Clinical Trials in Progress: COBRA

Background

In 2022, approximately 25% of all new cases of colon cancer will be diagnosed as stage II. Although adjuvant chemotherapy is recommended for patients with high-risk stage II colon cancer, its overall benefit is marginal (< 5%) in an unselected population and exposes many to excessive toxicity. This trial addresses the need for more objective criteria for patients with risk-stratifying stage II colon cancer who may (or may not) benefit from adjuvant chemotherapy.

Identification of circulating tumor DNA (ctDNA), which is shed into the bloodstream following cancer cell apoptosis, represents a highly sensitive approach to detecting minimal residual disease after surgery. Across all stages of colon cancer, the presence of ctDNA postoperatively is strongly associated with eventual recurrence. Conversely, those with undetectable ctDNA are likely to remain disease free.

Despite clear prognostic utility for ctDNA methodologies, observational series thus far have reported mixed outcomes regarding the ability of chemotherapy to clear ctDNA and improve survival for patients with resected locoregional colon cancer. NRG GI-005 (NCT04068103), a first-in-kind trial supported by the National Cancer Institute for any solid tumor to evaluate ctDNA as an integral biomarker, seeks to provide level 1 evidence in evaluating the role of ctDNA as a guide for clinicians in the decision to administer adjuvant chemotherapy to patients with stage IIA colon cancer.

The Guardant Health REVEAL assay will evaluate ctDNA status in this study. This assay is a next-generation sequencing diagnostic test that can detect ctDNA in cell-free DNA that is isolated from whole blood by identifying somatic variations and colorectal cancer–specific epigenetic signatures. No accompanying tumor tissue is required for analysis of ctDNA in a CLIA-certified central laboratory, and estimated turnaround time for results is less than 3 weeks.

The primary end points are ctDNA clearance (phase 2) and recurrence-free survival (phase 3) among ctDNA-detected participants. The phase 2 analysis will be performed after 16 ctDNA-detected patients have been on study for 6 months (ie, the time to complete adjuvant chemotherapy). If P > .35 for ctDNA clearance between the 2 arms of patients with detectable ctDNA who do or do not receive adjuvant chemotherapy on study, then the trial will be stopped for futility. If P ≤ .35, then enrollment will continue to the phase 3 portion. For the phase 3 primary analysis, using a 1-sided α = .025 and a power of 92%, we hypothesize that, among the “ctDNA detected” group, adjuvant chemotherapy will improve recurrence-free survival by 60%. Secondary end points will evaluate overall survival, recurrence-free survival, and time to recurrence according to ctDNA status and treatment arm.

Eligibility Criteria

Participants with low-risk pT3N0M0 stage IIA colon (nonrectal) cancer who would be deemed suitable for observation (and no adjuvant chemotherapy) according to current practice patterns by their evaluating provider are eligible. Participants are not allowed to have had prior testing for ctDNA status prior to study entry, and prior systemic therapy or radiotherapy for colon cancer is not permitted. At least 12 lymph nodes must have been resected, and there must be no evidence for micro- or macroperforation of the primary colon cancer. Study registration must occur within 60 days of resection.

Patient Accrual Information

NRG GI-005 (NCT04068103) is currently enrolling at sites across the United States and Canada. This trial opened in December 2019. As of September 16, 2022, 416 of 1408 planned participants (30%) have been enrolled.

Contact Information

Van Morris, MD, MS
The University of Texas MD Anderson Cancer Center
1400 Holcombe Blvd, Unit 426
Houston, TX 77030
vkmorris@mdanderson.org
Phone: (713) 792-2828
Fax: (713) 745-1163

Atif Iqbal, MD, FACS, FACRS
Associate Professor Chief, Section of Colorectal Surgery
Baylor College of Medicine
7200 Cambridge St, 7th Fl
Houston, TX 77030
Atif.iqbal@bcm.edu
Phone: (713) 798-4321
Fax: (713) 798-6244