Clinical Trials /

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

NCT04068103

Description:

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.

Related Conditions:
  • Colon Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIA Colon Cancer After Surgery
  • Official Title: Phase II/III Study of Circulating Tumor DNA as a Predictive Biomarker in Adjuvant Chemotherapy in Patients With Stage IIA Colon Cancer (COBRA)

Clinical Trial IDs

  • ORG STUDY ID: NRG-GI005
  • SECONDARY ID: NCI-2019-01068
  • SECONDARY ID: NRG-GI005
  • SECONDARY ID: NRG-GI005
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04068103

Conditions

  • Colon Adenocarcinoma
  • Stage IIA Colon Cancer AJCC v8

Interventions

DrugSynonymsArms
CapecitabineRo 09-1978/000, XelodaArm II (blood tested for ctDNA at baseline)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Arm II (blood tested for ctDNA at baseline)
LeucovorinFolinic acidArm II (blood tested for ctDNA at baseline)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinArm II (blood tested for ctDNA at baseline)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Arm II (blood tested for ctDNA at baseline)

Purpose

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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (blood stored and tested for ctDNA later)Active ComparatorPatients undergo active surveillance.
    Arm II (blood tested for ctDNA at baseline)ExperimentalPatients 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.
    • Capecitabine
    • Fluorouracil
    • Leucovorin
    • Leucovorin Calcium
    • Oxaliplatin

    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 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 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 of the cervix.
    
              -  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).
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure: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
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure:RFS
    Time Frame:Up to 3 years
    Safety Issue:
    Description:According to ctDNA marker status and treatment. Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment combination.
    Measure:Overall survival (OS)
    Time Frame:Up to 3 years
    Safety Issue:
    Description: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.
    Measure:Time to recurrence (TTR)
    Time Frame:Up to 3 years
    Safety Issue:
    Description: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.
    Measure:Compliance with adjuvant chemotherapy and/or active surveillance
    Time Frame:Up to 3 years
    Safety Issue:
    Description: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.
    Measure:Incidence (presence or absence) of ctDNA in blood following resection of stage II colon cancer
    Time Frame:Up to 3 years
    Safety Issue:
    Description:

    Details

    Phase:Phase 2/Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:NRG Oncology

    Last Updated

    January 24, 2020