A Study of ZN-c3 in Combination With Gemcitabine in Subjects With Osteosarcoma

Study Overview
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Brief Summary
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This is a phase 1/2 study of ZN-c3 in combination with gemcitabine in adult and pediatric subjects with relapsed or refractory osteosarcoma.

Detailed Description
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This is a phase 1/2 dose escalation and dose expansion study, evaluating the clinical activity and safety, pharmacodynamics, and pharmacokinetics of ZN-c3 in combination with gemcitabine in relapsed or refractory osteosarcoma.

Official Title
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A Phase 1/2 Dose Escalation and Dose Expansion Study of ZN-c3 in Combination With Gemcitabine in Adult and Pediatric Subjects With Relapsed or Refractory Osteosarcoma

Conditions
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Osteosarcoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 12 years at the time of informed consent Bodyweight ≥ 40 kg Histologically documented relapsed or metastatic osteosarcoma. Must have measurable disease according to RECIST Guideline version 1.1 criteria. Adequate hematologic and organ function. Female subjects of childbearing potential and male subjects must agree to use an effective method of contraception per institutional standard prior to the first dose and for 6 months after study treatment discontinuation. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria: Unresolved toxicity of Grade >1 attributed to prior therapies (excluding: Grade ≤2 neuropathy, alopecia, or skin pigmentation) Prior therapy with a WEE1 inhibitor A serious illness or medical condition(s). Pregnant or lactating females. Females of childbearing potential with a positive serum pregnancy test <14 days to Day 1. Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy. 12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of >470 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. Administration of strong and moderate CYP3A4 inhibitors/inducers and strong and moderate P-gp inhibitors.

Ages Eligible for Study
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Minimum Age: 12 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination ZN-c3 with Gemcitabine<br> | Drug: ZN-c3<br>* ZN-c3 is an investigational drug.<br>Drug: Gemcitabine<br>* Gemcitabine is an approved drug<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLT) in DLT evaluable subjects and the incidence and severity of adverse events. |  | Through Cycle 1 (21 days) Phase 1 | 
| Event-free survival (EFS) at 18 weeks per RECIST (Response Evaluation Criteria in Solid Tumors) Guideline version 1.1. | EFS at 18 weeks is defined as time from study enrollment until date of disease progression, or detection of disease at a previously uninvolved site, or date of death of the subjects at 18 weeks. | During phase 2, at 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) per RECIST Guideline version 1.1. | EFS is defined as time from study enrollment until date of last contact, date of disease progression, or detection of disease at a previously uninvolved site, or date of death. | At 12 months | 
| Median overall survival (OS) and OS at 12 months per RECIST Guideline version 1.1. | OS is defined as the time from date of first dosing until the date of death. | At 12 months | 
| The frequency and severity of adverse events (AEs) and laboratory abnormalities per the National Cancer Institute Common Terminology (NCI CTCAE) version 5.0.lities. |  | Through completion, approximately 42 months | 
| Plasma pharmacokinetics (PK) maximum concentration (Cmax). |  | Through completion, approximately 42 months | 
| Plasma PK time to maximum concentration (Tmax). |  | Through completion, approximately 42 months | 
| Area under the plasma concentration versus timepoint curve (AUC last). |  | Through completion, approximately 42 months | 
| Terminal half-life of the plasma PK concentration. |  | Through completion, approximately 42 months |