mFOLFOXIRI Plus PD-1 Inhibitor vs mFOLFOX6 as Neoadjuvant Therapy for Locally Advanced Colon Cancer

Official title

Chinese Modified FOLFOXIRI Combined With PD-1 Inhibitor Versus mFOLFOX6 as Neoadjuvant Therapy for Locally Advanced Colon Cancer (cT4/N2): A Multicenter, Randomized, Controlled, Phase II Trial

Overview

In patients with high-risk stage II and stage III colon cancer, curative surgery followed by adjuvant chemotherapy with FOLFOX or CAPOX regimens has become the standard treatment. However, 20 to 30% of these patients will develop distant metastasis, which ultimately results in death. In contrast to rectal cancer, the role of preoperative therapy in colon cancer is less well established. Relatively few phase III trials of preoperative therapy have been reported, although current NCCN guidelines do recommend neoadjuvant chemotherapy with FOLFOX or CAPOX regimen as an option for bulky T4b tumors. Neoadjuvant chemotherapy is an attractive approach for several reasons. The ability to deliver systemic therapies earlier in the treatment course to eradicate micrometastatic disease is conceptually appealing. In addition, surgery can stimulate tumor proliferation through inflammation and other immune pathways. Preoperative delivery of chemotherapy may also lead to higher rates of R0 resections, and chemotherapy tolerance can be better in the neoadjuvant setting, especially in colorectal surgeries that require prolonged recovery. In the phase III study of the FOxTROT trial, the pCR rate for 6 weeks of neoadjuvant FOLFOX chemotherapy was only 4%, and a moderate or greater tumor regression was reported in 21% of patients in the NAC group. Our team also conducted the phase III OPTICAL trial, which utilized a longer period of NAC (12 weeks) with FOLFOX or CAPOX. In this trial, the pCR rate for the neoadjuvant chemotherapy group was 7%, and the downstaging rate (ypT0-2N0) was 20%. However, for patients with locally advanced colon cancer, particularly those with T4b and bulky nodal disease, the use of oxaliplatin- and fluoropyrimidine-based doublet chemotherapy does not adequately meet the clinical need for tumor shrinkage and downstaging. There is an urgent need to explore drugs with different mechanisms of action in combination with chemotherapy to improve efficacy.

Detailed description

This trial is a two-arm, multicenter, open-label, prospective, randomized phase II study. Eligible patients with locally advanced (T4 or N2) colon cancer will be randomly assigned in a 1:1 ratio to receive either cmFOLFOXIRI plus a PD-1 inhibitor or mFOLFOX6 as neoadjuvant treatment.

Interventions

• Drug cmFOLFOXIRI plus PD-1 inhibitor
  cmFOLFOXIRI: oxaliplatin 85 mg/m² , irinotecan 150 mg/m², folinic acid 400 mg/m², 5-FU 2400 mg/m² continuous 46h infusion, repeat once every 2 weeks. PD-1 inhibitor 200mg, repeat once every 2 weeks.
• Drug mFOLFOX6
  mFOLFOX6: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 IV bolus, followed by 2400 mg/m2 continuous IV infusion over 46 hours, repeat once every 2 weeks.

Primary outcome measures

• Pathologic complete response rate [Time frame: 1 year]

Secondary outcome measures (4)

• R0 resection rate [Time frame: 1 year]
• Event-free survival (EFS) [Time frame: 3 years]
• Disease-free survival (DFS) [Time frame: 3 years]
• Overall survival (OS) [Time frame: 5 years]

Eligibility criteria

Inclusion criteria

• Willing and able to provide written informed consent.
• Histological or cytological documentation of adenocarcinoma of the colon (≥ 12 cm from the anal verge).
• Determined preoperatively by either spiral or multidetector CT: T4 or N2.
• Male or female subjects > 18 years < 70 of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• CT or MRI scans (done within 30 days of registration) of the chest, abdomen and pelvis all without clear evidence of distant metastatic (M1) disease.
• No clinically significant obstruction, perforation, or bleeding related to the primary tumor.
• No previous any systemic anticancer therapy for colon cancer disease.
• Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment

Exclusion criteria

• Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 5 years prior to randomization.
• Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.
• Heart failure grade III/IV (NYHA-classification).
• Unresolved toxicity higher than CTCAE v.5.0 Grade 1 attributed to any prior therapy/procedure.
• Subjects with known allergy to the study drugs or to any of its excipients.
• Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
• Breast- feeding or pregnant women
• Lack of effective contraception.

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

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06890624 · CSWOG-C06 · C06

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗