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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer, CRC, KRAS/NRAS Mutation

Intervention / Treatment
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* Drug: Onvansertib
* Drug: FOLFIRI
* Drug: Bevacizumab
* Drug: FOLFOX


Participation Criteria
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Eligibility Criteria
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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 for KRAS/NRAS status. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Colorectal Cancer, KRAS Mutation, NRAS Mutation, CRC, First-Line