Metastatic Colorectal Cancer, CRC, KRAS/NRAS Mutation
Conditions
Keywords
Metastatic Colorectal Cancer, KRAS Mutation, NRAS Mutation, CRC, First-Line
Brief summary
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.
Interventions
DRUGOnvansertib
Oral capsule
DRUGFOLFIRI
FOLFIRI (irinotecan + fluorouracil \[5-FU\] + leucovorin) as intravenous (IV) infusion
DRUGBevacizumab
IV Infusion
DRUGFOLFOX
FOLFOX (leucovorin + fluorouracil \[5-FU\] + oxaliplatin) as intravenous (IV) infusion
Sponsors
Pfizer
Cardiff Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to approximately 1 year | 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. |
| Number of Participants with an Adverse Event (AE) | Up to approximately 1 year | 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. |
| Disease Control Rate (DCR) | Up to approximately 1 year | DCR defined as CR plus PR plus stable disease (SD), as determined by independent central review. |
| Overall Survival (OS) | Up to approximately 1 year | OS defined as the time from drug administration to death due to any cause. |
| Overall Response (OR) | Up to approximately 1 year | Defined as CR or PR, PFS, DCR, DOR, and OS associated with a reduction in circulating tumor DNA (ctDNA) mutation allele frequency (MAF). |
| Progression Free Survival (PFS) | Up to approximately 1 year | 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. |
| 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 | — |
| 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) | — |
Countries
United States
Outcome results
None listed