Colon Adjuvant Chemotherapy Based On Evaluation of Residual Disease.
Primary Objective
ctDNA-ve Cohort (Arms 1 + 2):
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.
ctDNA+ve Cohort (Arms 3 + 4):
Phase II and III: To compare time to DFS event (recurrence, second primary colorectal cancer or death) in ctDNA (+ve) cohort following resection of colon cancer treated with 5-FU (or capecitabine) and oxaliplatin x 6 months or 5-FU, oxaliplatin and irinotecan x 6 months.
Secondary Objectives
- To describe the prevalence of detectable ctDNA in patients with stage III colon cancer following surgical resection. The finding will be reported together with the main results of the Phase II portion of the trial.
- To estimate time-to-event outcomes (overall survival and time to recurrence) by ctDNA marker status and treatment.
- To assess the compliance of adjuvant chemotherapy.
mFOLFIRINOX
mFOLFOX6
Chemotherapy (NOS)
Chemotherapy multiple agents systemic
- Rutgers Cancer Institute of New Jersey
- RWJBarnabas Health
- Community Medical Center
- Cooperman Barnabas, Livingston
- Jersey City Medical Center, Jersey City
- Monmouth Medical Center
- Monmouth Medical Center Southern Campus
- Newark Beth Israel Medical Center
- Robert Wood Johnson University Hospital, Hamilton
- Robert Wood Johnson University Hospital, Somerset
- Trinitas Hospital and Comprehensive Cancer Center
- Rutgers Cancer Institute of New Jersey-University Hospital
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.
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.