PRIMARY OBJECTIVES:
I. To compare the rate of ctDNA clearance in "ctDNA detected" patients treated with or without adjuvant chemotherapy following resection of stage IIA colon cancer. (Phase II) II. To compare recurrence-free survival (RFS) in "ctDNA detected" patients treated with or without adjuvant chemotherapy following resection of stage IIA colon cancer. (Phase III)
SECONDARY OBJECTIVES:
I. To describe the prevalence of detectable ctDNA in patients with stage IIA colon cancer following surgical resection.
II. To estimate time-to-event outcomes (overall survival \[OS\], recurrence-free survival \[RFS\], and time to recurrence \[TTR\]) by ctDNA marker status and treatment for patients with resected stage IIA colon cancer.
III. To estimate the rate of compliance with adjuvant chemotherapy and/or active surveillance for patients with resected stage IIA colon cancer.
EXPLORATORY OBJECTIVES:
I. To describe the association of quantitative ctDNA levels with time to event outcomes (RFS, OS, and TTR).
II. To characterize genomic profiles associated with recurrence using a ctDNA assay in patients with resected stage IIA colon cancer.
III. To model the cost effectiveness of the use of ctDNA versus standard of care in this setting.
IV. To evaluate performance of a ctDNA assay after incorporation of patient tumor and peripheral blood mononuclear cells.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (BLOOD STORED AND TESTED FOR ctDNA LATER): Patients undergo active surveillance.
ARM II (BLOOD TESTED FOR ctDNA AT BASELINE): Patients are assigned to 1 of 2 groups.
GROUP I (ctDNA DETECTED): At the discretion of the investigator, patients receive either oxaliplatin intravenously (IV) over 2 hours on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV bolus over 2-4 minutes on day 1 and then by continuous IV over 46-48 hours repeated every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14 repeated every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
GROUP II (ctDNA NOT DETECTED): Patients undergo active surveillance.
After completion of study treatment, patients are followed up at 12 months and then every 6 months for 2 years.
Inclusion Criteria:
- The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0,
M0) with at least 12 lymph nodes examined at the time of surgical resection.
- Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion
of and as documented by the evaluating oncologist based on current practice patterns.
- The distal extent of the tumor must be >= 12 cm from the anal verge on pre-surgical
endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with
chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the
distal extent of the tumor must be >= 12 cm from the anal verge as determined by
surgical examination or pre-operative imaging.
- The patient must have had an en bloc complete gross resection of tumor (curative
resection) as definitive surgical cancer treatment within 14 to 60 days of study
randomization. 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.
- Availability and provision of adequate surgical tumor tissue for molecular diagnostics
and confirmatory profiling.
- Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 28 days before
randomization).
- Platelet count must be >= 100,000/mm^3 (within 28 days before randomization); and
- Hemoglobin must be >= 9 g/dL (within 28 days before randomization).
- Total bilirubin must be =< ULN (upper limit of normal) for the lab (within 28 days
before randomization) unless the patient has a chronic grade 1 bilirubin elevation due
to Gilbert?s disease or similar syndrome involving slow conjugation of bilirubin; and
- Alkaline phosphatase must be < 2.5 x ULN for the lab (within 28 days before
randomization); and
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be < 1.5 x
ULN for the lab (within 28 days before randomization).
- Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine
clearance >= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine
levels > 1.5 x ULN for the lab (within 28 days before randomization).
- Pregnancy test (urine or serum according to institutional standard) done within 14
days before randomization 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 2 and receive
capecitabine.
Exclusion Criteria:
- Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma,
sarcoma, lymphoma, squamous cell carcinoma, etc.).
- Pathologic, clinical, or radiologic evidence of overt metastatic disease. This
includes isolated, distant, or non-contiguous intra-abdominal metastases, even if
resected (including the presence of satellite nodules constituting N1c disease in the
absence of lymph node involvement).
- Tumor-related bowel perforation.
- History of prior invasive colon malignancy, regardless of disease-free interval.
- History of organ transplantation.
- Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation
therapy administered as treatment for colorectal cancer (e.g., primary rectal
adenocarcinomas for which treatment with neoadjuvant chemoradiation is warranted are
not permitted).
- Other invasive malignancy within 5 years before randomization. Exceptions are colonic
polyps, non-melanoma skin cancer or carcinoma-in-situ including those of the cervix
and breast (DCIS).
- Synchronous primary rectal and/or colon cancers.
- Antineoplastic therapy (e.g., chemotherapy, targeted therapy, or immunotherapy) within
5 years before randomization. (For the purposes of this study, hormonal therapy is not
considered chemotherapy.).
- Uncontrolled cardiac disease, in the opinion of the treating medical oncologist, that
would preclude the use of any of the drugs included in the GI005 treatment regimen.
This includes but is not limited to:
- Clinically unstable cardiac disease, including unstable atrial fibrillation,
symptomatic bradycardia, unstable congestive heart failure, active myocardial
ischemia, or indwelling temporary pacemaker.
- Ventricular tachycardia or supraventricular tachycardia that requires treatment
with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide)
or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of
other antiarrhythmic drugs is permitted.
- Second- or third-degree atrioventricular (AV) block unless treated with a
permanent pacemaker.
- Complete left bundle branch block (LBBB) unless treated with a permanent
pacemaker.
- Sensory or motor neuropathy >= grade 2, according to Common Terminology Criteria for
Adverse Events (CTCAE) version (v) 5.0.
- Active seizure disorder uncontrolled by medication.
- Active or chronic infection requiring systemic therapy.
- Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.
- Pregnancy or lactation at the time of randomization.
- Co-morbid illnesses or other concurrent disease that, in the judgement of the
clinician obtaining informed consent, 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).
- Prior testing with any available ctDNA test as part of the management of colon cancer,
is not permitted.
