Circulating Tumor DNA Testing in Predicting Treatment for Patients with Stage IIA Colon Cancer After Surgery, COBRA Trial
Colon/Rectal Cancer
Unknown Primary
18 Years and older, Male and Female
NRG-GI005 (primary)
NRG-GI005
NCI-2019-01068
Summary
This phase II/III trial studies how well circulating tumor deoxyribonucleic acid (ctDNA) testing in the blood works to identify patients with stage IIA colon cancer who might benefit from additional treatment with chemotherapy after surgery. ctDNA are small pieces of genetic materials (DNA) that are shed by tumors into the blood. Finding ctDNA in the blood means that there are very likely small amounts of cancer remaining after surgery that may not be detectable using other tests, such as medical imaging. Testing for ctDNA levels may help identify patients with colon cancer who benefit from receiving chemotherapy after surgery. It is not yet known whether giving additional treatment with chemotherapy after surgery to patients who test positive for ctDNA and are at low risk for cancer recurrence would extend their time without disease compared to the usual approach (active surveillance).
Objectives
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.
EXPLORATORY OBJECTIVES:
I. To describe the association of quantitative ctDNA levels with time to event outcomes (RFS, OS, and TTR).
II. To characterize genomic profiles associated with recurrence using a ctDNA assay in patients with resected stage IIA colon cancer.
III. To model the cost effectiveness of the use of ctDNA versus standard of care in this setting.
IV. To evaluate performance of a ctDNA assay after incorporation of patient tumor and peripheral blood mononuclear cells.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (BLOOD STORED AND TESTED FOR ctDNA LATER): Patients undergo active surveillance.
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 intravenously (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 orally (PO) twice daily (BID) on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
After completion of study treatment, patients are followed up at 12 months and then every 6 months for 2 years.
Eligibility
- 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 1.
- 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).
- Total bilirubin must be =< ULN (upper limit of normal) for the lab (within 28 days before randomization) unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin; and
- Alkaline phosphatase must be < 2.5 x ULN for the lab (within 28 days before randomization); and
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be < 1.5 x ULN for the lab (within 28 days before randomization).
- Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before randomization).
- Pregnancy test (urine or serum according to institutional standard) done within 14 days before randomization must be negative (for women of childbearing potential only).
- Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of international normalized ratio (INR) if they are randomized to Arm 2 and receive capecitabine.
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