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

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

The purpose of this study is to evaluate the safety and efficacy of two dose levels of ONO-4578 with Opdivo® when added to mFOLFOX6 and bevacizumab versus SOC as first-line treatment for advanced CRC.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Leucovorin; Drug: Bevacizumab; Drug: ONO-4578; Drug: Opdivo®; Drug: 5-Fluorouracil

Detailed Description

Potential participants will be consented and screened for study eligibility. Eligible participants will be randomized in a 1:1:1 ratio to one of the three study intervention arms. Study intervention will be administered in 28-day treatment cycles and continued until disease progression, intolerable toxicity, Investigator decision or withdrawal of consent by the participant, or termination of the study by the Sponsor.

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: North America Clinical Trial Support Desk; Phone Number: +18665877745(Toll-Free); Email: clinical_trial@ono-pharma.com
• Study Contact Backup: Name: International Clinical Trial Support Desk; Phone Number: +17162141777(Standard); Email: clinical_trial@ono-pharma.com

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • Princess Margaret Cancer Centre- University Health Network
• France
  • Doubs
    • Besançon, Doubs, France
      • Recruiting
      • CHU Besançon - Hôpital Jean Minjoz
  • Gironde
    • Pessac, Gironde, France
      • Recruiting
      • CHU Bordeaux - Hôpital Haut-Lévêque
  • Loire Atlantique
    • Nantes, Loire Atlantique, France
      • Recruiting
      • Chru De Nantes Hotel-Dieu
  • Marseille
    • Marseille, Marseille, France
      • Recruiting
      • Hopital De La Timone
  • Paris
    • Paris, Paris, France
      • Recruiting
      • Hôpital Européen Georges Pompidou
    • Paris, Paris, France
      • Recruiting
      • Hôpital Saint-Antoine
  • Rhone
    • Lyon, Rhone, France
      • Recruiting
      • Centre Leon Berard
  • Vienne
    • Poitiers, Vienne, France
      • Recruiting
      • CHU Poitiers - Hôpital la Milétrie
• Italy
  • Italy
    • Milan, Italy, Italy
      • Recruiting
      • Istituto Europeo di Oncologia
    • Milan, Italy, Italy
      • Recruiting
      • Istituto Clinico Humanitas
  • Napoli
    • Naples, Napoli, Italy
      • Recruiting
      • Istituto Nazionale Tumori Fondazione G. Pascale
  • Padova
    • Padova, Padova, Italy
      • Recruiting
      • IOV-Istituto Oncologico
• Japan
  • Kobe-shi
    • Hyōgo, Kobe-shi, Japan
      • Recruiting
      • Kobe City Medical Center General Hospital
  • Osaka-shi
    • Osaka, Osaka-shi, Japan
      • Recruiting
      • National Hospital Organization Osaka National Hospital
    • Osaka, Osaka-shi, Japan
      • Recruiting
      • Osaka General Medical Center
    • Osaka, Osaka-shi, Japan
      • Recruiting
      • Osaka International Cancer Institute
• Spain
  • Barcelona
    • Barcelona, Barcelona, Spain
      • Recruiting
      • Hosptial Universitari Vall d'Hebron
  • Córdoba
    • Córdoba, Córdoba, Spain
      • Recruiting
      • Hospital Universitario Reina Sofia
  • Madrid
    • Madrid, Madrid, Spain
      • Recruiting
      • Hospital Universitario 12 de Octubre
  • Sevilla
    • Seville, Sevilla, Spain
      • Recruiting
      • Hospital Universitario Virgen del Rocio
  • Valencia
    • Valencia, Valencia, Spain
      • Recruiting
      • Hospital General Universitario de Valencia
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Arizona
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC Norris Comprehensive Cancer Center
  • Colorado
    • Lone Tree, Colorado, United States, 80124
      • Recruiting
      • Rocky Mountain Cancer Centers, LLP
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic Florida
    • Orlando, Florida, United States, 32803
      • Recruiting
      • Advent Health
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • May Clinic Rochester
  • Ohio
    • Columbus, Ohio, United States, 43221
      • Recruiting
      • The Ohio State University Comprehensive Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Thomas Jefferson University, Sidney Kimmel Cancer Center
  • Texas
    • Temple, Texas, United States, 76508
      • Recruiting
      • Baylor Scott & White Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Recruiting
      • Virginia Oncology Associates
    • Salem, Virginia, United States, 24153
      • Recruiting
      • Blue Ridge Cancer Care

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A ONO-4578 dose 1 + Opdivo® + SOC (mFOLFOX6 + bevacizumab)	Drug: Oxaliplatin; Specified dose on specified days; Drug: Leucovorin; Specified dose on specified days; Drug: Bevacizumab; Specified dose on specified days; Drug: ONO-4578; ONO-4578 tablets once a day; Drug: Opdivo®; Specified dose on specified days; Other Names: Nivolumab; Drug: 5-Fluorouracil; Specified dose on specified days
Experimental: Arm B ONO-4578 dose 2 + Opdivo® + SOC (mFOLFOX6 + bevacizumab)	Drug: Oxaliplatin; Specified dose on specified days; Drug: Leucovorin; Specified dose on specified days; Drug: Bevacizumab; Specified dose on specified days; Drug: ONO-4578; ONO-4578 tablets once a day; Drug: Opdivo®; Specified dose on specified days; Other Names: Nivolumab; Drug: 5-Fluorouracil; Specified dose on specified days
Active Comparator: Arm C SOC (mFOLFOX6+bevacizumab)	Drug: Oxaliplatin; Specified dose on specified days; Drug: Leucovorin; Specified dose on specified days; Drug: Bevacizumab; Specified dose on specified days; Drug: 5-Fluorouracil; Specified dose on specified days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) per Blinded Independent Central Review (BICR)	ORR (assessed by BICR per RECIST v1.1) is defined as the proportion of participants with a BOR of confirmed CR or PR. The ORR will be estimated as the number of participants achieving BOR of CR or PR assessed by BICR per RECIST v1.1 divided by the total number of participants.	From randomization to the end of treatment (Up to 39 months)
Number of participants with Adverse Events (AEs)	An AE is any untoward medical occurrence in a patient or clinical study patient, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.	From first dose to 28 days post last dose
Number of participants with Serious Adverse Events (SAEs)	SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in significant disability/incapacity.	From first dose to 28 days post last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) per Investigator assessment	ORR (assessed by site Investigator per RECIST v1.1) is defined as the proportion of participants with a BOR of confirmed CR or PR. The ORR will be estimated as the number of participants achieving BOR of CR or PR assessed by site Investigator per RECIST v1.1 divided by the total number of participants.	From randomization to the end of treatment (Up to 39 months)
Overall Survival (OS)	OS is defined as the time between the date of randomization and the date of death due to any cause.	From randomization to the end of treatment (Up to 39 months)
Progression-Free Survival (PFS) by BICR	PFS by BICR is defined as the time from date of randomization to the date of the first documented progressive disease (PD) as determined by BICR per RECIST version 1.1, or the date of death due to any cause, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)
Progression-Free Survival (PFS) by Investigator assessment	PFS by Investigator assessment is defined as the time from date of randomization to the date of the first documented progressive disease (PD) as determined by site Investigator per RECIST version 1.1, or the date of death due to any cause, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)
Best overall response (BOR) by BICR	BOR is defined as the best response designation, recorded between the start of the study intervention and the date of the initial objectively documented PD per RECIST v1.1 or the date of subsequent anti-cancer therapy, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)
Best overall response (BOR) by Investigator assessment	BOR is defined as the best response designation, recorded between the start of the study intervention and the date of the initial objectively documented PD per RECIST v1.1 or the date of subsequent anti-cancer therapy, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)
Duration of response (DOR) by BICR	DOR is defined as the time between the date of first confirmed CR or PR to the date of the first documented PD per RECIST v1.1 or death due to any cause, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)
Duration of response (DOR) by Investigator assessment	DOR is defined as the time between the date of first confirmed CR or PR to the date of the first documented PD per RECIST v1.1 or death due to any cause, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)
Disease Control Rate (DCR) by BICR	DCR is defined as the percentage of participants whose BOR is determined to be CR, PR, or stable disease (SD).	From randomization to the end of treatment (Up to 39 months)
Disease Control Rate (DCR) by Investigator assessment	DCR is defined as the percentage of participants whose BOR is determined to be CR, PR, or stable disease (SD).	From randomization to the end of treatment (Up to 39 months)
Time to Response (TTR) by BICR	TTR is defined as the time from the date of randomization to the date of first confirmed CR or PR.	From randomization to the end of treatment (Up to 39 months)
Time to Response (TTR) by Investigator assessment	TTR is defined as the time from the date of randomization to the date of first confirmed CR or PR.	From randomization to the end of treatment (Up to 39 months)
Maximum percent change in the sum of the diameters of the target lesions by BICR	In participants who have target lesions at baseline and at least 1 post-baseline imaging evaluation, the maximum percent change in the sum of diameters of target lesions is the percent change at the point of the minimum sum of diameters of the target lesions.	From randomization to the end of treatment (Up to 39 months)
Maximum percent change in the sum of the diameters of the target lesions by Investigator assessment	In participants who have target lesions at baseline and at least 1 post-baseline imaging evaluation, the maximum percent change in the sum of diameters of target lesions is the percent change at the point of the minimum sum of diameters of the target lesions.	From randomization to the end of treatment (Up to 39 months)
Progression-Free Survival of second line therapy (PFS2) by Investigator assessment	PFS2 is defined as the time from date of randomization to the date of an overall response of PD after subsequent anti-cancer therapy, initiating date of a second subsequent anti-cancer therapy, or date of death from any cause, whichever occurs first.	From randomization to the end of treatment (Up to 39 months)

Collaborators and Investigators

• Sponsor: Ono Pharmaceutical Co., Ltd.
• Investigators: Study Director: Project Leader, Ono Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2025
• Primary Completion (Estimated): February 15, 2028
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: April 21, 2025
• First Submitted That Met QC Criteria: April 21, 2025
• First Posted (Actual): April 29, 2025

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Enzymes and Coenzymes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Coordination Complexes; Pyrimidines; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Oxaliplatin; Nivolumab; Bevacizumab; Fluorouracil; Leucovorin
• Other Study ID Numbers: ONO-4578-10

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: Yes
• Studies a U.S. FDA-regulated device product: No