A 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 in Participants With Non-MSI-H/dMMR, PD-L1 Positive Advanced Colorectal Cancer

The film gives the main points. The full list below is copied from the registry; the study team makes the final decision.

• Age18 Years to no maximum
• SexAll
• Healthy volunteersNo

You may be able to join if

• Histologically confirmed advanced (locally advanced or metastatic) colorectal cancer not amenable to curative resection
• ECOG Performance Status of 0-1
• No prior systemic treatment for advanced local or mCRC
• Participants whose tumor is positive for PD-L1 expression as determined at a central laboratory

You cannot join if

• Participants with high microsatellite instability (MSI-High), or mismatch repair deficient (dMMR) tumor
• Participants with BRAF V600E mutation
• Unable to swallow tablets.
• Participants with complication or history of interstitial lung disease, pneumonitis or pulmonary fibrosis
• Participants with an active, known or suspected autoimmune disease.
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• Other protocol-defined inclusion/exclusion criteria apply

This is how the treatment is meant to work. Whether it helps, and how safe it is, is what this trial is testing.

EP4 antagonist ONO-4578. An orally bioavailable antagonist of the prostaglandin E2 receptor subtype 4 (PTGER4; EP4), with potential analgesic, immunomodulating and antineoplastic activities. Upon administration, the EP4 antagonist ONO-4578 selectively targets and binds to EP4, inhibiting the binding of the immunosuppressive prostaglandin E2 (PGE2) to EP4. This prevents the activation of EP4 and inhibits PGE2-EP4-mediated signaling, thereby inhibiting proliferation of tumor cells in which the PGE2-EP4 signaling pathway is over-activated. In addition, EP4 inhibition prevents the activity of tumor-associated myeloid cells (TAMCs) in the tumor microenvironment (TME) by inhibiting interleukin-23 (IL-23) production and the IL-23-mediated expansion of Th17 cells. EP4, a prostanoid receptor, is a G protein-coupled receptor that is expressed in certain types of cancers; it promotes tumor cell proliferation and invasion. NCI Drug Dictionary

nivolumab. A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Upon administration, nivolumab binds to and blocks the activation of PD-1, an immunoglobulin superfamily (IgSF) transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This results in the activation of T cells and cell-mediated immune responses against tumor cells. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity. NCI Drug Dictionary

Treatments listed in the registry

• ONO-4578 (Drug): ONO-4578 tablets once a day
• Opdivo® (Drug): Specified dose on specified days
• Oxaliplatin (Drug): Specified dose on specified days
• 5-Fluorouracil (Drug): Specified dose on specified days
• Bevacizumab (Drug): Specified dose on specified days
• Leucovorin (Drug): Specified dose on specified days

Randomized · Parallel · masking: None

Main goals

• Overall Response Rate (ORR) per Blinded Independent Central Review (BICR) (From randomization to the end of treatment (Up to 39 months))
• Number of participants with Adverse Events (AEs) (From first dose to 28 days post last dose)
• Number of participants with Serious Adverse Events (SAEs) (From first dose to 28 days post last dose)

Other goals

• Overall Response Rate (ORR) per Investigator assessment
• Overall Survival (OS)
• Progression-Free Survival (PFS) by BICR
• Progression-Free Survival (PFS) by Investigator assessment
• Best overall response (BOR) by BICR
• Best overall response (BOR) by Investigator assessment
• Duration of response (DOR) by BICR
• Duration of response (DOR) by Investigator assessment
• Disease Control Rate (DCR) by BICR
• Disease Control Rate (DCR) by Investigator assessment
• Time to Response (TTR) by BICR
• Time to Response (TTR) by Investigator assessment
• Maximum percent change in the sum of the diameters of the target lesions by BICR
• Maximum percent change in the sum of the diameters of the target lesions by Investigator assessment
• Progression-Free Survival of second line therapy (PFS2) by Investigator assessment

Planned enrollment: 144 (estimated).

• Mayo Clinic Arizona, Phoenix, Arizona
• USC Norris Comprehensive Cancer Center, Los Angeles, California
• Rocky Mountain Cancer Centers, LLP, Lone Tree, Colorado
• Mayo Clinic Florida, Jacksonville, Florida
• Advent Health, Orlando, Florida
• May Clinic Rochester, Rochester, Minnesota
• The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
• Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania
• Baylor Scott & White Medical Center, Temple, Texas
• Virginia Oncology Associates, Norfolk, Virginia
• Blue Ridge Cancer Care, Salem, Virginia

28 recruiting sites outside the US. Site status as of Oct 30, 2026. Check the live record before contacting a site.

• ClinicalTrials.gov NCT06948448
• NCI Drug Dictionary: C150376
• NCI Drug Dictionary: C68814

Registry record reviewed as fetched Oct 30, 2026, last updated by the sponsor Jul 15, 2026. Public record; not medical advice.