*Credentialing required. Please check your site's credentialing status.*

**Effective 05/09/18 Patient Pre-Registration (Step 0) is Temporarily Suspended

**Effective 08/13/18 Arm 2 is closed to accrual
CURRENT SITES CREDENTIALED:
SJMH, Lehigh, Saginaw

Pre-registration eligibility:
-Cytologic or histologic proof of adenocarcinoma of the pancreatic head or uncinate process.
-TX, T1-4N0-1orNxM0* *M1 disease includes spread to distant lymph nodes, organs, and ascites
-Local radiographic reading must be consistent with borderline resectable cancer of the pancreatic head and must meet one or more of the following on CT/MRI:
--An interface is present between the primary tumor and the superior mesenteric vein or portal vein and measures greater than or equal to 180° of the circumference of the vessel wall
--Short-segment occlusion of the SMV-PV is present with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
--Short segment interface (of any degree) is present between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and reconstruction
--An interface is present between the tumor and superior mesenteric artery or celiac axis measuring < 180° of the circumference of the vessel wall

Registration eligibility: 
-Confirmation of radiographic stage as borderline resectable disease by real-time Alliance central radiographic review
-No prior chemotherapy or radiation for pancreatic cancer
-No previous definitive resection of pancreatic cancer
-No grade 2 or greater neuropathy
-ECOG PS 0-1

*DTL Required- Physicians must sign toxicity grid

CURRENT SITES COMPLETED:  SJMH, SJMO, Saginaw, Sparrow, Genesys Hurley, Hurley, Livonia, St. John Detroit, St. John Macomb

-Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C).
-DNA Mismatch Repair (MMR) Status: Presence of deficient (d) DNA mismatch repair (dMMR). 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.
-Tumors must have been completely resected.
-Entire tumor must be in the colon (rectal involvement is an exclusion).
-No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging.
-ECOG Performance Status 0- 2
-No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for colon cancer except for one cycle of mFOLFOX6. Cycle 1 of mFOLFOX6 must have been administered

-No systemic daily treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration.

*DTL Required- Physicians must sign toxicity grid

CURRENT SITES COMPLETED: SJMH, Genesys Hurley, Hurley, Lehigh Valley, Saginaw, St. John, Macomb

-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: 1) well- or moderately-differentiated neuroendocrine tumor, 2) low- or intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor or atypical carcinoid tumor.
-Locally advanced/ unresectable or metastatic disease
-Histological documentation of neuroendocrine tumor of pancreatic, gastrointestinal (GI), lung, or unknown primary site.
-Target lesions must have shown evidence of disease progression in the 12 months prior to registration

-Patients must have measurable disease
-Patient must have failed at least one prior systemic therapy that included everolimus.
-Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to grade 1 or less.
-ECOG PS must be 0-2

*DTL Required- Physicians must sign toxicity grid CREDENTIALING REQUIRED. Please check your site's credentialing status. CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Sparrow, SJMO, GenHur, LVHN, Livonia, Saginaw, St. John, Macomb,

Eligibility Criteria:

*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, St. John Hospital, Macomb, LVHN

Eligibility Criteria:

3.2.1 Documentation of Disease

• Histologic Documentation: Histologically-proven advanced (metastatic or unresectable primary) pheochromocytoma or paraganglioma.
• Stage: Advanced (metastatic or unresectable primary) disease
• Tumor Site: Histologically-proven pheochromocytoma or paraganglioma
• Radiographic Evaluation: Radiographic evidence of disease progression by RECIST v1.1 criteria in the 12 months prior to registration.

3.2.2 Measurable disease as defined in Section 11.0.

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.

3.2.3 Prior Treatment

Prior treatment with other chemotherapy, radiotherapy (including peptide radionuclide receptor therapy [PRRT]), or surgery must be completed = 28 days prior to registration. Patients must have recovered from any effects of any major surgery prior to registration.

Prior treatment with radiolabeled MIBG must be completed = 12 weeks prior to registration and lifetime cumulative 131I-MIBG dose must be < 1000 MBq kg-1 (36 mCi kg-1).

Prior treatment with antibiotics must be completed = 7 days prior to registration.

No prior treatment with temozolomide, dacarbazine, or a poly ADP ribose polymerase (PARP) inhibitor.

No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).

3.2.4 Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects.

Therefore, for women of childbearing potential only, a negative pregnancy test done = 7 days prior to registration is required.

3.2.5 Contraception

Therapy utilized in this trial is associated with medium/high fetal risk.

Women of childbearing potential and their partners, who are sexually active, must agree to use two highly effective forms of contraception in combination (as listed in Appendix V). This should be started from the time of registration and continue throughout the period of taking study treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse (see Appendix V).

Male patients must use a condom during treatment and for 3 months after the last dose of study drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential (as listed in Appendix V). Male patients should not donate sperm throughout the period of taking study drug(s) and for 3 months following the last dose of study drug(s).

3.2.6 Age = 18 years

3.2.7 ECOG Performance Status: 0-2

3.2.8 Required Initial Laboratory Values

• Absolute Neutrophil Count = 1,500/mm3
• Platelet Count = 100,000/mm3
• Hemoglobin = 10 mg/dL*
• Total Bilirubin = 1.5 x upper limit of normal (ULN)**
• AST/ALT = 3.0 x ULN
• Creatinine < 1.5 x ULN

OR

Calc. Creatinine Clearance > 50 mL/min***

*In the absence of transfusion within the previous 24 hours.

**Except in the case of Gilbert’s syndrome, then Total Bilirubin must be = 3.0 x ULN.

***Calculated by Cockcroft-Gault equation.

3.2.9 Patient History

- No indication of uncontrolled, potentially reversible cardiac condition(s) as determined by investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 msec, electrolyte disturbances, etc.) and no known congenital long QT syndrome.

- No extensive bilateral lung disease or pneumonitis.

- No abnormal organ or bone marrow function = 28 days prior to registration.

- Patients with HIV positivity are allowed if CD4 Count > 250 cells/µL and they have an undetectable HIV viral load within 6 months of registration.

- No active infection.

- No history of myelodysplastic syndrome (MDS) (or any dysplastic leukocyte morphology suggestive of MDS) or acute myeloid leukemia.

- No known gastrointestinal condition(s) that might predispose for drug intolerability or poor drug absorption.

- 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 biologic composition to PARP inhibitors.

3.2.10 Concomitant Medications

Concurrent use of combination antiretroviral therapy (ART) is not permitted.

Chronic concomitant treatment with strong or moderate CYP3A4 inducers or inhibitors is not allowed. Patients must discontinue the agent(s) = 21 days prior to registration; enzalutamide and/or phenobarbital must be discontinued = 5 weeks prior to registration. See Section 8.1.8 for more information.

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Saginaw, St. John, LVHN

Eligibility Criteria:

Pre-Registration Eligibility Criteria (Step 0)

Documentation of Disease

Pathology: Histologic or cytologic proof of pancreatic adenocarcinoma or adenosquamous carcinoma.

TNM Stage: Tx-4, N0-1, M0*

*M0 disease does not include spread to distant lymph nodes and organs

Resectable Primary Tumor: Local radiographic reading must be consistent with resectable disease defined as the following on 1) arterial and venous phase contrast-enhanced abdominal/pelvic CT scan or abdominal/pelvic MRI scan and 2) chest CT:

• No involvement or abutment of the celiac artery, common hepatic artery, superior mesenteric artery, or replaced right hepatic artery (if applicable)
• Less than 180° interface between tumor and vessel wall of the portal vein or superior mesenteric vein, and patent portal vein/splenic vein confluence

• No evidence of metastatic disease

Measurable disease or non-measurable disease as defined in Section 11.0.

Non-measurable disease is defined as cytologic or histologic confirmation of adenocarcinoma of adenosquamous carcinoma by fine needle aspiration or core-biopsy of the pancreas without measurable disease by radiographic imaging.

Registration Eligibility Criteria (Step 1)

- A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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).

Disease Status

Confirmation of resectable disease by real-time central imaging review by the Alliance Imaging Core Lab at IROC Ohio.

Determined to be appropriate candidate for curative-intent pancreatectomy by surgeon intending to perform the resection.

- Prior Treatment

No prior radiation therapy, chemotherapy, targeted therapy, investigational therapy, or surgery for pancreatic cancer.

-Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects.

Therefore, for women of childbearing potential only, a negative pregnancy test done = 14 days prior to registration is required.

Age = 18 years

- ECOG Performance Status 0-1

- Total Neuropathy Score < 2

- Required Initial Laboratory Values

• Absolute Neutrophil Count (ANC) = 1,500/µL
• Platelet Count = 100,000/µL
• Total Bilirubin = 1.5 x upper limit of normal (ULN)*
• Creatinine = 1.5 x ULN

OR

Calc. Creatinine Clearance = 30 mL/min**

*If obstructive jaundice is present, then biliary drainage must be initiated and Total Bilirubin = 3.0.

**Calculated using the Cockcroft-Gault equation

Comorbid Conditions

- No known Gilbert’s Syndrome or known homozygosity for UGAT1A1*28 polymorphism.

- No comorbid conditions that would prohibit curative-intent pancreatectomy.

Concomitant Medications

- Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug prior to registration. See Section 8.1.11 for more information.

- Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inducers must discontinue the drug prior to registration. See Section 8.1.12 for more information.

** Lutetium LU177 credentialing requirements**

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED:

Eligibility Criteria:

3.2 Pre-Registration Eligibility Criteria

3.2.1 Documentation of Disease

• Pathologic Documentation: Well- or moderately differentiated neuroendocrine tumor(s) of bronchial origin (i.e. carcinoid) as assessed by local pathology. The pathology report must state ONE of the following: 1) well- or moderately differentiated neuroendocrine tumor, 2) low- or intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor (including typical or atypical carcinoid tumors). Documentation of histology from a primary or metastatic site is allowed. Functional (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing’s syndrome) or nonfunctional tumors are allowed. Patients with poorly-differentiated or high-grade neuroendocrine carcinoma (i.e. large cell neuroendocrine carcinoma of lung, small cell lung cancer) or mixed tumors (i.e. adenocarcinoid tumor) are not eligible. • Stage: Recurrent or locally-advanced/unresectable or metastatic disease.

• Tumor Site: Neuroendocrine tumor of bronchial (i.e. lung) primary site.

• Radiologic Evaluation: Lesions must have shown radiological evidence of disease progression in the 12 months prior to pre-registration. Tumor must have shown somatostatin receptor (SSTR) positivity on 68GaDOTATATE PET or other SSTR-PET scan in the 12 months prior to pre-registration; however, documentation of SSTR positivity in the 6 months prior to pre-registration is preferred. SSTR positivity is defined as uptake greater than background liver in all measurable lesions. 

3.2.2 Measurable Disease Patients must have measurable disease per RECIST v1.1 by computer tomography (CT) scan or magnetic imaging (MRI); see Section 11.0. Any lesions which have undergone percutaneous therapies or radiotherapy should not be considered measurable unless the lesion has clearly progressed since the procedure. 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, bone metastases, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung. See Section 11.0 for additional details.  

3.3 Registration Eligibility Criteria 

3.3.1 Disease Status Confirmation of SSTR positivity by Alliance ICL at IROC Ohio central radiographic review.

3.3.2 Prior Treatment Patients with treatment-naïve or previously treated disease are allowed. Patients with previously-treated disease must have demonstrated radiographic disease progression on the prior therapy. No prior treatment with peptide receptor radionuclide therapy (PRRT) (e.g. lutetium Lu 177 dotatate). No prior treatment with mammalian target of rapamycin (mTOR) inhibitors (e.g. deforolimus, everolimus, sirolimus, temsirolimus, etc.). Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective radioembolization) or ablative therapies (i.e. cryoablation, radiofrequency ablation, etc.) 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 90-Yttrium radioembolization must be completed at least 3 months prior to registration. Radiation therapy to the lung and/or mediastinum must be completed at least 14 days prior to registration for stereotactic ablative and at least 28 days prior to registration for conventional fractionation. Prior treatment with systemic anticancer therapy must be completed at least 28 days prior to registration (except for somatostatin analogs in patients with functional tumors). Continuation of treatment with somatostatin analogs while on protocol therapy is allowed provided that the patient: 1) has functional tumors (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing’s syndrome), and 2) has previously demonstrated radiographic disease progression while on somatostatin analog therapy. Patients must have completed any major surgery at least 28 days prior to registration. Complete wound healing from major surgery should occur prior to registration. Patients should have improvement of any toxic effects of prior therapy (except alopecia, fatigue, and other non-reversible toxic effects such as neuropathy from cisplatin) to NCI CTCAE, version 5.0, grade 1 or less.  

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

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health- SJMH (Ann Arbor, Brighton, Chelsea, Canton), Livonia, Genesys, Hurley, Lehigh

Eligibility Criteria:

Pre-Registration (Step 0) Eligibility Criteria

Pre-registration for central tumor testing will occur after colon resection. Pre-registration can occur at any time after surgery through a five week period after completion of standard adjuvant therapy.

3.2.1 BRAF Mutation Testing BRAF V600 mutational status may be determined either locally or by central testing. This testing is mandatory prior to registration to determine eligibility.

3.3 Registration (Step 1) Eligibility Criteria

 3.3.1 Documentation of Disease Histologically-proven stage III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk (pT4) stage II colon adenocarcinoma. Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve) and must have been completely resected. BRAF V600E mutation. MMR proficient (pMMR) or microsatellite stable (MSS) tumor. Histologic Documentation: adenocarcinoma Stage: III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk II (pT4) Tumor Site: colon

3.3.2 Prior Treatment Patients must have received at least 3 months of adjuvant chemotherapy with either FOLFOX (minimum of 5 cycles) or CAPOX (minimum of 3 cycles). Adjuvant therapy must be completed at most 8 weeks prior to registration. No other prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy) or radiation therapy for the current colon cancer is permitted. 

3.3.3 Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.

3.3.4 Age ≥ 18 years

3.3.5 ECOG Performance Status: 0-2 

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

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

Eligibility Criteria:

Pre-Registration Eligibility Criteria (see Section 3.2)

- Histologically-confirmed metastatic colorectal adenocarcinoma

- No known microsatellite instable tumor

- No known BRAF V600E mutation

- No known brain metastases

- No known peritoneal and/or omental metastases

- Primary tumor is already resected OR primary tumor is surgically amenable to resection, (See Sec 3.2.1). Patients with unresectable primary tumors are not eligible.

- Four or fewer apparent sites of metastatic disease based on review by local medical team of baseline radiographic imaging obtained prior to initiation of systemic therapy; (See Sec 3.2.1)

- Patients must have measurable disease per RECIST v1.1

- A maximum of 16 weeks (4 months) of systemic therapy may be administered prior to pre-registration Registration Eligibility Criteria (see Section 3.3)

- Patients must have no overt evidence of disease progression during systemic therapy prior to registration

- Not eligible for hepatic artery infusion pump (HAIP) therapy or benefit of HAIP therapy is undefined.

- Patients must have measurable disease per RECIST v1.1

- Patients must be receiving (or have received) first-line systemic therapy for metastatic disease for a minimum of 16 weeks (4 months) and a maximum of 24 weeks (6 months).

- Prior definitive therapy must have been completed at least 12 months prior to diagnosis of metastatic disease

- Not pregnant and not nursing (See Sec 3.3.4)

- Age ≥ 18 years

- ECOG Performance Status: 0-2

- Patients with known HIV are eligible (See Sec 3.3.8)

- No other planned concurrent investigational agents while on study 

***Please see the current version of protocol for full eligibility List***** 

Eligibility Criteria 

Required Initial Laboratory Values

• HER2 negative gastroesophageal adenocarcinoma with known PD-L1 CPS ANC ≥ 1500/mm3

• Measurable disease or non-measurable but evaluable disease as defined by RECIST 1.1 Platelet count: ≥ 100,000/mm3

• No prior treatment for metastatic disease (see Section 3.2 for prior neoadjuvant and/or adjuvant therapy parameters) Creatinine: ≤ 1.5 x upper limit of normal (ULN) OR

• Not pregnant and not nursing Calc. creatinine ≥ 30 mL/min

• Age ≥ 18 years clearance

• ECOG performance status 0 or 1

• 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.

• No allogeneic tissue/organ transplant Total bilirubin: AST/ALT: ≤ 1.5 x ULN ≤ 3 x ULN (< 5 x ULN if clearly attributable to liver metastases)

• No known Gilbert’s Syndrome or known homozygosity for UGAT1A1*28 polymorphism

• No grade ≥ 2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per CTCAE v5.0 regardless of causality

• No medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

• No active autoimmune disease requiring systemic treatment with disease modifying agents or immunosuppressive drugs within 6 months.

• No history of noninfectious pneumonitis requiring steroid

**SEE CURRENT PROTOCOL FOR COMPLETE ELIGIBILITY LIST***