Study of Onvansertib in Combination With FOLFIRI and Bevacizumab or FOLFOX and Bevacizumab Versus FOLFIRI and Bevacizumab or FOLFOX and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer in Adult Participants With a KRAS or NRAS Mutation

A Phase 2, Randomized, Open-label Study of Onvansertib in Combination With FOLFIRI and Bevacizumab or FOLFOX and Bevacizumab Versus FOLFIRI and Bevacizumab or FOLFOX and Bevacizumab for First-line Treatment of Metastatic Colorectal Cancer in Patients With a KRAS or NRAS Mutation

The purpose of this study is to assess 2 different doses of onvansertib to select the lowest dose that is maximally effective, and to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of onvansertib in combination with FOLFIRI + bevacizumab or FOLFOX + bevacizumab in patients with KRAS or NRAS-mutated metastatic colorectal cancer (CRC) in the first-line setting.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Colorectal Cancer; CRC; KRAS/NRAS Mutation
• Intervention / Treatment: Drug: Onvansertib; Drug: FOLFIRI; Drug: Bevacizumab; Drug: FOLFOX

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic - Arizona
    • Tucson, Arizona, United States, 85724
      • The University of Arizona Cancer Center
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • St. Bernards Medical Center
    • Springdale, Arkansas, United States, 72762
      • Highlands Oncology Group
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center
    • Bakersfield, California, United States, 93309
      • Comprehensive Blood and Cancer Center - Bakersfield
    • Fountain Valley, California, United States, 92708
      • Orange Coast Memorial Medical Center
    • La Jolla, California, United States, 92037
      • UC San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Department of Medicine-Hematology/Oncology
    • Los Angeles, California, United States, 90089
      • Norris Comprehensive Cancer Center
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital
    • Torrance, California, United States, 90505
      • Torrance Memorial Physician Network - Cancer Care and Infusion Center
    • Whittier, California, United States, 90602
      • PIH Health
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Florida
    • Stuart, Florida, United States, 34994
      • Cleveland Clinic Martin Health
  • Hawaii
    • Honolulu, Hawaii, United States, 96819
      • Kaiser Permanente
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Fort Wayne Medical Oncology and Hematology
  • Kansas
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center - Westwood
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Cancer & Hematology Centers of Western Michigan - Lemmen-Holton Cancer Pavilion
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine Center for Advanced Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • CCCN
  • New York
    • New York, New York, United States, 10016
      • Manhattan Hematology Oncology (MHO) Research Foundation, Inc.
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Trihealth Kenwood
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • West Cancer Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77024
      • Oncology Consultants, PA
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • Utah Cancer Specialists
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute
    • Richmond, Virginia, United States, 23298
      • Vcu Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
  • Wisconsin
    • Appleton, Wisconsin, United States, 54911
      • ThedaCare Regional Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed metastatic colorectal cancer.
• Documented KRAS or NRAS mutation.
• No previous systemic therapy in the metastatic setting.
• Participants must be willing to submit archival tissue or undergo fresh biopsy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Women of childbearing potential must use contraception or take measures to avoid pregnancy.
• Imaging computed tomography (CT) or magnetic resonance imaging (MRI) of chest/abdomen/pelvis and other scans as necessary to document all sites of disease performed within 28 days prior to the first dose of onvansertib.
• Must have acceptable organ function

Exclusion Criteria:

• Concomitant KRAS or NRAS and BRAF-V600 mutation or microsatellite instability high/deficient mismatch repair.
• Prior treatment with a VEGF inhibitor, including bevacizumab or biosimilars.
• Previous oxaliplatin treatment within 12 months prior to randomization, when arm open.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Anticancer chemotherapy or biologic therapy administered within 28 days prior to the first dose of study drug.
• Untreated or symptomatic brain metastasis.
• Gastrointestinal (GI) disorder(s) that would significantly impede the absorption of an oral agent.
• Unable or unwilling to swallow study drug.
• Uncontrolled intercurrent illness.
• Known hypersensitivity to fluoropyrimidine or leucovorin, irinotecan, or oxalipatin.
• Abnormal glucuronidation of bilirubin; known Gilbert's syndrome.
• Use of strong CYP3A4 or CYP2C19 inhibitors or strong CYP3A4 inducers.
• QTc >470

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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Onvansertib 20mg + Standard of Care; Participants will receive 20 mg of onvansertib on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFIRI/BEV on Day 1 and Day 15 of each 28-day treatment cycle.	Drug: Onvansertib; Oral capsule; Drug: FOLFIRI; FOLFIRI (irinotecan + fluorouracil [5-FU] + leucovorin) as intravenous (IV) infusion; Drug: Bevacizumab; IV Infusion
Experimental: Onvansertib 30 mg + Standard of Care (SOC); Participants will receive 30 mg of onvansertib + on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFIRI on Day 1 and Day 15 of each 28-day treatment cycle.	Drug: Onvansertib; Oral capsule; Drug: FOLFIRI; FOLFIRI (irinotecan + fluorouracil [5-FU] + leucovorin) as intravenous (IV) infusion; Drug: Bevacizumab; IV Infusion
Active Comparator: Standard of Care (SOC); Participants will receive FOLFIRI/Bev on Day 1 and Day 15 of each 28-day treatment cycle.	Drug: FOLFIRI; FOLFIRI (irinotecan + fluorouracil [5-FU] + leucovorin) as intravenous (IV) infusion; Drug: Bevacizumab; IV Infusion
Experimental: Onvansertib 20 mg + Standard of Care; Participants will receive 20 mg of onvansertib on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFOX on Day 1 and Day 15 of each 28-day treatment cycle.	Drug: Onvansertib; Oral capsule; Drug: Bevacizumab; IV Infusion; Drug: FOLFOX; FOLFOX (leucovorin + fluorouracil [5-FU] + oxaliplatin) as intravenous (IV) infusion
Experimental: Onvansertib 30 mg + Standard of Care; Participants will receive 30 mg onvansertib on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFOX on Day 1 and Day 15 of each 28-day treatment cycle.	Drug: Onvansertib; Oral capsule; Drug: Bevacizumab; IV Infusion; Drug: FOLFOX; FOLFOX (leucovorin + fluorouracil [5-FU] + oxaliplatin) as intravenous (IV) infusion
Active Comparator: Standard of Care; Participants will receive FOLFOX/Bev on Day 1 and Day 15 of each 28-day treatment cycle.	Drug: Bevacizumab; IV Infusion; Drug: FOLFOX; FOLFOX (leucovorin + fluorouracil [5-FU] + oxaliplatin) as intravenous (IV) infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR defined as the proportion of participants who achieved a best overall Response (BOR) of CR or PR per RECIST Version 1.1 from randomization until disease progression, or death due to any cause, as determined by blinded independent central review.	Up to approximately 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS defined as the time from the date of randomization to the earliest documented disease progression per RECIST version 1.1, or death due to any cause, as determined by blinded independent central review.	Up to approximately 1 year
Duration of Response (DOR)	DOR defined as the time from the date of first documentation of objective tumor response (CR or PR) to the earliest documented disease progression per RECIST version 1.1, or death due to any cause, as determined by blinded independent central review.	Up to approximately 1 year
Number of Participants with an Adverse Event (AE)	Type, incidence, causality and severity of AEs based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Clinically significant changes from baseline in vital signs, laboratory parameters, electrocardiograms (ECGs), weight, and Eastern Cooperative Oncology Group (ECOG) performance status will be recorded as AEs.	Up to approximately 1 year
Disease Control Rate (DCR)	DCR defined as CR plus PR plus stable disease (SD), as determined by independent central review.	Up to approximately 1 year
Overall Survival (OS)	OS defined as the time from drug administration to death due to any cause.	Up to approximately 1 year
Overall Response (OR)	Defined as CR or PR, PFS, DCR, DOR, and OS associated with a reduction in circulating tumor DNA (ctDNA) mutation allele frequency (MAF).	Up to approximately 1 year
Maximum Concentration (Cmax) of Onvansertib and metabolites in combination w/FOLFIRI and bevacizumab or FOLFOX and bevacizumab		Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
Area Under the Plasma Concentration Curve (AUC) of Onvansertib and metabolites in combination w/FOLFIRI and bevacizumab or FOLFOX and bevacizumab		Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
Trough Concentration (Ctrough) of Onvansertib and metabolites in combination w/FOLFIRI and bevacizumab or FOLFOX and bevacizumab		Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
Efficacy: Exposure Response Evaluation of Onvansertib		Up to approximately 1 year
Safety: Exposure Response Evaluation of Onvansertib		Up to approximately 1 year

Collaborators and Investigators

• Sponsor: Cardiff Oncology
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Ahn DH, Ridinger M, Cannon TL, Mendelsohn L, Starr JS, Hubbard JM, Kasi A, Barzi A, Samuelsz E, Karki A, Subramanian RA, Yemane D, Kim R, Wu CC, Croucher PJP, Smeal T, Kabbinavar FF, Lenz HJ. Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial. J Clin Oncol. 2025 Mar;43(7):840-851. doi: 10.1200/JCO-24-01266. Epub 2024 Oct 30.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: October 24, 2023
• First Submitted That Met QC Criteria: October 24, 2023
• First Posted (Actual): October 30, 2023

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: First-Line; CRC; Metastatic Colorectal Cancer; KRAS Mutation; NRAS Mutation
• 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; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Bevacizumab; Folfox protocol; IFL protocol; onvansertib
• Other Study ID Numbers: CRDF-004

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
• product manufactured in and exported from the U.S.: No