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

Phase 1

Active, not recruiting

• Conditions: Primary Peritoneal Carcinoma; Ovarian Cancer; Platinum-resistant Ovarian Cancer; Fallopian Tube Cancer
• Interventions: Drug: ZN-c3; Drug: Niraparib

• Registration Number: NCT05198804
• Lead Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Brief Summary

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.

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 Timeline

• Study First Submitted: 2021-12-08
• Study First Submitted QC: 2022-01-06
• Study First Posted: 2022-01-20
• Study Start: 2022-01-27
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-19
• Last Update Posted: 2024-06-24
• Primary Completion: 2025-05
• Study Completion: 2025-05

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Female
• Target Recruitment: 117

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ZN-c3 and Niraparib	ZN-c3	ZN-c3 in combination with Niraparib
ZN-c3	ZN-c3	ZN-c3 Monotherapy
ZN-c3 and Niraparib	Niraparib	ZN-c3 in combination with Niraparib

Primary Outcome Measures

Name	Time	Method
Phase 1b: To investigate the safety and tolerability of ZN-c3 in combination with niraparib, including identification of the MTD and RP2D	6 months	Incidence and severity of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects during Cycle 1
To investigate the antitumor activity of ZN-c3 monotherapy	12 months	ORR as defined by the revised RECIST Guideline version 1.1 and assessed by ICR.
Phase 2: To investigate the antitumor activity of ZN-c3 in combination with niraparib - Objective Response Rate	18 months	Stage 2 (Promising Clinical Activity): Objective response rate (ORR) as defined by the revised RECIST Guideline version 1.1 and assessed by Independent Central Review (ICR)
Phase 2: To investigate the antitumor activity of ZN-c3 in combination with niraparib - Progression Free Survival at 4 months	12 months	Stage 1 (Futility): Progression-Free Survival at 4 months (PFS@4) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.1
To determine the safety and tolerability of ZN-c3 monotherapy	12 months	Frequency and severity of AEs and dose modifications

Secondary Outcome Measures

Name	Time	Method
To further investigate the antitumor activity of ZN-c3 in combination with niraparib and ZN-c3 monotherapy	30 months	Objective Response Rate (ORR) based on investigator assessment
To investigate the OS of subjects receiving ZN-c3 in combination with niraparib and ZN-c3 monotherapy	30 months	OS (median and at 12 months)
To investigate the safety and tolerability of ZN-c3 in combination with niraparib and ZN-c3 monotherapy	30 months	Frequency and severity of AEs and dose modifications
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Maximum Plasma Concentration	30 months	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
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Trough concentration	30 months	Trough concentration \[Ctrough\] of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined
To evaluate changes in Patient Reported Outcomes (PROs) and quality of life	30 months	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
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	30 months	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
To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Time to maximum plasma concentration	30 months	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

Trial Locations

Locations (20)

Rutgers New Jersey Medical School; 🇺🇸 Newark, New Jersey, United States

Virginia Cancer Specialists; 🇺🇸 Fairfax, Virginia, United States

Arizona Oncology Associates (Wilmot HOPE) - USOR; 🇺🇸 Tucson, Arizona, United States

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States

Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States

Spectrum Health System; 🇺🇸 Grand Rapids, Michigan, United States

Optimum Clinical Research Group- Women's Oncology; 🇺🇸 Albuquerque, New Mexico, United States

The Blavatnik Family - Chelsea Medical Center at Mount Sinai; 🇺🇸 New York, New York, United States

Texas Oncology-Fort Worth Cancer Center; 🇺🇸 Fort Worth, Texas, United States

Women and Infants Hospital of Rhode Island; 🇺🇸 Providence, Rhode Island, United States

Willamette Valley Cancer Institute and Research Center; 🇺🇸 Eugene, Oregon, United States

Centre Oscar Lambret; 🇫🇷 Lille, France

Centre Hospitalier Lyon Sud; 🇫🇷 Saint-Genis-Laval, France

Centre Georges François Leclerc; 🇫🇷 Dijon, France

ICANS - Institut de cancérologie Strasbourg Europe; 🇫🇷 Strasbourg, France

Institut Gustave Roussy; 🇫🇷 Villejuif, France

EDOG - Institut Claudius Regaud; 🇫🇷 Toulouse, France

University of Colorado; 🇺🇸 Aurora, Colorado, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Rocky Mountain Cancer Centers; 🇺🇸 Aurora, Colorado, United States