Clinical Trial 21459

• Overview

  Study Title:

  Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease (CIRCULATE-US)

  Summary:

  This Phase II/III trial will evaluate the what kind of chemotherapy to recommend to patients based on the presence or absences of circulating tumor DNA (ctDNA) after surgery for colon cancer.

  Objective:

  Phase II: To compare time to ctDNA (+ve) status in ctDNA (-ve) cohort following resection of stage III colon cancer treated with immediate vs delayed (based on serial ctDNA surveillance) chemotherapy. Time to positive event is defined as time from randomization to the first ctDNA positive result for the immediate arm (Arm 1) and to the 2nd ctDNA positive result for the delayed arm (Arm 2) to allow for the potential effect of delayed adjuvant chemotherapy. Patients recurred without a positive ctDNA result will be considered to have ctDNA positive status at the time of recurrence for both study arms. Phase III: To compare time to DFS event (recurrence, second primary colorectal cancer or death) in ctDNA (-ve) cohort following resection of stage III colon cancer treated with immediate vs delayed (based on serial ctDNA surveillance) chemotherapy.

• Treatments

  Therapies:

  Chemotherapy (NOS)

  Medications:

  5-fluorouracil (); CAPOX (); CPT-11 (irinotecan); Camptosar (irinotecan); FOLFIRINOX (); FOLFOX6 (); Oxaliplatin (); Xeloda (capecitabine); capecitabine (); eloxatin (Oxaliplatin); irinotecan (); leucovorin ()

• Inclusion Criteria

  • Must have an ECOG performance status of 0 or 1
  • Patients must have histologically/pathologically confirmed colon adenocarcinoma (T1-3, N1/N1c) with R0 resection accordingly to AJCC 8th edition criteria
  • No radiographic evidence of overt metastatic disease within 28 days prior to study entry (CT with IV contrast or MRI imaging is acceptable and must include chest, abdomen, and pelvis).
  • The distal extent of the tumor must be greater than or equal to 12 cm from the anal verge on colonoscopy or above the peritoneal reflection as documented during surgery or on pathology specimen (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation).
  • Must have had an en bloc complete gross resection of tumor (curative resection). 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.
  • The resected tumor specimen and a blood specimen from patients with Stage IIIA or Stage IIIB colon cancer must have central testing for ctDNA using the Signatera assay by Natera
  • Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through CLIA-approved laboratory testing. Patients whose tumors are MSI-H or dMMR are excluded
  • The treating investigator must deem the patient a candidate for all potential agents used in this trial (5FU, LV, oxaliplatin and irinotecan)
  • The interval between surgery (post-operative Day 7) and study entry must be no more than 60 days
  • Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling
  • Adequate hematologic function within 28 days before study entry defined by protocol
  • Adequate renal function within 28 days before study entry
  • Additional Criteria will apply

• Exclusion Criteria

  • Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
  • Pathologic, clinical, or radiologic overt evidence of metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.
  • Tumor-related bowel perforation.
  • History of prior invasive colon malignancy, regardless of disease-free interval.
  • History of bone marrow or solid organ transplantation (regardless of current immunosuppressive therapy needs). Bone grafts, skin grafts, corneal transplants and organ/tissue donation are not exclusionary.
  • Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer (e.g., primary colon adenocarcinomas for which treatment with neoadjuvant chemotherapy and/or radiation is warranted are not permitted).
  • Other invasive malignancy within 5 years before study entry. Exceptions are colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.
  • Synchronous primary rectal and/ or colon cancers.
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
  • Sensory or motor neuropathy greater than or equal to grade 2, according to CTCAE v5.0.
  • Blood transfusion within two weeks before collection of blood for central ctDNA testing.
  • Active seizure disorder uncontrolled by medication.
  • Active or chronic infection requiring systemic therapy.
  • Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.
  • Patients known to have Gilbert's Syndrome or homozygosity for UGT1A1*28 polymorphism.
  • Pregnancy or lactation at the time of study entry.
  • Co-morbid illnesses or other concurrent disease that 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).
  • Ineligibility Criteria for Cohort A Arm-2 patients on Second Randomization
  • Pregnancy or lactation at the time of randomization.
  • No longer a candidate for systemic chemotherapy (FOLFOX, CAPOX, and mFOLFIRINOX) in the opinion of the treating investigator.

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