 times the normal limits

- SGOT (AST) or SGPT (ALT) within 2.0 times the normal limits AND Alkaline  Phosphatase within 1.5 times the normal limits

• Women must not be pregnant or breast-feeding
• Patients must have measurable disease as defined in Section 6.1.
• Patients must have tumor measurements with CT of neck and CT of chest (or CT of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 2 registration.

Eligibility Criteria:

 3.1.1 Patient must be ≥ 18 years of age.

3.1.2 Patient must have an ECOG Performance Status 0-2.

3.1.3 Patient must have differentiated thyroid cancer (DTC) with BRAF V600E mutation as determined by local testing, including the following subtypes (Note: results of a previous biopsy will be accepted): • Papillary thyroid carcinoma including histological variants of PTC such as follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin-like, trabecular, tumor with nodular fasciitis like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated.

• Follicular thyroid carcinoma including histological variants of FTC such as Hürthle cell, clear cell, insular, and poorly differentiated.

3.1.4 Patient must have been previously treated with or deemed ineligible for treatment with Iodine-131 for DTC, and must be receiving thyroxine suppression therapy

3.1.5 Patient must have had prior treatment with at least one of the following vascular endothelial growth factor receptors (VEGFR)-targeting tyrosine kinase inhibitor (TKI) agents for DTC: lenvatinib or sorafenib. NOTE: Up to two prior VEGFR-targeting TKI agents are allowed including, but not limited to lenvatinib and sorafenib.

3.1.6 Patient must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1·1 on chest CT (computed tomography) /abdominal/pelvis CT/MRI (magnetic resonance imaging) performed within 4 weeks prior to randomization.

3.1.7 Patient must have radiographic progression by RECIST 1.1 over any time interval on or after most recent prior systemic treatment.

3.1.8 Patient must not have any of the following cardiovascular and thromboembolic disorders or medical conditions:

• Congestive heart failure class 3 or 4 as defined by the New York Heart Association, unstable angina pectoris, or serious cardiac arrhythmias.

• Uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.

• Stroke, myocardial infarction, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months prior to randomization. Patients with more recent diagnosis of deep venous thrombosis are allowed if stable and treated with therapeutic anticoagulation for at least 6 weeks prior to randomization

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST **

**Credentialing must be completed prior to enrollment to main ALCHEMIST screening study (A151216)**

*DTL Required- Physicians must sign toxicity grid
CURRENT SITES CREDENTIALED:
Genesys, SJMH, Saginaw, Sparrow, St. Alphonsus, Lehigh, SJMO, St. Marys

-Patients must have undergone complete surgical resection of their stage IB (at least 4cm), II, or IIIA NSCLC and have had negative margins
-Patients must have no evidence of disease
-ECOG PS must be 0-1
-Patients must be registered to the ALCHEMIST-SCREEN (A151216)
-Non-squamous tumors must be EGFR and ALK wild-type
-Tumors must have PD-L1 status tested centrally
-Must not have prior treatment with an immune checkpoint inhibitor (anti-PD-L1, anti-CTLA4 monoclonal antibody)
-Patients must have adequately recovered from surgery and prior chemotherapy (grade 1 or less with exception of alopecia, ototoxicity and neuropathy)
-Patients must not require systemic corticosteroids equivalent to more than 10mg prednisone/d or other immunosuppressive meds

-Patients must have histologically or cytologically confirmed stage IV non-squamous NSCLC (includes M1a, M1b, and M1c stage disease, AJCC 8th edition). Patients with T4NX disease (Stage IIIB) with nodule in ipsilateral lung lobe are eligible if they are not candidates for combined chemotherapy and radiation.

-Patients must have PD-L1 expression Tumor Proportion Score (TPS = 1% in tumor cells. The assay must have been performed by a CLIA (or equivalent) certified laboratory.

-Patients must have measurable or non-measureable disease as defined in Section 6.1.2. Presence of malignant pleural fluid alone is allowed as study eligibility.

-Patients must have an ECOG Performance Status of 0 to 1

-Patients must NOT have received the following:

---Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) or immunotherapy for locally advanced Stage III disease is allowed if at least 6 months have elapsed since the prior therapy and registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed since completion.

---Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.

-Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600) or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded.

-Patients with symptomatic brain metastases are excluded. Patients with treated or asymptomatic brain metastases are eligible if off steroids for at least 14 days prior to protocol treatment. Anticonvulsants are allowed.

-Patients with another active malignancy within the last 2 years are excluded. Adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from

which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years are permitted.

-Patients must not have known pre-existing and clinically active interstitial lung disease, or a known history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.

-Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn’s disease, malabsorption,etc.)

-Patients must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 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.

-Patients must not have history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, NYHA classification of 3, unstable angina or poorly controlled

arrhythmia, or myocardial infarction within 6 months prior to registration.

*Credentialing required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED: SJMH, Livonia, Genesys, Sparrow, Saginaw, SJMO, Holy Cross

Eligibility Criteria:

Step 1 Eligibility Criteria – Concurrent Therapy

• Patient must be = 18 years old
• Patient must have one of the following: 
• Newly diagnosed stage IIIA/B/C NSCLC (per the AJCC 8th Edition) that is unresectable and is histologically and/or cytologically confirmed. 
• Nodal recurrence after surgery for early stage NSCLC. Please see Section 3.1.11 for associated requirements.
• Patient must have an ECOG Performance Status of 0 or 1.
• Body weight > 30 kg of patients.
• Patient should have a life expectancy greater than 12 weeks.
• Patient must have a baseline ECG obtained within 6 weeks of registration. 
• Patient must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version v1.1, as defined in Section 6.1. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to registration.
• Absolute neutrophil count (ANC) = 1500 cells/uL
• White blood cells (WBC) counts = 2500/uL
• Platelet count = 100,000/uL
• Hemoglobin = 9.0 g/dL
• Total bilirubin = 1.5 x upper limit of normal (ULN) with the following exception: patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled.
• Aspartate aminotransferase (AST) and alanine transaminase (ALT) = 3.0 x ULN.
• Patient must have acceptable organ and marrow function as defined below. These values must be obtained = 7 days prior to registration.
• Serum creatinine = 1.5 x ULN or creatinine clearance = 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (see Appendix VI).
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) = 1.5 x ULN.
• Patient must have pulmonary function tests (PFTs) with both FEV1 and DLCO = 40% of predicted, obtained within 5 months of registration.
• Patient should be expected to have Lung V20 of = 35%.
• Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met:
• No prior chemotherapy or radiation was ever administered for this lung cancer.
• Prior curative-intent surgery was at least 90 days prior to the nodal recurrence.
• No prior radiation was administered to the region of study cancer that would cause overlap of treatment fields.
• Patients who are Human Immunodeficiency Virus (HIV) positive may participate in the study IF they meet all of the following eligibility requirements:
• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective.
• They must have a CD4 count of greater than 250 cells/mcL.
• They must not be receiving prophylactic therapy for an opportunistic infection.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients must not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration.
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until 90 days after the last dose of study treatment. All females of childbearing potential must have a negative blood test or urine study, with a minimum sensitivity 50 mlU/L or equivalent units of HCG, within 7 days prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use accepted and highly effective method(s) of contraception during sexual intercourse for at least one week prior to the start of treatment, during protocol treatment, and continue for 90 days after the last dose of protocol treatment.
• Patient must not have any active, known or suspected autoimmune disease and neuromuscular paraneoplastic syndromes including, but not limited to myasthenia gravis, Lambert-Eaton myasthenic syndrome, limbic encephalitis, myositis, Guillain-Barré, systemic lupus erythematosus, and systemic sclerosis. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia), not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible.
• Patient must not have a history of active hepatitis B (chronic or acute) or hepatitis C infection. Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for hepatitis C virus ribonucleic acid (HCV RNA).
• Patient must not have a known active tuberculosis infection.
• Patient must not have any severe infections within 4 weeks prior to registration including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Patient must not have signs or symptoms of severe infection (sepsis) within 2 weeks prior registration.
• Patient must not have been treated with systemic immunostimulatory agents (including but not limited to interferon-a [IFN-a], interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to registration; or treated with an investigational agent within 4 weeks prior to registration (or within five half-lives of the investigational agent, whichever is longer).
• Unstable angina and/or congestive heart failure requiring hospitalization within 180 days prior to registration.
• Uncontrolled cardiac arrhythmia within 180 days prior to registration. weeks prior to registration (or within five half-lives of the investigational agent, whichever is longer).
• Patient must not have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Patient must not have been treated with systemic immunosuppressive medications (equivalent to > 10 mg prednisone per day) or other immunosuppressive medications within 7 days of registration. Inhaled or topical steroids and adrenal replacement steroid doses equivalent to > 10 mg prednisone per day are permitted in the absence of active autoimmune disease.
• Patient must not have had a prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• Patient must not have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan within 4 weeks of registration.
• Patient must not have had any prior systemic 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 costimulation or immune checkpoint pathways.
• Patient with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. For example, patients must not have the following:
• Unstable angina and/or congestive heart failure requiring hospitalization within 180 days prior to registration.
• Uncontrolled cardiac arrhythmia within 180 days prior to registration.
• Patient must not have an uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Patient must not have received a live, attenuated vaccine within 4 weeks prior to registration.
• Patient must not have unintentional weight loss > 10% within 30 days prior to registration.
• Patient must not have had past radiation to the current intended treatment site.
• Patient must not donate blood while on study treatment.

Step 2 Eligibility Criteria – Consolidation

• Patients must not receive any non-protocol anti-cancer therapy after the end of chemo/radiation or during consolidation.
• Patients with any > Grade 2 non-hematologic or > Grade 3 hematologic toxicities must recover to grade 2 (or less) within 45 days after the end of concurrent chemo/radiation, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with suspected cases of = Grade 2 pneumonitis (non-infectious) are not eligible for consolidative MEDI4736 (durvalumab) and will proceed onto follow-up instead.
• Patients must not have disease progression on the first post-treatment (for concurrent chemo/radiation) chest CT scan, which must be obtained within 14 days after the last dose of radiation therapy. If so, the patient is not eligible for consolidative MEDI4736 (durvalumab) and will proceed onto follow-up instead.