A Study of ZN-c3 in Participants With Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1 open-label, multicenter study of ZN-c3 monotherapy which consists of Dose Escalation, a Food Effect Cohort, and Dose Expansion.

Detailed Description
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This study will evaluate the safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics of ZN-c3. In Dose Escalation, the study will identify the Maximum Tolerated Dose (MTD) of ZN-c3 monotherapy in solid tumors. The Food Effect cohort sub-study will examine ZN-c3 PK after a single dose and determine the bioavailability of ZN-c3 under fed and fasted conditions. In Dose Expansion, single agent ZN-c3 will be evaluated at the RP2D in subjects with recurrent or persistent uterine serous carcinoma (USC) or subjects with locally advanced or metastatic solid tumor malignancies harboring biomarkers related to deoxyribonucleic acid (DNA) damage pathways.

Official Title
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A Phase 1 Study of ZN-c3 as a Single Agent in Subjects With Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: ZN-c3


Participation Criteria
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Eligibility Criteria
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Major Eligibility Criteria: Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of informed consent. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Adequate hematologic and organ function. Female subjects of childbearing potential and male subjects must agree to use an effective method of contraception and for 6 months and 90 days, respectively, after the last dose of ZN-c3. Dose Escalation Inclusion Criteria: Subjects must have a solid tumor with advanced or metastatic disease, refractory to standard therapy or for whom no standard therapy is available, or the subject is ineligible for standard therapy(ies). Measurable or evaluable disease per RECIST version 1.1. Food Effect Cohort Inclusion Criteria: Subjects with solid tumors with advanced or metastatic disease who are refractory or ineligible to standard therapy(ies) or for whom no standard therapy is available. Subjects must have no relevant dietary restrictions, and be willing to consume a high-calorie, high-fat breakfast and other standard meals provided during the study. Dose Expansion Inclusion Criteria: Measurable disease, defined as at least one lesion that can be accurately measured per RECIST version 1.1 criteria. Recurrent or persistent USC or locally advanced or metastatic malignancy with one or more relevant biomarkers related to deoxyribonucleic acid (DNA) damage pathways. Major Exclusion Criteria: Prior therapy with ZN-c3 or known hypersensitivity to any drugs similar to ZN-c3 in class or any inactive ingredients present in ZN-c3. Prior therapy with a WEE1 inhibitor. A serious illness or medical condition(s). Unresolved toxicity of Grade >1 attributed to any prior therapies (excluding Grade ≤2 neuropathy, alopecia or skin pigmentation). Pregnant or lactating females (including the cessation of lactation) or females of childbearing potential who have a positive serum pregnancy test within 14 days prior to C1D1. Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy. 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 Torsade de Pointes (TdP).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: USC Cohort is Parallel Assignment and MOI Cohort is Single Group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Agent Dose Escalation<br>Subjects with solid tumors with advanced or metastatic disease who are refractory or ineligible to standard therapy(ies) or for whom no standard therapy is available. | Drug: ZN-c3<br>* ZN-c3 is a study drug<br>* Other names: Study Drug;|
| Experimental: Single Agent Food Effect Cohort<br>Subjects with solid tumors with advanced or metastatic disease who are refractory or ineligible to standard therapy(ies) or for whom no standard therapy is available. This cohort will give subjects the option to continue treatment after PK assessments are completed. | Drug: ZN-c3<br>* ZN-c3 is a study drug<br>* Other names: Study Drug;|
| Experimental: Single Agent Dose Expansion<br>Subjects with histologically confirmed recurrent or persistent USC who have had treatment with at least 1 prior platinum-based chemotherapy regimen for management of advanced or metastatic USC and subjects with locally advanced or metastatic malignancy with one or more relevant biomarkers related to DNA damage pathways. | Drug: ZN-c3<br>* ZN-c3 is a study drug<br>* Other names: Study Drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation | To investigate the safety and tolerability of single agent ZN-c3, including identification of the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D), based on the incidence and severity of adverse events (AEs) and dose-limiting toxicities (DLTs) in DLT-evaluable subjects. | Through completion, average of 1 year | 
| Food Effect Cohort | To characterize and compare the PK (Cmax.) of ZN-c3 following a single dose of ZN-c3 under fed and fasting conditions. | Through completion, approx 6 months | 
| Food Effect Cohort | To characterize and compare the PK (Tmax) of ZN-c3 following a single dose of ZN-c3 under fed and fasting conditions. | Through completion, approximately 6 months | 
| Food Effect Cohort | To characterize and compare the PK (AUC0-last,AUC0-∞) of ZN-c3 following a single dose of ZN-c3 under fed and fasting conditions. | Through completion approximately 6 month | 
| Food Effect Cohort | To characterize and compare the PK (T1/2) of ZN-c3 following a single dose of ZN-c3 under fed and fasting conditions. | Through completion, approximately 6 mth | 
| Dose Expansion | To investigate the clinical activity of WEE1 inhibition based on the objective response rate (ORR) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | Through completion, approximately 43 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation, Food Effect cohort & Dose Expansion | To obtain preliminary estimates of antitumor efficacy of single agent ZN-c3 based on objective response rate (ORR) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Through completion | 
| Food Effect Cohort | To investigate electrocardiogram intervals (QTc Interval) via Holter monitoring after a single dose of ZN-c3 under fed and fasting conditions. | Through completion | 
| Dose Escalation, Food Effect cohort and Dose Expansion | To obtain preliminary estimates of antitumor efficacy of single agent ZN-c3 based on Duration of Response (DOR) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Through completion. | 
| Dose Escalation, Food Effect cohort and Dose Expansion | To obtain preliminary estimates of antitumor efficacy of single agent ZN-c3 based on Progression Free Survival (PFS) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Through completion.. | 
| Dose Escalation, Food Effect cohort and Dose Expansion | To obtain preliminary estimates of antitumor efficacy of single agent ZN-c3 based on Clinical Benefit Rate (CBR) defined as complete response, partial response or stable disease according to the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Through completion... | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uterine Serous Carcinoma, Solid Tumors Harboring Biomarkers Related to DNA Damage Pathways