Summary

This phase II/III trial aims to determine the type of chemotherapy that will benefit patients who have had surgery for their stage II or III colon cancer based on presence or absence of circulating tumor deoxyribonucleic acid (ctDNA). In ctDNA positive patients, this trial compares the effect of usual chemotherapy versus mFOLFIRINOX. In ctDNA negative patients, this trial compares the effect of usual chemotherapy versus ctDNA testing every 3 months to determine which approach might be better to prevent colon cancer from returning. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It works by damaging cell’s DNA and may kill cancer cells. Leucovorin is in a class of medications called folic acid analogs. It works by protecting healthy cells from the effects of chemotherapy medications while allowing chemotherapy agent to enter and kill cancer cells. Fluorouracil is in a class of medications called antimetabolites. It stops cells from making DNA and may slow or stop the growth of cancer cells. Capecitabine is in a class of medications called antimetabolites. It Is taken up by cancer cells and breaks down to a substance that kills cancer cells. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It works by stopping the growth of cancer cells. This trial may help doctors determine what kind of chemotherapy to recommend to colon cancer patients based on the presence or absence of ctDNA after surgery for colon cancer.

Objectives

PRIMARY OBJECTIVES:
I. To compare time to ctDNA (positive [+ve]) status in ctDNA (negative [-ve]) cohort following resection of stage III colon cancer treated with immediate vs delayed (based on serial ctDNA surveillance) chemotherapy. (Phase II, ctDNA-ve Cohort [Arms 1 + 2])
II. To compare time to disease free survival (DFS) event (recurrence, second primary colorectal cancer or death) in ctDNA (-ve) cohort following resection of stage III colon cancer treated with immediate vs delayed (based on serial ctDNA surveillance) chemotherapy. (Phase III, ctDNA-ve Cohort [Arms 1 + 2])
III. To compare time to DFS event (recurrence, second primary colorectal cancer or death) in ctDNA (+ve) cohort following resection of colon cancer treated with fluorouracil (5-FU) (or capecitabine) and oxaliplatin x 6 months or 5-FU, oxaliplatin and irinotecan x 6 months. (Phase II and III, ctDNA+ve Cohort [Arms 3 + 4])

SECONDARY OBJECTIVES:
II. To describe the prevalence of detectable ctDNA in patients with stage III colon cancer following surgical resection.
II. To estimate time-to-event outcomes (overall survival and time to recurrence) by ctDNA marker status and treatment.
III. To assess the compliance of adjuvant chemotherapy.

EXPLORATORY OBJECTIVES:
I. To explore the kinetics of quantitative ctDNA levels over time and its association with time to event outcomes (relapse free survival [RFS], overall survival [OS], and time to recurrence [TTR]).
II. To characterize genomic profiles associated with recurrence using a ctDNA assay in patients with resected colon cancer.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin IV over 2 hours, and fluorouracil over 2-4 minutes and then over 46-48 hours on day 1. Cycles repeat every 14 days for 6-12 cycles in the absence of disease progression or unacceptable toxicity. Patients may alternatively receive oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo blood sample collection for serial ctDNA testing every 3-6 months for 3 years.

COHORT B: Patients are randomized to 1 of 2 arms.

ARM III: Patients receive oxaliplatin IV over 2 hours, leucovorin IV over 2 hours, and fluorouracil over 2-4 minutes and then over 46-48 hours on day 1. Cycles repeat every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may alternatively receive oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

ARM IV: Patients receive oxaliplatin IV over 2 hours, leucovorin IV over 2 hours, irinotecan IV over 30-90 minutes, and fluorouracil over 2-4 minutes and then over 46-48 hours on day 1. Cycles repeat every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

All patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study. Patients also undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up until year 5 from randomization.

Eligibility

1. The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
2. The patient must be >= 18 years old
3. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Patients must have histologically/pathologically confirmed stage IIB, IIC or stage III colon adenocarcinoma with R0 resection according to American Joint Committee on Cancer (AJCC) 8th edition criteria
5. No radiographic evidence of overt metastatic disease within 45 days prior to Step 1/Study entry (computed tomography [CT] with IV contrast or magnetic resonance imaging [MRI] imaging is acceptable and must include chest, abdomen, and pelvis)
6. 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)
7. 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
8. The resected tumor specimen and a blood specimen from patients with stage IIB, IIC or stage III colon cancer must have central testing for ctDNA using the Signatera assay by Natera (after step 1/study entry and before step 2/randomization). Patient must have sufficient tissue to meet protocol requirements. This blood specimen for the Signatera assay must be collected after surgery (and recommended at least 14 days post-surgery)
9. Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through Clinical Laboratory Improvement Act (CLIA)-approved laboratory testing. Patients whose tumors are microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) are excluded
10. The treating investigator must deem the patient a candidate for all potential agents used in this trial (5FU, LV, oxaliplatin and irinotecan)
11. The interval between surgery (post-operative day 7) and Step 1/Study entry must be no more than 60 days. Note: Step 1/Study entry may occur as early as post-operative day 7, but it cannot occur beyond 60 days from the actual date of the patient’s surgery
12. Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling
13. Absolute neutrophil count (ANC) must be >= 1500/mm^3 (within 28 days before Step 1/Study entry) * Participants with benign ethnic neutropenia (BEN): ANC < 1300 mm^3 are eligible. * BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups
14. Platelet count must be >= 100,000/mm^3 (within 28 days before Step 1/Study entry)
15. Hemoglobin must be >= 9 g/dL (within 28 days before Step 1/Study entry)
16. Total bilirubin must be =< ULN (upper limit of normal) for the lab (within 28 days before Step 1/Study entry)
17. Alkaline phosphatase must be < 2.5 x ULN for the lab (within 28 days before Step 1/Study entry)
18. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be < 2.5 x ULN for the lab (within 28 days before Step 1/Study entry)
19. Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before Step 1/Study entry)
20. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
21. Pregnancy test (urine or serum according to institutional standard) done within 14 days before Step 1/Study entry must be negative (for women of childbearing potential only)
22. Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of international normalized ratio (INR) if they are randomized to Arm 1 or Arm 3 and receive capecitabine
23. Cohort A Arm-2 patients on Second Randomization: Patient must have developed a ctDNA +ve assay during serial monitoring
24. Cohort A Arm-2 patients on Second Randomization: Patient's willingness to be re-randomized affirmed. (A reaffirmation form will be available on Cancer Trials Support Unit (CTSU) for patients to sign)
25. Cohort A Arm-2 patients on Second Randomization: The patient must continue to have an ECOG performance status of 0 or 1
26. Cohort A Arm-2 patients on Second Randomization: No radiographic evidence of overt metastatic disease
27. Cohort A Arm-2 patients on Second Randomization: Pregnancy test (urine or serum according to institutional standard) done within 14 days before second randomization must be negative (for women of childbearing potential only)
28. Cohort A Arm-2 patients on Second Randomization: Absolute neutrophil count (ANC) must be >= 1500/mm^3 (within 28 days before second randomization) * Participants with benign ethnic neutropenia (BEN): ANC < 1300 mm^3 are eligible. * BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups
29. Cohort A Arm-2 patients on Second Randomization: Platelet count must be >= 100,000/mm^3 (within 28 days before second randomization)
30. Cohort A Arm-2 patients on Second Randomization: Hemoglobin must be >= 9 g/dL (within 28 days before second randomization)
31. Cohort A Arm-2 patients on Second Randomization: Total bilirubin must be =< ULN (upper limit of normal) for the lab (within 28 days before second randomization)
32. Cohort A Arm-2 patients on Second Randomization: Alkaline phosphatase must be < 2.5 x ULN for the lab (within 28 days before second randomization)
33. Cohort A Arm-2 patients on Second Randomization: AST and ALT must be < 2.5 x ULN for the lab (within 28 days before second randomization)
34. Cohort A Arm-2 patients on Second Randomization: Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before second randomization)

Treatment Sites in Georgia