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

Ovarian Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05198804
• Other study ID #: ZN-c3-006
• Secondary ID: GOG-30672021-004
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 27, 2022
• Est. completion date: November 2023

Study information

• Verified date: June 2023
• Source: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Contact: Project Director
• Phone: (858) 263-4333
• Email: medicalaffairs[@]zentalis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 in subjects with platinum-resistant ovarian cancer.

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 in subjects with platinum-resistant ovarian cancer who have failed Poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 138
• Est. completion date: November 2023
• Est. primary completion date: November 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

1. Female and at least 18 years old.

2. Histologically or cytologically confirmed recurrent high grade epithelial ovarian, primary peritoneal, or fallopian tube cancer with histologic subtypes of serous, clear cell or endometrial for which there is no known or established treatment available with curative intent.

3. Have demonstrated relapse within 6 months of platinum therapy (platinum-free interval <6 months).

4. Must have evaluable or measurable disease according to RECIST v1.1 criterion: defined as at least one lesion that can be accurately measured.

5. Adequate hematologic and organ function.

6. Ability and willingness to take oral medication.

7. If unknown homologous recombination deficiency (HRD) status, subjects must provide formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy prior to study treatment initiation.

8. Willingness to release archival tissue for research purposes or to undergo a tumor tissue biopsy prior to dosing on Cycle 1 Day 1.

Additional Key Inclusion Criteria for Phase II:

9. This supersedes inclusion criterion 3 (above). Demonstrated relapse within 6 months of platinum therapy, while taking a PARPi as maintenance: a minimum of 3 months is required if the participant received PARPi maintenance following first-line chemotherapy.

10. Must have measurable disease according to RECIST V1.1 criterion: defined as at least one lesion that can be accurately measured.

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).

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Fallopian Tube Cancer
• Fallopian Tube Neoplasms
• Ovarian Cancer
• Ovarian Neoplasms
• Platinum-resistant Ovarian Cancer
• Primary Peritoneal Carcinoma

Intervention

Drug:
• ZN-c3
ZN-c3 will be administered.
• Niraparib
Niraparib will be administered.

Locations

Country	Name	City	State
France	Centre Georges François Leclerc	Dijon
France	Centre Oscar Lambret	Lille
France	Centre Hospitalier Lyon Sud	Saint-Genis-Laval
France	ICANS - Institut de cancérologie Strasbourg Europe	Strasbourg
France	EDOG - Institut Claudius Regaud	Toulouse
France	Institut Gustave Roussy	Villejuif
United States	Optimum Clinical Research Group- Women's Oncology	Albuquerque	New Mexico
United States	Rocky Mountain Cancer Centers	Aurora	Colorado
United States	University of Colorado	Aurora	Colorado
United States	University of Virginia	Charlottesville	Virginia
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Willamette Valley Cancer Institute and Research Center	Eugene	Oregon
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	Texas Oncology-Fort Worth Cancer Center	Fort Worth	Texas
United States	Spectrum Health System	Grand Rapids	Michigan
United States	The Blavatnik Family - Chelsea Medical Center at Mount Sinai	New York	New York
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Women and Infants Hospital of Rhode Island	Providence	Rhode Island
United States	Arizona Oncology Associates (Wilmot HOPE) - USOR	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Primary	Phase 1: Incidence and severity of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects during Cycle 1	Phase 1: To investigate the safety and tolerability of ZN-c3 in combination with niraparib, including identification of the MTD and RP2D	6 months
Primary	Phase 2: To investigate the antitumor activity of ZN-c3 in combination with niraparib - Progression Free Survival at 4 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	12 months
Primary	Phase 2: To investigate the antitumor activity of ZN-c3 in combination with niraparib - Objective Response Rate	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)	18 months
Secondary	To further investigate the antitumor activity of ZN-c3 in combination with niraparib - Duration of response	Duration of response (DOR) as key secondary endpoint	30 months
Secondary	To further investigate the antitumor activity of ZN-c3 in combination with niraparib - Clinical Benefit Rate	Clinical Benefit Rate (CBR), Progression Free Survival (PFS) (median and 4-month rate), as defined by the revised RECIST version 1.1	30 months
Secondary	To further investigate the antitumor activity of ZN-c3 in combination with niraparib - Objective Response Rate	Objective Response Rate (ORR) based on investigator assessment	30 months
Secondary	To investigate the OS of subjects receiving ZN-c3 in combination with niraparib	OS (median and at 12 months)	30 months
Secondary	To investigate the safety and tolerability of ZN-c3 in combination with niraparib	Frequency and severity of AEs, including laboratory abnormalities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0	30 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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