Protocol: NRG-GI008

Schema – NRG-GI008

Please Note: Below is partial eligibility, for full eligibility requirements, please contact Genesys Hurley Cancer Institute, Research Department at (810)762-8181, (810)762-8079 and/or (810)762-8038. Thank you!

Eligibility:

1. The patient must be ≥ 18 years old.
2. The patient must have an ECOG performance status of 0 or 1.
3. Patients must have histologically/pathologically confirmed Stage IIIA or Stage IIIB colon adenocarcinoma (T1-3, N1/N1c) with R0 resection accordingly to AJCC 8th edition criteria.
4. No radiographic evidence of overt metastatic disease within 28 days prior to study entry (CT with IV contrast or MRI imaging is acceptable and must include chest, abdomen, and pelvis).
5. The distal extent of the tumor must be ≥ 12 cm from the anal verge on colonoscopy or above the peritoneal reflection as documented during surgery or on pathology specimen (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation).
6. The patient must have had an en bloc complete gross resection of tumor (curative resection). Patients who have had a two-stage surgical procedure, to first provide a decompressive colostomy and then in a later procedure to have the definitive surgical resection, are eligible.
7. The resected tumor specimen and a blood specimen from patients with Stage IIIA or Stage IIIB colon cancer must have central testing for ctDNA using the Signatera assay by Natera. NOTE: Patients with stage IIIA or IIIB colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera assay as routine care outside of the study, are allowed to be enrolled, and will be retested and placed in either Cohort A or Cohort
   B depending on the central ctDNA testing result. NOTE: Patients with stage II or IIIC colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera assay as routine care outside of the study
   AND have a ctDNA+ve result, are allowed to be enrolled. Patients will have central ctDNA testing, confirmed to be ctDNA+ve, and placed in Cohort B.  Patients whose tumors are MSI-H or dMMR are excluded.
8. The treating investigator must deem the patient a candidate for all potential agents used in this trial (5FU, LV, oxaliplatin and irinotecan)

Ineligibility:

1. Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
2. Pathologic, clinical, or radiologic overt evidence of metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.
3. Tumor-related bowel perforation.
4. History of prior invasive colon malignancy, regardless of disease-free interval.
5. Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer (e.g., primary colon adenocarcinomas for which treatment with neoadjuvant chemotherapy and/or radiation is warranted are not permitted).
6. Other invasive malignancy within 5 years before study entry. Exceptions are colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.
7. Synchronous primary rectal and/ or colon cancers.
8. 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.
9. Sensory or motor neuropathy ≥ grade 2.

10. Co-morbid illnesses or other concurrent disease that would make the patient inappropriate for entry into this study (i.e., unable to tolerate 6 months of combination chemotherapy or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or prevent required follow-up).

Protocol: SWOG – S2107

Schema – S2107

Please Note: Below is partial eligibility, for full eligibility requirements, please contact Genesys Hurley Cancer Institute at (810)762-8181, (810)762-8079 and/or (810)762-8038, Thank you!

Eligibility:

1. Participants must have a histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum.
2. Participants must have measurable disease.
3. Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging.
4. Participants must have BRAFV600E mutated colorectal cancer as tested in a CLIAcertified laboratory.
5. Participants must have proficient mismatch repair (pMMR) or Microsatellite Stable (MSS) status as tested in a CLIA-certified laboratory and documented by the treating clinician. Proficient mismatch repair status can be determined by intact expression by immunohistochemistry of all 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Microsatellite instability can be determined by polymerase chain reaction (PCR).
6. Participants with brain metastases must have completed surgery or radiation therapy ≥ 28 days prior to registration. These participants must have a CT or MRI of the brain showing no new or enlarging lesions within 42 days prior to registration. These participants must also be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration. Metastatic brain parenchymal disease must have been treated and participant must be off steroids for 7 days prior to registration. The presence of leptomeningeal disease (LMD) is not considered stable disease, and participants with LMD are not eligible for this study.
7. Participants must have had one or two prior regimens of systemic chemotherapy for metastatic or locally advanced, unresectable disease. (A maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment. The re-introduction of an initially successful induction regimen will not be counted as one additional line of treatment) Prior treatment for metastatic disease is not required for patients who
   experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy.
8. Participants must not have had prior treatment with a BRAF inhibitor (including, but not limited to, encorafenib, dabrafenib, or vemurafenib), MEK inhibitor (including, but not limited to, trametinib, selumetinib, or binimetinib), or ERK
   inhibitor (of note, regorafenib is not considered a BRAF inhibitor for the context of eligibility criteria).
9. Participants must not have had prior treatment with anti-EGFR therapies.

10. Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, antiPD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.

11. Participants must not have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. 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 nonautoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as long as there has been a washout period for corticosteroids of ≥7 days prior to registration.

12. Participants must be of age ≥ 18 years.

13. Participants must have a Zubrod performance status of 0 or 1.

14. Participants must be able to swallow and retain pills.

15. Participants must have adequate cardiac function.

16. Participants must not have impaired gastrointestinal function or disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with
decreased intestinal absorption).

17. Participants must not have a history of inflammatory bowel disease, (including ulcerative colitis and Crohn’s disease), symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis, multiple sclerosis). Note: Participants with Graves’ disease will be allowed.

18.Participants must not have a history of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) within 6 months prior to study registration.

19. Participants must not have uncontrolled blood pressure and hypertension within 28 days prior to registration.

20. Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen or requires concurrent therapy.

21. Participants must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type.

Protocol: NRG – GI005

Schema – NRG-GI005

Please Note:  Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810)762-8038. Thank you!

Eligibility:

1. At least 18 years of age at diagnosis.
2. ECOG Performance Status 0-1.
3. Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0, M0) with at least 12 lymph nodes examined at the time of surgical resection.
4. Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion of and as documented by the evaluating oncologist based on current practice patterns.
5. The distal extent of the tumor must be ≥12 cm from the anal verge on pre-surgical endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the distal extent of the tumor must be ≥12 cm from the anal verge as determined by surgical examination or pre-operative imaging.
6. The patient must have had an en bloc complete gross resection of tumor (curative resection) as definitive surgical cancer treatment within 14 to 60 days of study randomization. Patients who have had a two-stage surgical procedure to first provide a decompressive colostomy and then, in a later procedure, to have the definitive surgical resection.

Ineligibility:

1. Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
2. Pathologic, clinical, or radiologic evidence of overt metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected (including the presence of satellite nodules constituting N1c disease in the absence of lymph node involvement).
3. History of prior invasive colon malignancy, regardless of disease-free interval.
4. Other invasive malignancy within 5 years before randomization. Exceptions are colonic polyps, non-melanoma skin cancer or carcinoma-in-situ including those of the cervix and breast (DCIS).

Protocol – NRG – GI004

Schema – NRG-GI004 SWOG-S1610

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810)762-8038. Thank you!

Eligibility:

1. At least 18 years of age.
2. ECOG Performance Status 0-2.
3. Diagnosis of metastatic adenocarcinoma of colon or rectum without previous chemotherapy or any other systemic therapy for metastatic colorectal cancer.
4. Tumor determined to be mismatch-repair deficient (dMMR) by CLIA-certified immunohistochemical (IHC) assay with a panel of all four IHC markers, including MLH1, MSH2, PMS2, and MSH6. Alternatively, MSI-H diagnosed by polymerase chain reaction (PCR)-based assessment of microsatellite alterations (either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) are eligible.
5. Documentation by PET/CT scan, CT scan, or MRI that the patient has measurable metastatic disease.
6. No immediate need for surgical intervention for the primary tumor or palliative diversion/bypass.

Ineligibility:

1. Patients with CNS metastases are excluded, with the following exceptions: Patients with asymptomatic untreated CNS metastases may be enrolled, provided all
   eligibility criteria are met. Patients with asymptomatic treated CNS metastases may be enrolled, provided all eligibility criteria are met.
2. Other malignancies are excluded unless the patient has completed therapy for the malignancy ≥ 12 months prior to randomization and is considered disease-free. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: in situ carcinomas or basal cell and squamous cell carcinoma of the skin.
3. Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization.
4. Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
5. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier are excluded.
6. Treatment with systemic immunostimulatory medications (including, but not limited to interferon [IFN]-α or interleukin [IL]-2 within 42 days prior to randomization.
7. Treatment with systemic immunosuppressive medications (including, but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization.
8. Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed.
9. Patients requiring treatment with a RANKL inhibitor (e.g., denosumab) who cannot discontinue it before treatment with atezolizumab.
10. Treatment with any other investigational agent within 4 weeks prior to randomization.

Protocol: SWOG – S1922

Schema – S1922

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810)762-8038. Thank you!

Eligibility:

1. Patients must have histologically or cytologically confirmed small bowel adenocarcinoma. Ampullary adenocarcinomas are not eligible. Patients must have metastatic disease or locally advanced unresectable disease.
2. Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to registration. Patients must be neurologically asymptomatic and without corticosteroid treatment for at
   least 7 days prior to registration.
3. Patients must have measurable or non-measurable disease. A diagnostic quality CT scan or MRI used to assess all disease must be performed within 28 days prior to registration.
4. Patients must have progressed on prior therapy with a fluoropyrimidine and/or oxaliplatin, given either for metastatic / locally advanced disease or as adjuvant therapy completed within the previous 12 months.
5. Patients must not have received prior treatment with irinotecan, taxane, or ramucirumab for small bowel adenocarcinoma.
6. Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to registration and all toxicity must be resolved to Grade 1 (with the exception of Grade 2 neuropathy) prior to registration.
7. Patients must not have had major surgery within 28 days prior to registration.
8. Patients must not be currently enrolled in or have discontinued within the last 28 days a clinical trial involving an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
9. Must be at least 18 years of age.
10. Zubrod Performance Status 0-1.
11. 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.