A Randomized, Open Label, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Two Dose Levels of ONO-4578 With Opdivo® in Combination With mFOLFOX6 and Bevacizumab Versus Standard of Care for First-line Treatment of Non-MSI-H/dMMR, PD-L1 Positive Advanced Colorectal Cancer

Trial Details

Sponsor: Ono Pharmaceutical Co. Ltd (industry)

Phase: 2

Start date: Nov. 18, 2025

Planned enrollment: 144

Trial ID: NCT06948448

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More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: ONO-4578 (BMS-986310)

TrialFetch AI Analysis

Goal: To determine whether adding the EP4 antagonist ONO-4578 plus nivolumab to first-line mFOLFOX6 and bevacizumab improves antitumor activity and has an acceptable safety profile versus standard mFOLFOX6 plus bevacizumab in patients with non–MSI-H/dMMR, PD-L1–positive advanced colorectal cancer, and to compare two ONO-4578 dose levels.

Patients: Adults with histologically confirmed locally advanced unresectable or metastatic colorectal cancer, ECOG 0–1, no prior systemic therapy for advanced disease, and centrally confirmed PD-L1–positive tumor. Key exclusions include MSI-H/dMMR disease, BRAF V600E mutation, prior immune checkpoint inhibitor therapy, active/suspected autoimmune disease, and history/complications of interstitial lung disease/pneumonitis/pulmonary fibrosis.

Design: Randomized, open-label, multicenter phase 2 trial with 1:1:1 allocation to three arms (planned n=144). Treatment is delivered in 28-day cycles and continues until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or sponsor termination. Tumor response is assessed by RECIST v1.1 with blinded independent central review for key efficacy endpoints.

Treatments: Arm A: ONO-4578 (dose level 1, oral) plus nivolumab (Opdivo) in combination with mFOLFOX6 (oxaliplatin, leucovorin, 5-fluorouracil) and bevacizumab. Arm B: ONO-4578 (dose level 2, oral) plus nivolumab with the same mFOLFOX6 and bevacizumab backbone. Arm C (control): standard mFOLFOX6 plus bevacizumab. ONO-4578 is an oral small-molecule antagonist of the prostaglandin E2 receptor EP4 (PTGER4), intended to counter PGE2-driven immunosuppression in the tumor microenvironment and thereby enhance antitumor immunity, particularly in combination with PD-1 blockade. In first-in-human testing of ONO-4578 with nivolumab in advanced solid tumors, objective responses were limited (one partial response reported in the combination cohort) with additional patients achieving stable disease; dose-limiting toxicities included gastrointestinal ulceration and immune-mediated/inflammatory events, and an MTD was not reached in the reported dose ranges.

Outcomes: Primary efficacy endpoint is overall response rate by blinded independent central review (RECIST v1.1); primary safety endpoints are incidence of adverse events and serious adverse events through 28 days after the last dose. Secondary endpoints include investigator-assessed ORR, overall survival, progression-free survival (by central review and investigator), best overall response, duration of response, disease control rate, time to response, maximum percent change in target-lesion size, and PFS2.

Burden on patient: Moderate burden. Treatment is standard-of-care intensive first-line therapy (biweekly infusional chemotherapy with bevacizumab) with the addition of nivolumab infusions and daily oral ONO-4578, increasing visit time and monitoring needs compared with chemotherapy alone. Central PD-L1 testing is required, and response assessments are scheduled regularly for RECIST-based evaluation with central review; however, there is no indication of mandatory serial biopsies or intensive pharmacokinetic sampling typical of early phase dose-escalation studies, and treatment cycles and safety follow-up are consistent with standard metastatic colorectal cancer management plus immunotherapy monitoring.

Last updated: Jan 2026

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