mFOLFOXIRI Plus PD-1 Inhibitor vs mFOLFOX6 as Neoadjuvant Therapy for Locally Advanced Colon Cancer (OPTICAL-3)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Colon Cancer (Stage II &Amp;Amp; III)
• Intervention / Treatment: Drug: cmFOLFOXIRI plus PD-1 inhibitor; Drug: mFOLFOX6

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.

• Study Type: Interventional
• Enrollment (Estimated): 138
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yanhong Deng Professor Deng, M.D.; Phone Number: 008613925106525; Email: dengyanh@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Histological or cytological documentation of adenocarcinoma of the colon (≥ 12 cm from the anal verge).
3. Determined preoperatively by either spiral or multidetector CT: T4 or N2.
4. Male or female subjects > 18 years < 70 of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. 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.
7. No clinically significant obstruction, perforation, or bleeding related to the primary tumor.
8. No previous any systemic anticancer therapy for colon cancer disease.
9. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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. For 4 cycles before surgery.	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.
Active Comparator: 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. For 4 cycles before surgery.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response rate	The percentage of subjects with no residual viable tumor in the resected primary tumor specimen and all sampled regional lymph nodes after radical surgery (ypT0N0).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 resection rate	The proportion of patients whose tumors are completely removed without residual cancer cells under the microscope. None of the following conditions can be considered as R0 resection: non-complete resection of the tumor, positive circumferential, proximal, or distal resection margin (resection margin of >1 mm).	1 year
Event-free survival (EFS)	The time between randomization and one of the following events: locally progressive disease leading to an unresectable tumor, local R2 resection, local recurrence after an R0/1 resection, distant metastases, a new primary colorectal cancer, or death from any cause, whichever occurred first.	3 years
Disease-free survival (DFS)	The time from the date of surgery to the date of locoregional recurrence, distant metastases, a new primary colorectal cancer, or death from any cause, whichever occurred first.	3 years
Overall survival (OS)	The time from randomization to death from any cause. Subjects who are still alive at the time of the analysis will be censored for OS on the latest known survival date.	5 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2031

Study Registration Dates

• First Submitted: March 17, 2025
• First Submitted That Met QC Criteria: March 17, 2025
• First Posted (Actual): March 24, 2025

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: colon cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Colonic Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: CSWOG-C06; C06 (Other Identifier: CSWOG)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No