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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05174169
Recruitment Status : Recruiting
First Posted : December 30, 2021
Last Update Posted : April 2, 2024
Sponsor:
Collaborators:
Natera, Inc.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Stage III Colon Cancer Device: Signatera test Drug: mFOLFOX6 3-6 month Drug: CAPOX 3 month Drug: mFOLFIRINOX Drug: mFOLFOX6 6 month Drug: CAPOX 6 month Phase 2 Phase 3

Detailed Description:
Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer to determine need for adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying microscopic or residual tumor cells in colon cancer patients and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. Colon cancer patients who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need adjuvant chemotherapy. Furthermore, for colon cancer pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal adjuvant chemotherapy regimen has not been established. We hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to risk stratify for making decisions about adjuvant chemotherapy.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1912 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease
Actual Study Start Date : March 10, 2022
Estimated Primary Completion Date : March 10, 2029
Estimated Study Completion Date : March 10, 2030
Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Cohort A - Arm 1 (ctDNA-ve)

Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 6-12 cycles

OR

Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 4 cycles

 Device: Signatera test
Central ctDNA testing for all patients

Drug: mFOLFOX6 3-6 month
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 6-12 cycles

Drug: CAPOX 3 month
Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 4 cycles
Experimental: Cohort A - Arm 2 (ctDNA-ve)
Serial ctDNA monitoring no treatment
 Device: Signatera test
Central ctDNA testing for all patients
Active Comparator: Cohort B - Arm 3 (ctDNA+ve)

Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles

OR

Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 8 cycles

 Device: Signatera test
Central ctDNA testing for all patients

Drug: mFOLFOX6 6 month
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles

Drug: CAPOX 6 month
Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 8 cycles
Experimental: Cohort B - Arm 4 (ctDNA+ve)
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + Irinotecan 150 mg/m2 IV continuous infusion (30-90 minutes) + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles
 Device: Signatera test
Central ctDNA testing for all patients

Drug: mFOLFIRINOX
Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + Irinotecan 150 mg/m2 IV continuous infusion (30-90 minutes) + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles


Outcome Measures
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Primary Outcome Measures :
  1. ctDNA positive status (TTPos) [ Time Frame: Time from randomization to the first TTPos event, a maximum of 3 years ]
    TTPos is defined as time from randomization until ctDNA positive event: TTPos events are first ctDNA positive result after randomization for the immediate adjuvant chemo arm (Arm 1), 2nd ctDNA positive result after randomization for the delayed adjuvant chemo (Arm 2) and recurrence without a positive ctDNA result for both arms.

  2. Disease-Free Survival (DFS) [ Time Frame: Time from randomization to disease-free survival event, a maximum of 5 years] ]
    Time from randomization to first disease-free survival event (recurrence, second primary colorectal cancer or death from any cause).


Secondary Outcome Measures :
  1. Baseline post-surgery ctDNA positivity rate [ Time Frame: At time of randomization ]
    percentage of patients with ctDNA positive results post-surgery at study entry.

  2. Overall Survival (OS) [ Time Frame: Time from randomization to death, a maximum of 5 years. ]
    Time from randomization to death of any cause.

  3. Recurrence [ Time Frame: Time from randomization to disease recurrence, a maximum of 5 years ]
    Time from randomization to disease recurrence.

  4. Compliance with adjuvant chemotherapy [ Time Frame: from randomization to the last cycle of chemotherapy, a maximum of 6 months. ]
    number of cycles of chemotherapy received.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

The patient 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. NOTE: Patients with pathologic stages II or IIIC colon adenocarcinoma with R0 resection who have a commercially obtained Signatera™ ctDNA+ve assay result post-operatively meeting all timelines and eligibility requirements otherwise, are eligible for enrollment and inclusion in Cohort B.

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).

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 IIIA or Stage IIIB colon cancer must have central testing for ctDNA using the Signatera™ assay by Natera.

NOTE: Patients with stage IIIA or IIIB colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera™ assay as routine care outside of the study, are allowed to be enrolled, and will be retested and placed in either Cohort A or Cohort B depending on the central ctDNA testing result.

NOTE: Patients with stage II or IIIC colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera™ assay as routine care outside of the study AND have a ctDNA+ve result, are allowed to be enrolled. Patients will have central ctDNA testing, confirmed to be ctDNA+ve, and placed in Cohort B.

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 as follows:

  • Absolute neutrophil count (ANC) must be greater than or equal to 1500/mm3;
  • Platelet count must be greater than or equal to 100,000/mm3; and
  • Hemoglobin must be greater than or equal to 9 g/dL.

Adequate hepatic function within 28 days before study entry defined as follows:

  • total bilirubin must be less than or equal to ULN (upper limit of normal) for the lab and
  • alkaline phosphatase must be less than 2.5 x ULN for the lab; and
  • AST and ALT must be less than 2.5 x ULN for the lab.

Adequate renal function within 28 days before study entry defined as serum creatinine less than or equal to 1.5 x ULN for the lab or measured or calculated creatinine clearance greater than or equal to 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels greater than 1.5 x ULN for the lab.

For Women Creatinine Clearance (mL/min) = (140 - age) x weight (kg) x 0.85 72 x serum creatinine (mg/dL) For Men Creatinine Clearance (mL/min) = (140 - age) x weight (kg) 72 x serum creatinine (mg/dL)

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 study entry must be negative (for women of childbearing potential only).

Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of INR if they are randomized to Arm 1 or Arm 3 and receive capecitabine.

Eligibility Criteria for Cohort A Arm-2 patients on Second Randomization

Patient must have developed a ctDNA +ve assay during serial monitoring.

Patient's willingness to be re-randomized affirmed.

The patient must continue to have an ECOG performance status of 0 or 1.

No radiographic evidence of overt metastatic disease.

Pregnancy test (urine or serum according to institutional standard) done within 14 days before study entry must be negative (for women of childbearing potential only).

Adequate hematologic function within 28 days before randomization defined as follows:

  • Absolute neutrophil count (ANC) must be greater than or equal to 1500/mm3;
  • Platelet count must be greater than or equal to 100,000/mm3; and
  • Hemoglobin must be greater than or equal to 9 g/dL.

Adequate hepatic function within 28 days before randomization defined as follows:

  • total bilirubin must be less than or equal to ULN (upper limit of normal) for the lab and
  • alkaline phosphatase must be less than 2.5 x ULN for the lab; and
  • AST and ALT must be less than 2.5 x ULN for the lab.

Adequate renal function within 28 days before randomization defined as serum creatinine less than or equal to 1.5 x ULN for the lab or measured or calculated creatinine clearance greater than or equal to 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels greater than 1.5 x ULN for the lab.

For Women Creatinine Clearance (mL/min) = (140 - age) x weight (kg) x 0.85 72 x serum creatinine (mg/dL) For Men Creatinine Clearance (mL/min) = (140 - age) x weight (kg) 72 x serum creatinine (mg/dL)

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.

Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05174169


Contacts
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Contact: Judy Langer, MD, MS 412-339-5300 langerj@nrgoncology.org
Contact: Langer

Locations
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Sponsors and Collaborators
NRG Oncology
Natera, Inc.
National Cancer Institute (NCI)
More Information
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Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT05174169    
Other Study ID Numbers: NRG-GI008
U10CA180868 ( U.S. NIH Grant/Contract )
NRG-GI008 ( Other Identifier: NRG Oncology )
NCI-2021-08397 ( Other Identifier: NCI )
First Posted: December 30, 2021    Key Record Dates
Last Update Posted: April 2, 2024
Last Verified: April 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by NRG Oncology:
ctDNA positive
ctDNA negative
Adjuvant Chemotherapy
Natera
Signatera
mFOLFOX6
Stage III
CAPOX
 mFOLFIRINOX
Oxaliplatin
5-Fluorouracil (5-FU)
Capecitabine
Leucovorin
Irinotecan
Stage II
Additional relevant MeSH terms:
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Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
 Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases