Phase II/III Study of Circulating Tumor DNA as a Predictive Biomarker in Adjuvant Chemotherapy in Patients With Stage IIA Colon Cancer (COBRA)
Overview
- Phase
- Phase 2
- Intervention
- Patient Observation
- Conditions
- Colon Adenocarcinoma
- Sponsor
- NRG Oncology
- Enrollment
- 635
- Locations
- 953
- Primary Endpoint
- Clearance of Circulating Tumor Deoxyribonucleic Acid (ctDNA) (to Undetectable Levels) for the "Baseline ctDNA Detected" Patient Subset (Phase II)
- Status
- Active, not recruiting
- Last Updated
- 12 months ago
Overview
Brief Summary
This phase II/III trial studies how well circulating tumor deoxyribonucleic acid (ctDNA) testing in the blood works in predicting treatment for patients with stage IIA colon cancer after surgery. ctDNA are circulating tumor cells that are shed by tumors into the blood. Finding ctDNA in the blood means that there is very likely some small amounts of cancer that remain after surgery. However, this cancer, if detected, cannot be found on other tests usually used to find cancer, as it is too small. Testing for ctDNA levels may help identify patients with colon cancer after surgery who do benefit, and those who do not benefit, from receiving chemotherapy.
Detailed Description
PRIMARY OBJECTIVES: I. To compare the rate of ctDNA clearance in "ctDNA detected" patients treated with or without adjuvant chemotherapy following resection of stage IIA colon cancer. (Phase II) II. To compare recurrence-free survival (RFS) in "ctDNA detected" patients treated with or without adjuvant chemotherapy following resection of stage IIA colon cancer. (Phase III) SECONDARY OBJECTIVES: I. To describe the prevalence of detectable ctDNA in patients with stage IIA colon cancer following surgical resection. II. To estimate time-to-event outcomes (overall survival \[OS\], recurrence-free survival \[RFS\], and time to recurrence \[TTR\]) by ctDNA marker status and treatment for patients with resected stage IIA colon cancer. III. To estimate the rate of compliance with adjuvant chemotherapy and/or active surveillance for patients with resected stage IIA colon cancer.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •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.
- •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.
- •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.
- •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, are eligible.
- •Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.
- •Absolute neutrophil count (ANC) must be \>= 1200/mm\^3 (within 28 days before randomization).
- •Platelet count must be \>= 100,000/mm\^3 (within 28 days before randomization); and
- •Hemoglobin must be \>= 9 g/dL (within 28 days before randomization).
Exclusion Criteria
- •Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
- •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).
- •Tumor-related bowel perforation.
- •History of prior invasive colon malignancy, regardless of disease-free interval.
- •History of organ transplantation.
- •Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer (e.g., primary rectal adenocarcinomas for which treatment with neoadjuvant chemoradiation is warranted are not permitted).
- •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).
- •Synchronous primary rectal and/or colon cancers.
- •Antineoplastic therapy (e.g., chemotherapy, targeted therapy, or immunotherapy) within 5 years before randomization. (For the purposes of this study, hormonal therapy is not considered chemotherapy.).
- •Uncontrolled cardiac disease, in the opinion of the treating medical oncologist, that would preclude the use of any of the drugs included in the GI005 treatment regimen. This includes but is not limited to:
Arms & Interventions
Arm I (blood stored and tested for ctDNA later)
Patients undergo active surveillance.
Intervention: Patient Observation
Arm II (blood tested for ctDNA at baseline)
Patients are assigned to 1 of 2 groups. GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin IV over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity at the discretion of the investigator. GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
Intervention: Capecitabine
Arm II (blood tested for ctDNA at baseline)
Patients are assigned to 1 of 2 groups. GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin IV over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity at the discretion of the investigator. GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
Intervention: Fluorouracil
Arm II (blood tested for ctDNA at baseline)
Patients are assigned to 1 of 2 groups. GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin IV over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity at the discretion of the investigator. GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
Intervention: Leucovorin
Arm II (blood tested for ctDNA at baseline)
Patients are assigned to 1 of 2 groups. GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin IV over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity at the discretion of the investigator. GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
Intervention: Leucovorin Calcium
Arm II (blood tested for ctDNA at baseline)
Patients are assigned to 1 of 2 groups. GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin IV over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity at the discretion of the investigator. GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
Intervention: Oxaliplatin
Arm II (blood tested for ctDNA at baseline)
Patients are assigned to 1 of 2 groups. GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin IV over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity at the discretion of the investigator. GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
Intervention: Patient Observation
Outcomes
Primary Outcomes
Clearance of Circulating Tumor Deoxyribonucleic Acid (ctDNA) (to Undetectable Levels) for the "Baseline ctDNA Detected" Patient Subset (Phase II)
Time Frame: Baseline up to 6 months
A two by two contingency table of clearance by treatment arm will be created. The one-sided Fisher exact p-value will be used to determine futility based on the rule specified. Degenerate tables where the Fisher p-value cannot be calculated (no patients clear on either arm or all patients clear on both arms) will count as a failure and a recommendation for early termination.
Recurrence-free Survival (RFS) the "Baseline ctDNA Detected" Patient Subset (Phase III)
Time Frame: Time to recurrence or death, assessed up to 3 years
RFS will be compared by treatment arm using the logrank test with no stratification in the intent to treat (ITT) cohort. Kaplan Meier curves will be computed to describe the distribution of time to event. A summary hazard ratio and associated confidence interval will be computed from a Cox model with treatment arm as the only covariate.
Secondary Outcomes
- RFS(Up to 3 years)
- Overall Survival (OS)(Up to 3 years)
- Time to Recurrence (TTR)(Up to 3 years)
- Compliance With Adjuvant Chemotherapy and/or Active Surveillance(Up to 3 years)
- Incidence (Presence or Absence) of ctDNA in Blood Following Resection of Stage II Colon Cancer(Up to 3 years)