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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Ovarian Cancer, Platinum-resistant Ovarian Cancer, Primary Peritoneal Carcinoma, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: ZN-c3
* Drug: Niraparib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Female and at least 18 years old. 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. Have demonstrated relapse within 6 months of platinum therapy (platinum-free interval <6 months). Must have evaluable or measurable disease according to RECIST v1.1 criterion: defined as at least one lesion that can be accurately measured. Adequate hematologic and organ function. Ability and willingness to take oral medication. 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. 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: 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. Must have measurable disease according to RECIST V1.1 criterion: defined as at least one lesion that can be accurately measured. Key Exclusion Criteria: 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). A minimum of 10 days between termination of the prior PARPi and administration of ZN-c3 and niraparib treatment is required. Any investigational drug therapy <28 days. Prior treatment with a WEE1 inhibitor. Known hypersensitivity to any drugs similar to ZN-c3 and/or niraparib in class or its excipients. Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Uncontrolled hypertension (Diastolic BP > 90 mmHg or Systolic BP > 140 mmHg). 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). 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. 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. History or current evidence of congenital or family history of long QT syndrome or Torsades de Pointes (TdP). Taking medications with a known risk of TdP (according to current information provided at https://crediblemeds.org).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZN-c3 and Niraparib<br>ZN-c3 in combination with Niraparib | Drug: ZN-c3<br>* ZN-c3 will be administered.<br>Drug: Niraparib<br>* Niraparib will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| To investigate the OS of subjects receiving ZN-c3 in combination with niraparib | OS (median and at 12 months) | 30 months | 
| 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 | 
| 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 |