Platform Study of Circulating Tumor DNA Directed Adjuvant Chemotherapy in Colon Cancer (KCSG CO22-12)

Official title

A Randomized Controlled Phase III Trial of Treatment Intensification in Stage II-III Colon Cancer Patients With Positive MRD During Adjuvant Chemotherapy

Overview

This study is a prospective, open-label, randomized phase 3 clinical trial. It aims to investigate if the early introduction of intensified chemotherapy (3 months of modified FOLFIRINOX) improves the 3-year disease-free survival rate compared to standard treatment (FOLFOX/CAPOX for an additional three months to complete six months of standard adjuvant chemotherapy) in patients with stage 2-3 colon cancer in whom ctDNA MRD in the part 1 study remained positive during adjuvant FOLFOX/CAPOX chemotherapy

Detailed description

About 25% of resectable high-risk stage 2 or stage 3 colon cancers are known to relapse despite standard treatments, including radical resection and adjuvant chemotherapy.

Using circulating tumor DNA (ctDNA)-based minimal residual cancer (MRD) detection technology, patients whose MRD is not eradicated after adjuvant chemotherapy could be identified. Early introduction of intensified chemotherapy for this group of patients could prolong survival time and increase cure rates.

This study is part of the Platform Study of Circulating Tumor DNA Directed Adjuvant Chemotherapy in Colon Cancer (CLADIA Colon Cancer). Part 1 of the platform study (Prospective Observational Study of ctDNA Monitoring During Adjuvant) is a large-scale, prospective observational study that follows ctDNA up to three years after resection in about 1,200 patients with stage 2-3 colon cancer.

This study (Part 2) aims to study the efficacy of early intensified chemotherapy (3 months of modified FOLFIRINOX ) compared to standard treatment (FOLFOX/CAPOX for an additional three months to complete six months of standard adjuvant chemotherapy) in patients with stage 2-3 colon cancer in whom ctDNA MRD in the part 1 study remained positive during adjuvant FOLFOX/CAPOX chemotherapy.

Interventions

• Drug mFOLFIRINOX-FOLFIRI intensified chemotherapy
  (1) Modified FOLFIRINOX (mFOLFIRINOX) regimen: 6 cycles every 2 weeks * Oxaliplatin 85mg/m2 IV infusion over 120 min D1 * Leucovorin 400mg/m2 IV (concurrently with oxaliplatin) * Irinotecan 150mg/m2 IV infusion over 60-90 min D1 * 5-fluorouracil 2,400mg/m2 IV infusion continuously over 46-48h D1-2
• Drug FOLFOX or CAPOX adjuvant chemotherapy
  1. FOLFOX regimen: 6 cycles every 2 weeks * Oxaliplatin 85mg/m2 IV infusion over 120 min D1 * Leucovorin 400mg/m2 IV infusion over 120 min (concurrently with oxaliplatin) * 5-fluorouracil 400mg/m2 IV bolus D1 * 5-fluorouracil 2,400mg/m2 IV infusion continuously over 46-48h D1-2 or 2. CAPOX regimen: 4 cycles every 3 weeks * Oxaliplatin 130mg/m2 IV infusion over 120 min D1 * Capecitabine 1,000mg/m2 PO bid D1-14

Primary outcome measures

• 3-year disease-free survival rate [Time frame: Through completion of follow-up (estimated to be 36 months)]

Secondary outcome measures (4)

• Circulating tumor DNA (ctDNA) clearance rate [Time frame: The data of ctDNA clearance rate will be collected at 10 time points]
• 5-year overall survival rate (5y-OS rate) [Time frame: Through completion of follow-up (estimated to be 60 months)]
• Treatment-Related Adverse Events [Time frame: Through completion of follow-up (estimated to be 36 months)]
• EORTC QLQ-C30 scale [Time frame: Through completion of follow-up (estimated to be 36 months)]

Eligibility criteria

Inclusion criteria

• Patients who willingly consented and signed the informed consent form to participate in the study
• Age range of 19 to 75 years
• Adenocarcinoma of colon confirmed by histology
• Patients with stage II-III colon cancer as defined by the American Joint Committee on Cancer's eighth edition (Stage II cancer is limited to patients who are at a high risk, with more than one risk factor for recurrence.)
• Patients who have completed the sixth cycle of FOLFOX or the fourth cycle of CAPOX adjuvant chemotherapy for colon cancer following radical resection (R0 resection)
• A ctDNA test performed 3 to 6 weeks after surgery reveals a positive MRD
• ECOG performance scale of 0-1 (only 1 is allowed for 70-75 years old)
• Adequate bone marrow function \[ANC ≥1,300/LL, platelets ≥75,000/LL, hemoglobin ≥8.0g/dL (may be eligible in study if intermittent transfusion is required)\]
• Appropriate liver function (total bilirubin ≤1.5xULN, AST and ALT ≤3xULN)
• Appropriate renal function (serum creatine ≤1.5xULN, renal clearance rate ≥50 ml/min)
• Patients who are deemed to understand the study protocol and are willing to participate in the trial until it is completed

Exclusion criteria

• Pregnant or lactating women
• Pregnant women who had a positive pregnancy test at the time of the baseline examination (postmenopausal women must be amenable for at least 12 months to be considered non-fertility)
• Sexually active men and women of reproductive age who are unwilling to use contraception throughout the study treatment and for a period of 6 months (female) or 3 months (male) following the discontinuation of study treatment
• Clinically significant heart condition \[unstable angina requiring medication, symptomatic coronary artery disease, congestive heart failure, or significant heart arrhythmia above NYHA II, or acute coronary syndrome, including myocardial infarction within the last 6 months\]
• Active viral infections such as HIV (However, HBV carriers may enroll if their HBV DNA titer is less than 20,000 IU/ml, and antiviral drugs for hepatitis B may be administered prophylactically at the investigator's discretion)
• Significant uncontrolled infections or other uncontrolled comorbidities
• Symptomatic inflammatory bowel disease
• Allogeneic transplantation history necessitating immunosuppressive therapy
• A history of other malignancies identified within the last three years, except for completed removed basal cell carcinoma of the skin, completely removed cervical epithelial carcinoma, and thyroid cancer that has been treated, including surgery
• Recurrent or residual disease identified clinically or radiographically
• Previous history of irinotecan treatment
• Polyposis including familial adenomatous polyps
• Two or more colon or rectal cancers with a pathologic stage greater than II that were detected concurrently or within the last three years
• When the investigator determines that the subjects' safety may be jeopardized during the study because of other serious or unstable pre-existing medical or mental conditions
• Prior clinical trial participation and usage of investigational drugs or devices following radical resection of colon cancer
• Patients with peripheral neuropathy who have a CTCAE v5 grade 3 or higher functional disability (corresponds to "severe symptoms, limiting self-care activity of daily living" according to CTCAE v5 criteria)
• Previous anaphylactic reaction or severe and unexpected reactions to fluoropyrimidines or platinum
• Gilbert's syndrome, dehydro-pyridine dehydrogenase (DPD) deficiency, or homozygous UGT1A1\*28 alleles

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 3 centers

• National Cancer Center — Goyang
• Jin Won Kim — Seongnam
• Seoul National University Hospital — Seoul

Identifiers

NCT: NCT05534087 · H-2205-029-1322

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗