Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease
Overview
- Phase
- Phase 2
- Intervention
- Signatera test
- Conditions
- Stage III Colon Cancer
- Sponsor
- NRG Oncology
- Enrollment
- 1912
- Locations
- 2092
- Primary Endpoint
- ctDNA positive status (TTPos)
- Status
- Recruiting
- Last Updated
- 9 days ago
Overview
Brief Summary
This Phase II/III trial will evaluate the what kind of chemotherapy to recommend to patients based on the presence or absences of circulating tumor DNA (ctDNA) after surgery for colon cancer.
Detailed Description
Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer to determine need for adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying microscopic or residual tumor cells in colon cancer patients and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. Colon cancer patients who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need adjuvant chemotherapy. Furthermore, for colon cancer pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal adjuvant chemotherapy regimen has not been established. We hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to risk stratify for making decisions about adjuvant chemotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The patient must have an ECOG performance status of 0 or
- •Patients must have histologically/pathologically confirmed Stage IIB, IIC, or Stage III colon adenocarcinoma with R0 resection according to AJCC 8th edition criteria.
- •No radiographic evidence of overt metastatic disease within 45 days prior to Step 1/Study entry (CT with IV contrast or MRI imaging is acceptable and must include chest, abdomen, and pelvis).
- •The distal extent of the tumor must be greater than or equal to 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).
- •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.
- •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 Step2/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).
- •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.
- •The treating investigator must deem the patient a candidate for all potential agents used in this trial (5FU, LV, oxaliplatin and irinotecan).
- •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.
- •Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.
Exclusion Criteria
- •Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
- •Pathologic, clinical, or radiologic overt evidence of metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.
- •Tumor-related bowel perforation.
- •History of prior invasive colon malignancy, regardless of disease-free interval.
- •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.
- •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). EXCEPTION: one cycle of chemotherapy (regimen per treating physicians' discretion - 5-FU or capecitabine with or without oxaliplatin) is allowed but not required after consent. The optional cycle of chemotherapy should be started greater than or equal to 4 weeks from surgery and while awaiting Step 2 randomization.
- •Other invasive malignancy within 5 years before Step 1/Study entry. Exceptions are colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.
- •Synchronous primary rectal and/ or colon cancers.
- •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.
- •Sensory or motor neuropathy greater than or equal to grade 2, according to CTCAE v5.
Arms & Interventions
Cohort A - Arm 1 (ctDNA-ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 6-12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 4 cycles
Intervention: Signatera test
Cohort A - Arm 1 (ctDNA-ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 6-12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 4 cycles
Intervention: mFOLFOX6 3-6 month
Cohort A - Arm 1 (ctDNA-ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 6-12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 4 cycles
Intervention: CAPOX 3 month
Cohort B - Arm 3 (ctDNA+ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 8 cycles
Intervention: mFOLFOX6 6 month
Cohort B - Arm 4 (ctDNA+ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + Irinotecan 150 mg/m2 IV continuous infusion (30-90 minutes) + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles
Intervention: mFOLFIRINOX
Cohort A - Arm 2 (ctDNA-ve)
Serial ctDNA monitoring no treatment
Intervention: Signatera test
Cohort B - Arm 3 (ctDNA+ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 8 cycles
Intervention: Signatera test
Cohort B - Arm 4 (ctDNA+ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + Irinotecan 150 mg/m2 IV continuous infusion (30-90 minutes) + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles
Intervention: Signatera test
Cohort B - Arm 3 (ctDNA+ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 8 cycles
Intervention: CAPOX 6 month
Outcomes
Primary Outcomes
ctDNA positive status (TTPos)
Time Frame: Time from randomization to the first TTPos event, a maximum of 3 years
TTPos is defined as time from randomization until ctDNA positive event: TTPos events are first ctDNA positive result after randomization for the immediate adjuvant chemo arm (Arm 1), 2nd ctDNA positive result after randomization for the delayed adjuvant chemo (Arm 2) and recurrence without a positive ctDNA result for both arms.
Disease-Free Survival (DFS)
Time Frame: Time from randomization to disease-free survival event, a maximum of 5 years]
Time from randomization to first disease-free survival event (recurrence, second primary colorectal cancer or death from any cause).
Secondary Outcomes
- Overall Survival (OS)(Time from randomization to death, a maximum of 5 years.)
- Baseline post-surgery ctDNA positivity rate(At time of randomization)
- Recurrence(Time from randomization to disease recurrence, a maximum of 5 years)
- Compliance with adjuvant chemotherapy(from randomization to the last cycle of chemotherapy, a maximum of 6 months.)