Protocol: NRG – GI008

SCHEMA GI008

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. 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. NOTE: Patients with pathologic stages II or IIIC colon adenocarcinoma with R0 resection who have a commercially obtained Signatera ctDNA+ve assay result post-operatively meeting all timelines and eligibility requirements otherwise, are eligible for enrollment and inclusion in Cohort B.
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.
8. Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through CLIA-approved laboratory testing. Patients whose tumors are MSI-H or dMMR are excluded.
9. 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. History of bone marrow or solid organ transplantation (regardless of current immunosuppressive therapy needs). Bone grafts, skin grafts, corneal transplants and organ/tissue donation are not exclusionary.
6. 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).
7. Other invasive malignancy within 5 years before study entry. Exceptions are colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.
8. Synchronous primary rectal and/ or colon cancers.

Protocol: NRG – GI005

Schema 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 GI004-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.

PROTOCOL: Alliance-A021703

SCHEMA A021703

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. Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which metastasectomy is not planned. No known dMMR or MSI-H disease.
2. Measurable disease.
3. No prior systemic treatment for metastatic disease.Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or chemoradiation. The last course of adjuvant therapy must have been completed > 12 months prior to colorectal cancer recurrence.  Patients may have received prior standard rectal cancer chemoradiation. Previous radiation therapy must have been completed ≥ 4 weeks prior to registration.
4. No continuous daily use of vitamin D supplements ≥ 2,000 IU per day for the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements ≥ 2,000 IU per day if total duration < 12 months in the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements < 2,000 IU per day for any duration prior to registration.
5. Patients must have completed any major surgery or open biopsy ≥ 4 weeks prior to registration and must have completed any minor surgery or core biopsy ≥ 1 week prior to registration.
6. At least 18 years of age.
7. ECOG Performance Status 0-1.
8. No resectable metastatic disease for which potentially curative metastasectomy is planned.
9. No “currently active” second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a “currently active” malignancy if they have completed therapy and have been free of disease for ≥ 3 years.
10. Concurrent use of supplemental calcium and/or vitamin D is not permitted. Patients must discontinue the supplement(s) at least 7 days prior to registration.

PROTOCOL: Alliance-A021502

SCHEMA A021502

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

ELIGIBILITY:

1. Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C). 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).
2. Presence of deficient (d) DNA mismatch repair (dMMR). Patients who are known to have Lynch Syndrome, have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), and have been
   shown to be dMMR by IHC are eligible to participate.
3. Tumors must have been completely resected. In patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented in the operative report or otherwise confirmed by the surgeon. Near or positive radial margins are acceptable so long as en bloc resection was performed. Proximal or distal margin positivity is not permitted. Entire tumor must be in the colon (rectal involvement is an exclusion). Surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon vs. rectal primary.
4. No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging.
5. Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (included with distal).
6. No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current colon cancer except for one cycle of mFOLFOX6.
7. At least 12 years of age.
8. Patients ≥18 years of age: ECOG Performance Status ≤ 2.
9. No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study.
10. No systemic daily treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration.