Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a KRAS Mutation

NCT03829410 | Completed Phase 1 Results FDA Drug

• 1 other identifier: TROV-054
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 7

Brief Summary

The purpose of the Phase 1b/2 study is to determine the safety and efficacy of Onvansertib, administered orally, daily on Day 1-5 and Day 15-19 of each 28-day cycle, in combination with FOLFIRI + Bevacizumab, as second-line treatment in adult participants who have metastatic colorectal cancer with a KRAS mutation. Participants must have histologically confirmed metastatic and unresectable disease, and previously failed treatment or be intolerant to fluoropyrimidine and oxaliplatin with or without bevacizumab.

Conditions

Metastatic Colorectal Cancer; KRAS Gene Mutation

Keywords

KRAS mutation; PCM-075; Onvansertib; FOLFIRI; Irinotecan; 5-Fluorouracil; Leucovorin; Avastin; Bevacizumab; PLK1; PLK Inhibitor

Outcome Measures

Primary Outcomes (3)

• Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)

  DLTs were defined as a Grade 4 hematologic adverse events (AEs), Grade ≥ 3 non-hematologic AEs that were considered related to the study drug and that did not resolve within 14 days following presentation with standard management and care, Grade ≥ 3 thrombocytopenia with bleeding, neutropenic fever, any death not clearly due to the underlying disease or extraneous causes, or any change in liver function that met Hy's Law criteria of a DLT.

  Up to Day 28

• Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered "serious" if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and Eastern Cooperative Oncology Group (ECOG) performance status were reported as AEs.

  Up to a maximum of 81 weeks

• All-Treated Analysis Set: Objective Response Rate (ORR)

  ORR was defined as the percentage of participants documented to have a confirmed complete response (CR) or partial response (PR) using the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1). Two-sided 95% confidence interval (CI) was calculated using the exact binomial Clopper-Pearson method. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

  Up to a maximum of 131 weeks

Secondary Outcomes (7)

• Phase 2: Number of Participants With TEAEs

  Up to a maximum of 131 weeks

• All-Treated Analysis Set: Disease Control Rate (DCR)

  Up to a maximum of 131 weeks

• All-Treated Analysis Set: Progression-free Survival (PFS)

  Up to a maximum of 131 weeks

• All-Treated Analysis Set: Duration of Response (DoR)

  Up to a maximum of 131 weeks

• All-Treated Analysis Set: Overall Survival (OS)

  Up to a maximum of 131 weeks

Study Arms (1)

Onvansertib + FOLFIRI + Bevacizumab

EXPERIMENTAL

Phase 1b: Onvansertib escalating starting dose of 12 mg/m\^2 orally Day 1 through Day 5 and Day 15 through Day 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab. This Phase 1b portion of the study has been completed. Phase 2: Onvansertib Recommended Phase 2 Dose (RP2D) of 15 mg/m\^2 orally Day 1 through Day 5 and Day 15 through Day 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.

Drug: Onvansertib; Biological: Bevacizumab; Drug: FOLFIRI

Interventions

Onvansertib DRUG

Onvansertib orally.

Also known as: PCM-075

Onvansertib + FOLFIRI + Bevacizumab

Bevacizumab BIOLOGICAL

Bevacizumab intravenously.

Also known as: Avastin®

Onvansertib + FOLFIRI + Bevacizumab

FOLFIRI DRUG

FOLFIRI intravenously.

Onvansertib + FOLFIRI + Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed metastatic and unresectable colorectal cancer (CRC).
• Documentation of a KRAS mutation in exon 2, 3 or 4 in primary tumor or metastasis, assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Participants with concomitant KRAS and BRAF-V600 mutations are excluded from this study. Participants with Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/ddMMR) are also ineligible for enrollment in this study.
• Formalin-fixed, paraffin-embedded (FFPE) tumor tissue must be available for submission to a central laboratory in order for a participant to be eligible. If no archival tissue biopsy is available the participant must have a biopsy obtained at screening.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Signed informed consent for participation in the study.
• Participant is not receiving any other standard-of-care or experimental cancer therapy. Participants participating in non-interventional surveys or observational studies are allowed.
• Has failed treatment or is intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab.
• Participants must have had systemic therapy within 180 days of the screening visit, but can have no anti-cancer therapy within 28 days of the planned first day of treatment on study.
• Participants must have received oxaliplatin based chemotherapy with or without bevacizumab (\>6 weeks in duration). Participants who received maintenance therapy with fluoropyrimidines are eligible with or without re-challenge with oxaliplatin in combination with fluoropyrimidines.
• Participants who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression \> 6 months from their last dose of neoadjuvant or adjuvant treatment (or \> 6 months from surgery if no adjuvant therapy was administered) will be required to have received fluoropyrimidine/oxaliplatin-based therapy with or without bevacizumab as first-line treatment for metastatic disease.
• Participants must not have received prior irinotecan.
• For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen for advanced disease.
• Participants who discontinued first-line therapy because of toxicity are eligible for as long as progression occurred \< 6 months after the last dose of first-line therapy.
• Chemotherapy regimen of irinotecan, fluorouracil \[5-FU\], and leucovorin (FOLFIRI) therapy is appropriate for the participant as determined by the Investigator.

You may not qualify if:

• Concomitant KRAS and BRAF-V600 mutations or MSI-H/dMMR
• Anti-cancer chemotherapy or biologic therapy administered within 28 days prior to the first dose of study drug. The exception is a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.
• More than one prior chemotherapy regimen administered in the metastatic setting.
• Major surgery within 6 weeks prior to enrollment.
• Untreated or symptomatic brain metastasis.
• Women who are pregnant or breastfeeding.
• Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection).
• Unable or unwilling to swallow study drug.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Known active infection with Human Immunodeficiency Virus (HIV), with measurable viral titer, and/or active infection with hepatitis B or C (participants who have had a hepatitis B virus \[HBV\] immunization are eligible).
• Known active infection with SARS-CoV-2.
• Clinically significant ascites or pleural effusions.
• Known hypersensitivity to 5-FU/leucovorin.
• Known hypersensitivity to irinotecan.
• Abnormal glucuronidation of bilirubin: known Gilbert's syndrome.

Sponsors & Collaborators

• Cardiff Oncology: lead

Study Sites (7)

Mayo Clinic Cancer Center

Phoenix, Arizona, 85054, United States

Location

CARTI Cancer Center

Little Rock, Arkansas, 72205, United States

Location

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

University of Kansas Medical Center Research Institute

Kansas City, Kansas, 66160, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

Inova Schar Cancer Institute

Fairfax, Virginia, 22031, United States

Location

Related Publications (3)

• Ahn DH, Barzi A, Ridinger M, Samuelsz E, Subramanian RA, Croucher PJP, Smeal T, Kabbinavar FF, Lenz HJ. Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study. Clin Cancer Res. 2024 May 15;30(10):2039-2047. doi: 10.1158/1078-0432.CCR-23-3053.

  PMID: 38231047 RESULT

• 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.

  PMID: 39475591 RESULT

• Hagege A, Ambrosetti D, Boyer J, Bozec A, Doyen J, Chamorey E, He X, Bourget I, Rousset J, Saada E, Rastoin O, Parola J, Luciano F, Cao Y, Pages G, Dufies M. The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy. Theranostics. 2021 Sep 21;11(19):9571-9586. doi: 10.7150/thno.61711. eCollection 2021.

  PMID: 34646387 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

onvansertib; Bevacizumab; IFL protocol

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Nancy Sherman, Head of Clinical Operations
• Organization: Cardiff Oncology

clinops@cardiffoncology.com

858-952-7570

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: February 1, 2019
• First Posted: February 4, 2019
• Study Start: June 24, 2019
• Primary Completion: January 29, 2024
• Study Completion: January 29, 2024
• Last Updated: March 4, 2025
• Results First Posted: March 4, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)