A Study of Azenosertib (ZN-c3) and Niraparib in Subjects With Platinum-Resistant Ovarian Cancer

A Phase 1/2 Dose-Escalation and Dose-Expansion Study of ZN-c3 in Combination With Niraparib and ZN-c3 Monotherapy in Subjects With Platinum-Resistant Ovarian Cancer

This is a Phase 1/2 study to evaluate the safety, clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD) of ZN-c3 in combination with niraparib and of ZN-c3 Monotherapy in subjects with platinum-resistant ovarian cancer.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Platinum-resistant Ovarian Cancer; Primary Peritoneal Carcinoma
• Intervention / Treatment: Drug: Niraparib; Drug: Azenosertib

Detailed Description

This is a Phase 1/2 open-label, multicenter study to evaluate the safety, clinical activity, PK, and PD of ZN-c3 in combination with niraparib and of ZN-c3 Monotherapy in subjects with platinum-resistant ovarian cancer who have failed Poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment.

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Dijon, France
    • Centre Georges Francois Leclerc
  • Lille, France
    • Centre Oscar Lambret
  • Saint-Genis-Laval, France
    • Centre Hospitalier Lyon Sud
  • Strasbourg, France
    • ICANS - Institut de cancérologie Strasbourg Europe
  • Toulouse, France
    • EDOG - Institut Claudius Regaud
  • Villejuif, France
    • Institut Gustave Roussy
• United States
  • Arizona
    • Tucson, Arizona, United States, 85711
      • Arizona Oncology Associates (Wilmot HOPE) - USOR
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Comprehensive Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health System
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Optimum Clinical Research Group- Women's Oncology
  • New York
    • New York, New York, United States, 10011
      • The Blavatnik Family - Chelsea Medical Center at Mount Sinai
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Willamette Valley Cancer Institute and Research Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital of Rhode Island
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology-Fort Worth Cancer Center
    • Texas City, Texas, United States, 77030
      • MD Anderson Cancer Center, Gynecologic Oncology Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

1. Histologically or cytologically confirmed recurrent high grade epithelial ovarian, primary peritoneal, or fallopian tube cancer with histologic subtypes of serous, clear cell or endometroid for which there is no known or established treatment available with curative intent.
2. Subjects must have platinum-resistant disease.
3. Must have evaluable or measurable disease according to RECIST v1.1 criterion: defined as at least one lesion that can be accurately measured.
4. Adequate hematologic and organ function.
5. Ability and willingness to take oral medication.
6. Subjects must provide formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer.

Key Exclusion Criteria:

1. Prior therapy directed at the malignant tumor within the last four weeks prior to Cycle 1 Day 1 (6 weeks for nitrosoureas or mitomycin C).
2. A minimum of 10 days between termination of the prior PARPi and administration of ZN-c3 and niraparib treatment is required.
3. Any investigational drug therapy <28 days.
4. Prior treatment with a WEE1 inhibitor.
5. Known hypersensitivity to any drugs similar to ZN-c3 and/or niraparib in class or its excipients.
6. Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
7. Uncontrolled hypertension (Diastolic BP > 90 mmHg or Systolic BP > 140 mmHg).
8. Myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV).
9. Significant gastrointestinal abnormalities, requirement for IV alimentation, active peptic ulcer, chronic diarrhea, or vomiting considered to be clinically significant in the judgment of the Investigator, or prior surgical procedures affecting absorption.
10. 12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of >480 ms, except for subjects with atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that render the QT measurement invalid.
11. History or current evidence of congenital or family history of long QT syndrome or Torsades de Pointes (TdP).
12. Taking medications with a known risk of TdP (according to current information provided at https://crediblemeds.org).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azenosertib and Niraparib; Azenosertib in combination with Niraparib	Drug: Niraparib; Niraparib; Drug: Azenosertib; Azenosertib; Other Names: ZN-c3
Experimental: Azenosertib; Azenosertib Monotherapy	Drug: Azenosertib; Azenosertib; Other Names: ZN-c3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the safety and tolerability of ZN-c3 monotherapy	Frequency and severity of AEs and dose modifications	12 months
To investigate the antitumor activity of ZN-c3 monotherapy	ORR as defined by the revised RECIST Guideline version 1.1 and assessed by ICR.	12 months
To investigate the safety and tolerability of ZN-c3 in combination with niraparib, including identification of the MTD and RP2D	Incidence and severity of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects during Cycle 1	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate changes in Patient Reported Outcomes (PROs) and quality of life	Ongoing measurement of subject-reported symptomatic toxicity according to the PRO-CTCAE, and determination of change from Baseline in self-reported quality of life using EQ-5D-5L	30 months
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Maximum Plasma Concentration	The maximum plasma concentration (Cmax) of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined	30 months
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Area under the plasma concentration-time curve from 0 to 24h	Area under the plasma concentration-time curve from 0 to 24h [AUC0-24h] of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined	30 months
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Trough concentration	Trough concentration [Ctrough] of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined	30 months
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Time to maximum plasma concentration	Time to maximum plasma concentration (Tmax) of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined	30 months
To further investigate the antitumor activity of ZN-c3 in combination with niraparib and ZN-c3 monotherapy	Duration of response (DOR) as key secondary endpoint	30 months
To further investigate the antitumor activity of ZN-c3 in combination with niraparib and ZN-c3 monotherapy	Clinical Benefit Rate (CBR), Progression Free Survival (PFS) (median and 4-month rate), as defined by the revised RECIST version 1.1	30 months
To further investigate the antitumor activity of ZN-c3 in combination with niraparib and ZN-c3 monotherapy	Objective Response Rate (ORR) based on investigator assessment	30 months
To investigate the OS of subjects receiving ZN-c3 in combination with niraparib and ZN-c3 monotherapy	OS (median and at 12 months)	30 months
To investigate the safety and tolerability of ZN-c3 in combination with niraparib and ZN-c3 monotherapy	Frequency and severity of AEs and dose modifications	30 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the PD and downstream effects of ZN-c3 when given in combination with niraparib - Baseline Cyclin E expression	Baseline Cyclin E expression in pre-dose tumor tissue	30 months
To investigate the PD and downstream effects of ZN-c3 when given in combination with niraparib - Molecular determinants of sensitivity to ZN-c3	Molecular determinants of sensitivity to ZN-c3 including but not limited to Baseline DNA Damage Repair (DDR) gene mutations, deletions, copy number variations or indices of genetic instability in either tumor tissue or cell-free DNA (cfDNA)	30 months
To investigate the PD and downstream effects of ZN-c3 when given in combination with niraparib - Changes in genomic or protein biomarkers	Changes in genomic or protein biomarkers in peripheral blood samples	30 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2022
• Primary Completion (Actual): October 15, 2025
• Study Completion (Actual): January 19, 2026

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: January 6, 2022
• First Posted (Actual): January 20, 2022

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Wee-1; Wee1
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Fallopian Tube Diseases; Ovarian Neoplasms; Fallopian Tube Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; niraparib
• Other Study ID Numbers: ZN-c3-006; GOG-3067 (Other Identifier: GOG); 2021-004161-13 (EudraCT Number); 2024-515196-35-00 (Other Identifier: EMA)

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