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

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.

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.

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.