ZN-c3 in Adult Participants With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and potential clinical benefits of ZN-c3 administered in combination with encorafenib and cetuximab in adult participants with metastatic BRAF V600E mutant colorectal cancer previously treated with one or two treatment regimens.

Official Title
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A Phase 1/2, Open-Label, Multi-Center Study of ZN-c3 Administered in Combination With Encorafenib and Cetuximab in Adults With Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: ZN-c3
* Drug: Encorafenib
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma. Documented evidence of a BRAF V600E mutation in tumor tissue or blood Presence of measurable disease per RECIST version 1.1 guidelines. Disease progression after 1 or 2 previous systemic regimens for metastatic disease Adequate bone marrow function Adequate hepatic and renal function Exclusion Criteria: Documented clinical disease progression or radiographic disease progression during the screening period Leptomeningeal disease. Symptomatic brain metastasis. Presence of acute or chronic pancreatitis. Unable to swallow, retain, and absorb oral medications. Clinically significant cardiovascular diseases Evidence of active noninfectious pneumonitis. Evidence of active and uncontrolled bacterial or viral infection, within 2 weeks prior to start of any of the study interventions Participants with known positivity for HIV Active hepatitis B or hepatitis C infection Concurrent or previous other malignancy within 2 years of study entry Has had an allogeneic tissue/solid organ transplant Pregnant or females of childbearing potential who have a positive β-hCG laboratory test result within 14 days prior to enrollment or is breastfeeding

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants will receive different doses of ZN-c3 in combination with different doses of Encorafenib and a fixed dose of Cetuximab | Drug: ZN-c3<br>* ZN-c3 tablet by mouth, in combination with encorafenib<br>Drug: Encorafenib<br>* Encorafenib capsule by mouth, in combination with ZN-c3<br>* Other names: BRAFTOVI®;Drug: Cetuximab<br>* Infusion<br>* Other names: ERBITUX®;|
| Experimental: Dose Expansion<br>Participants will receive recommended dose of ZN-c3 and encorafenib as determined in dose escalation phase in combination with cetuximab | Drug: ZN-c3<br>* ZN-c3 tablet by mouth, in combination with encorafenib<br>Drug: Encorafenib<br>* Encorafenib capsule by mouth, in combination with ZN-c3<br>* Other names: BRAFTOVI®;Drug: Cetuximab<br>* Infusion<br>* Other names: ERBITUX®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase - Incidence of Dose Limiting Toxicities (DLTs) | DLTs defined as treatment-related AEs occurring within the first 29 days after the start of any study treatment that in the opinion of the investigator cannot be reasonably attributed to the participant's underlying disease, concomitant medications, or pre-existing conditions. | From Lead-in Day -1 to Cycle 1 Day 28 | 
| Dose Expansion Phase - Objective response rate (ORR) | ORR defined as the proportion of participants who achieves a best overall response of Complete Response (CR) or Partial Response (PR), assessed by Investigator per RECIST Version 1.1. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase - Incidence and severity of adverse events (AEs) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 | Safety will be assessed by monitoring adverse events and clinically relevant changes in vital signs and clinical laboratory results. | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Proportion of participants with dose interruptions due to AEs in Dose Escalation Phase |  | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Proportion of participants with dose modifications due to AEs in Dose Escalation Phase |  | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Proportion of participants with discontinuations due to AEs in Dose Escalation Phase |  | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Dose Escalation Phase - Objective response rate (ORR) | ORR defined as the proportion of participants who achieved a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) per RECIST Version 1.1. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Escalation Phase - Duration of Response (DOR) | DOR defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented disease progression per RECIST version 1.1, or death due to any cause. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Escalation Phase - Progression Free Survival (PFS) | PFS defined as the time from the first dose to the earliest documented disease progression per RECIST version 1.1, or death due to any cause. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Escalation Phase - Disease Control Rate (DCR) | DCR defined as the proportion of participants with BOR of CR, PR, or stable disease (SD), per RECIST version 1.1. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Escalation Phase - Time to Response (TTR) | TTR defined as the time from first dose to first radiographic evidence of response (CR or PR) per RECIST version 1.1. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Escalation - ZN-c3 plasma exposure: AUC |  | From lead in day -1 visit through Cycle 1 Day 15 | 
| Dose Escalation - ZN-c3 plasma exposure: Cmax |  | From lead in day -1 visit through Cycle 1 Day 15 | 
| Dose Escalation - ZN-c3 plasma exposure: Tmax |  | From lead in day -1 visit through Cycle 1 Day 15 | 
| Dose Escalation - Encorafenib plasma exposure: AUC |  | From lead in day -1 visit through Cycle 1 Day 15 | 
| Dose Escalation - Encorafenib plasma exposure: Cmax |  | From lead in day -1 visit through Cycle 1 Day 15 | 
| Dose Escalation - Encorafenib plasma exposure: Tmax |  | From lead in day -1 visit through Cycle 1 Day 15 | 
| Dose Expansion Phase - Duration of Response (DOR) | DOR defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented disease progression per RECIST version 1.1, or death due to any cause. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Expansion Phase - Progression Free Survival (PFS) | PFS defined as the time from the first dose to the earliest documented disease progression per RECIST version 1.1, or death due to any cause. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Expansion Phase - Disease Control Rate (DCR) | DCR defined as the proportion of participants with BOR of CR, PR, or stable disease (SD), per RECIST version 1.1. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Expansion Phase - Time to Response (TTR) | TTR defined as the time from first dose to first radiographic evidence of response (CR or PR) per RECIST version 1.1. | From first dose of any study intervention every 8 weeks during treatment, up to 12 months | 
| Dose Expansion Phase - Incidence and severity of adverse events (AEs) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 | Safety will be assessed by monitoring adverse events and clinically relevant changes in vital signs and clinical laboratory results. | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Proportion of participants with dose interruptions due to AEs in Dose Expansion Phase |  | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Proportion of participants with dose modifications due to AEs in Dose Expansion Phase |  | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Proportion of participants with discontinuations due to AEs in Dose Expansion Phase |  | From first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Dose Expansion - ZN-c3 in combination with combination with E+C plasma exposure: AUC |  | Lead in day 7 | 
| Dose Expansion - ZN-c3 in combination with combination with E+C plasma exposure: Cmax |  | Lead in day 7 | 
| Dose Expansion - ZN-c3 in combination with combination with E+C plasma exposure: Tmax |  | Day 7 | 
| Dose Expansion - Encorafenib in combination with ZN-c3 and cetuximab plasma exposure: AUC |  | Cycle 1 Day 15 | 
| Dose Expansion - Encorafenib in combination with ZN-c3 and cetuximab plasma exposure: Cmax |  | Cycle 1 Day 15 | 
| Dose Expansion - Encorafenib in combination with ZN-c3 and cetuximab plasma exposure: Tmax |  | Cycle 1 Day 15 | 
| Dose Expansion - ZN-c3 plasma exposure: AUC |  | Cycle 1 Day 15 | 
| Dose Expansion - ZN-c3 plasma exposure: Cmax |  | Cycle 1 Day 15 | 
| Tumor tissue BRAF V600E mutational status |  | From lead in day 1 visit through the last dose of any study intervention, up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Colorectal Cancer, CRC, BRAF V600E