Using Cancer Cells in the Blood (ctDNA) to Determine the Type of Chemotherapy that will Benefit Patients who Have Had Surgery for Colon Cancer, (CIRCULATE-NORTH AMERICA)
Using Cancer Cells in the Blood (ctDNA) to Determine the Type of Chemotherapy that will Benefit Patients who Have Had Surgery for Colon Cancer, (CIRCULATE-NORTH AMERICA)
This phase II/III trial aims to determine the type of chemotherapy that will benefit patients who have had surgery for their stage II or III colon cancer based on presence or absence of circulating tumor deoxyribonucleic acid (ctDNA). In ctDNA positive patients, this trial compares the effect of usual chemotherapy versus mFOLFIRINOX. In ctDNA negative patients, this trial compares the effect of usual chemotherapy versus ctDNA testing every 3 months to determine which approach might be better to prevent colon cancer from returning. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It works by damaging cells DNA and may kill cancer cells. Leucovorin is in a class of medications called folic acid analogs. It works by protecting healthy cells from the effects of chemotherapy medications while allowing chemotherapy agent to enter and kill cancer cells. Fluorouracil is in a class of medications called antimetabolites. It stops cells from making DNA and may slow or stop the growth of cancer cells. Capecitabine is in a class of medications called antimetabolites. It Is taken up by cancer cells and breaks down to a substance that kills cancer cells. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It works by stopping the growth of cancer cells. This trial may help doctors determine what kind of chemotherapy to recommend to colon cancer patients based on the presence or absence of ctDNA after surgery for colon cancer.
Colon,
Rectal
Phase II/III
Adults
Chemotherapy - cytotoxic,
Supportive Care
5-FU (Fluorouracil),
Capecitabine,
Irinotecan,
Leucovorin,
Oxaliplatin
Ciombor, Kristen
National
Vanderbilt University
09-28-2022
Eligibility
18 Years
BOTH
NO
Inclusion Criteria:
The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
The patient must be >= 18 years old
The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Patients must have histologically/pathologically confirmed stage IIB, IIC or stage III colon adenocarcinoma with R0 resection according to American Joint Committee on Cancer (AJCC) 8th edition criteria
No radiographic evidence of overt metastatic disease within 45 days prior to Step 1/Study entry (computed tomography [CT] with IV contrast or magnetic resonance imaging [MRI] imaging is acceptable and must include chest, abdomen, and pelvis)
The distal extent of the tumor must be >= 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)
The patient 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 IIB, IIC or stage III colon cancer must have central testing for ctDNA using the Signatera assay by Natera (after step 1/study entry and before step 2/randomization). Patient must have sufficient tissue to meet protocol requirements. This blood specimen for the Signatera assay must be collected after surgery (and recommended at least 14 days post-surgery)
Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through Clinical Laboratory Improvement Act (CLIA)-approved laboratory testing. Patients whose tumors are microsatellite instability-high (MSI-H) or mismatch repair deficiency (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 Step 1/Study entry must be no more than 60 days. Note: Step 1/Study entry may occur as early as post-operative day 7, but it cannot occur beyond 60 days from the actual date of the patients surgery
Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling
Absolute neutrophil count (ANC) must be >= 1500/mm^3 (within 28 days before Step 1/Study entry) * Participants with benign ethnic neutropenia (BEN): ANC 1300 mm^3 are eligible. * BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups
Platelet count must be >= 100,000/mm^3 (within 28 days before Step 1/Study entry)
Hemoglobin must be >= 9 g/dL (within 28 days before Step 1/Study entry)
Total bilirubin must be = ULN (upper limit of normal) for the lab (within 28 days before Step 1/Study entry)
Alkaline phosphatase must be 2.5 x ULN for the lab (within 28 days before Step 1/Study entry)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be 2.5 x ULN for the lab (within 28 days before Step 1/Study entry)
Serum creatinine = 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before Step 1/Study entry)
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Pregnancy test (urine or serum according to institutional standard) done within 14 days before Step 1/Study entry 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 1 or Arm 3 and receive capecitabine
Cohort A Arm-2 patients on Second Randomization: Patient must have developed a ctDNA +ve assay during serial monitoring
Cohort A Arm-2 patients on Second Randomization: Patient's willingness to be re-randomized affirmed. (A reaffirmation form will be available on Cancer Trials Support Unit (CTSU) for patients to sign)
Cohort A Arm-2 patients on Second Randomization: The patient must continue to have an ECOG performance status of 0 or 1
Cohort A Arm-2 patients on Second Randomization: No radiographic evidence of overt metastatic disease
Cohort A Arm-2 patients on Second Randomization: Pregnancy test (urine or serum according to institutional standard) done within 14 days before second randomization must be negative (for women of childbearing potential only)
Cohort A Arm-2 patients on Second Randomization: Absolute neutrophil count (ANC) must be >= 1500/mm^3 (within 28 days before second randomization) * Participants with benign ethnic neutropenia (BEN): ANC 1300 mm^3 are eligible. * BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups
Cohort A Arm-2 patients on Second Randomization: Platelet count must be >= 100,000/mm^3 (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Hemoglobin must be >= 9 g/dL (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Total bilirubin must be = ULN (upper limit of normal) for the lab (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Alkaline phosphatase must be 2.5 x ULN for the lab (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: AST and ALT must be 2.5 x ULN for the lab (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Serum creatinine = 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before second randomization)
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). Exception: one cycle of chemotherapy (regimen per treating physicians discretion fluorouracil (5-FU) or capecitabine with or without oxaliplatin) is allowed but not required after consent. The optional cycle of chemotherapy should be started >= 4 weeks from surgery and while awaiting step 2 randomization
Other invasive malignancy within 5 years before Step1/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 >= grade 2, according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
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 Step1/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).
Cohort A Arm-2 patients on Second Randomization: Pregnancy or lactation at the time of second randomization
Cohort A Arm-2 patients on Second Randomization: No longer a candidate for systemic chemotherapy (leucovorin calcium [calcium folinat], 5-fluorouracil and oxaliplatin [FOLFOX], capecitabine and oxaliplatin (CAPOX), and modified fluorouracil, irinotecan, leucovorin and oxaliplatinm [FOLFIRINOX]) in the opinion of the treating investigator
The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
The patient must be >= 18 years old
The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Patients must have histologically/pathologically confirmed stage IIB, IIC or stage III colon adenocarcinoma with R0 resection according to American Joint Committee on Cancer (AJCC) 8th edition criteria
No radiographic evidence of overt metastatic disease within 45 days prior to Step 1/Study entry (computed tomography [CT] with IV contrast or magnetic resonance imaging [MRI] imaging is acceptable and must include chest, abdomen, and pelvis)
The distal extent of the tumor must be >= 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)
The patient 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 IIB, IIC or stage III colon cancer must have central testing for ctDNA using the Signatera assay by Natera (after step 1/study entry and before step 2/randomization). Patient must have sufficient tissue to meet protocol requirements. This blood specimen for the Signatera assay must be collected after surgery (and recommended at least 14 days post-surgery)
Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through Clinical Laboratory Improvement Act (CLIA)-approved laboratory testing. Patients whose tumors are microsatellite instability-high (MSI-H) or mismatch repair deficiency (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 Step 1/Study entry must be no more than 60 days. Note: Step 1/Study entry may occur as early as post-operative day 7, but it cannot occur beyond 60 days from the actual date of the patients surgery
Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling
Absolute neutrophil count (ANC) must be >= 1500/mm^3 (within 28 days before Step 1/Study entry) * Participants with benign ethnic neutropenia (BEN): ANC 1300 mm^3 are eligible. * BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups
Platelet count must be >= 100,000/mm^3 (within 28 days before Step 1/Study entry)
Hemoglobin must be >= 9 g/dL (within 28 days before Step 1/Study entry)
Total bilirubin must be = ULN (upper limit of normal) for the lab (within 28 days before Step 1/Study entry)
Alkaline phosphatase must be 2.5 x ULN for the lab (within 28 days before Step 1/Study entry)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be 2.5 x ULN for the lab (within 28 days before Step 1/Study entry)
Serum creatinine = 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before Step 1/Study entry)
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Pregnancy test (urine or serum according to institutional standard) done within 14 days before Step 1/Study entry 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 1 or Arm 3 and receive capecitabine
Cohort A Arm-2 patients on Second Randomization: Patient must have developed a ctDNA +ve assay during serial monitoring
Cohort A Arm-2 patients on Second Randomization: Patient's willingness to be re-randomized affirmed. (A reaffirmation form will be available on Cancer Trials Support Unit (CTSU) for patients to sign)
Cohort A Arm-2 patients on Second Randomization: The patient must continue to have an ECOG performance status of 0 or 1
Cohort A Arm-2 patients on Second Randomization: No radiographic evidence of overt metastatic disease
Cohort A Arm-2 patients on Second Randomization: Pregnancy test (urine or serum according to institutional standard) done within 14 days before second randomization must be negative (for women of childbearing potential only)
Cohort A Arm-2 patients on Second Randomization: Absolute neutrophil count (ANC) must be >= 1500/mm^3 (within 28 days before second randomization) * Participants with benign ethnic neutropenia (BEN): ANC 1300 mm^3 are eligible. * BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups
Cohort A Arm-2 patients on Second Randomization: Platelet count must be >= 100,000/mm^3 (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Hemoglobin must be >= 9 g/dL (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Total bilirubin must be = ULN (upper limit of normal) for the lab (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Alkaline phosphatase must be 2.5 x ULN for the lab (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: AST and ALT must be 2.5 x ULN for the lab (within 28 days before second randomization)
Cohort A Arm-2 patients on Second Randomization: Serum creatinine = 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 28 days before second randomization)
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). Exception: one cycle of chemotherapy (regimen per treating physicians discretion fluorouracil (5-FU) or capecitabine with or without oxaliplatin) is allowed but not required after consent. The optional cycle of chemotherapy should be started >= 4 weeks from surgery and while awaiting step 2 randomization
Other invasive malignancy within 5 years before Step1/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 >= grade 2, according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
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 Step1/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).
Cohort A Arm-2 patients on Second Randomization: Pregnancy or lactation at the time of second randomization
Cohort A Arm-2 patients on Second Randomization: No longer a candidate for systemic chemotherapy (leucovorin calcium [calcium folinat], 5-fluorouracil and oxaliplatin [FOLFOX], capecitabine and oxaliplatin (CAPOX), and modified fluorouracil, irinotecan, leucovorin and oxaliplatinm [FOLFIRINOX]) in the opinion of the treating investigator
