Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIA Colon Cancer After Surgery

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II/III Study of Circulating Tumor DNA as a Predictive Biomarker in Adjuvant Chemotherapy in Patients With Stage IIA Colon Cancer (COBRA)

Conditions
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Colon Adenocarcinoma, Stage IIA Colon Cancer AJCC v8

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Fluorouracil
* Drug: Leucovorin
* Drug: Leucovorin Calcium
* Drug: Oxaliplatin
* Other: Patient Observation


Participation Criteria
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Eligibility Criteria
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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 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. 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: Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker. Ventricular tachycardia or supraventricular tachycardia that requires treatment with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted. Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker. Complete left bundle branch block (LBBB) unless treated with a permanent pacemaker. Sensory or motor neuropathy >= grade 2, according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Active seizure disorder uncontrolled by medication. Active or chronic infection requiring systemic therapy. Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency. Pregnancy or lactation at the time of randomization. Co-morbid illnesses or other concurrent disease that, in the judgement of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study (i.e., unable to tolerate 6 months of combination chemotherapy or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or prevent required follow-up). Prior testing with any available ctDNA test as part of the management of colon cancer, is not permitted.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (blood stored and tested for ctDNA later)<br>Patients undergo active surveillance. | Other: Patient Observation<br>* Undergo active surveillance<br>* Other names: Watchful Waiting;|
| Experimental: Arm II (blood tested for ctDNA at baseline)<br>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. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: Oxaliplatin<br>* Give IV<br>* Other names: SR-96669;Other: Patient Observation<br>* Undergo active surveillance<br>* Other names: Watchful Waiting;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance of circulating tumor deoxyribonucleic acid (ctDNA) (to undetectable levels) for the baseline ctDNA detected patient subset (Phase II) | 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. | Baseline up to 6 months | 
| Recurrence-free survival (RFS) the baseline ctDNA detected patient subset (Phase III) | 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. | Time to recurrence or death, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RFS | According to ctDNA marker status and treatment. Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment combination. | Up to 3 years | 
| Overall survival (OS) | According to ctDNA marker status and treatment. Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment combination. The unstratified logrank test will be used to compare treatments for patients ?ctDNA positive? at baseline and a Cox model will estimate the hazard ratio. | Up to 3 years | 
| Time to recurrence (TTR) | According to ctDNA marker status and treatment. Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment combination. The unstratified logrank test will be used to compare treatments for patients ?ctDNA positive? at baseline and a Cox model will estimate the hazard ratio. | Up to 3 years | 
| Compliance with adjuvant chemotherapy and/or active surveillance | The duration of chemotherapy will be categorized as none, less than 3 months, and at least 3 months by treatment arm and baseline ctDNA status. Arms will be compared by a chi square test within each baseline ctDNA status. | Up to 3 years | 
| Incidence (presence or absence) of ctDNA in blood following resection of stage II colon cancer |  | Up to 3 years |