ZN-c3 in Adult Participants With Metastatic Colorectal Cancer

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

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: ZN-c3; Drug: Encorafenib; Drug: Cetuximab

• Study Type: Interventional
• Enrollment (Estimated): 82
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: K-Group Beta, Inc. a subsidiary of Zentalis Pharmaceuticals; Phone Number: (212) 433-3791; Email: info@zenopharma.com

Study Locations

• Australia
  • South Australia
    • Woodville South, South Australia, Australia, 5011
      • Recruiting
      • The Queen Elizabeth Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter Maccallum Cancer Centre
• Germany
  • Berlin, Germany, 12559
    • Recruiting
    • DRK Kliniken Berlin - Köpenick
  • Bayern
    • Augsburg, Bayern, Germany, 86150
      • Recruiting
      • Hämatologie- Onkologie im Zentrum MVZ GmbH
    • Muenchen, Bayern, Germany, 81737
      • Recruiting
      • Muenchen Klinik Neuperlach, Klinik fuer Haematologie und Onkologie
    • Muenchen, Bayern, Germany, 81377
      • Recruiting
      • Klinikum der Universität München Großhadern
  • Hessen
    • Frankfurt, Hessen, Germany, 60488
      • Recruiting
      • Institut für Klinisch Onkologische Forschung
• Hungary
  • Budapest, Hungary, 1083
    • Recruiting
    • Semmelweis University-Department of Internal Medicine and Oncology
  • Gyöngyös, Hungary, 3200
    • Recruiting
    • Clinexpert Kft. Bugat Pal Korhaz
• Italy
  • Milano, Italy, 20141
    • Recruiting
    • Istituto Europeo Di Oncologia
  • Milano, Italy, 20162
    • Recruiting
    • ASST Grande Ospedale Metropolitano Niguarda
  • Campania
    • Napoli, Campania, Italy, 80131
      • Recruiting
      • Istituto Nazionale Tumori Irccs Fondazione Pascale
  • Foggia
    • San Giovanni Rotondo, Foggia, Italy, 71013
      • Recruiting
      • IRCCS Casa Sollievo della Sofferenza
  • Veneto
    • Verona, Veneto, Italy, 37126
      • Recruiting
      • AOUI Verona
• Poland
  • Malopolskie
    • Kraków, Malopolskie, Poland, 31-826
      • Recruiting
      • Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie
    • Kraków, Malopolskie, Poland, 31-501
      • Recruiting
      • Szpital Uniwersytecki w Krakowie
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 02-034
      • Recruiting
      • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie
  • Opolskie
    • Opole, Opolskie, Poland, 45-061
      • Recruiting
      • Opolskie Centrum Onkologii w Opolu im. prof. Tadeusza Koszarowskiego
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28046
    • Recruiting
    • Hospital Universitario La Paz
  • Madrid, Spain, 28222
    • Recruiting
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Cataluna
    • Barcelona, Cataluna, Spain, 08003
      • Recruiting
      • Parc de Salut Mar - Hospital del Mar
  • Cordoba
    • Córdoba, Cordoba, Spain, 14004
      • Recruiting
      • Hospital Universitario Reina Sofia
  • Valenciana, Comunitat
    • Valencia, Valenciana, Comunitat, Spain, 46009
      • Recruiting
      • Fundacion Instituto Valenciano de Oncologia
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC Norris Comprehensive Cancer Center
  • Kansas
    • Merriam, Kansas, United States, 66204
      • Recruiting
      • Alliance for Multispecialty Research, LLC
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Collaborators: Pfizer

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2023
• Primary Completion (Estimated): August 21, 2026
• Study Completion (Estimated): September 25, 2026

Study Registration Dates

• First Submitted: January 26, 2023
• First Submitted That Met QC Criteria: February 15, 2023
• First Posted (Actual): February 24, 2023

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: CRC; Metastatic Colorectal Cancer; BRAF V600E
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: ZN-c3-016; Z0011001 (Other Identifier: Pfizer)

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