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

  • STATUS
    Recruiting
  • End date
    Mar 10, 2030
  • participants needed
    1912
  • sponsor
    NRG Oncology
Updated on 23 April 2022

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.

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.

Details
Condition Stage III Colon Cancer
Treatment mFOLFIRINOX, Signatera test, mFOLFOX6 3-6 month, CAPOX 3 month, mFOLFOX6 6 month, CAPOX 6 month
Clinical Study IdentifierNCT05174169
SponsorNRG Oncology
Last Modified on23 April 2022

Eligibility

Yes No Not Sure

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 UGT1A128 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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