A Study of ZN-c3 in Patients With Platinum-Resistant Ovarian Cancer

Study Overview
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Brief Summary
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This is a Phase 1b open-label, multicenter study, evaluating the safety, tolerability, preliminary clinical activity, pharmacokinetics (PK), and pharmacodynamics of ZN-c3 in combination with other drugs.

Detailed Description
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This is a Phase 1b open-label, multicenter study, evaluating the safety, tolerability, preliminary clinical activity, pharmacokinetics (PK), and pharmacodynamics of ZN-c3. This study consists of 4 cohorts in participants with platinum-resistant ovarian, peritoneal, or fallopian tube cancer. Each cohort will test a combination of ZN-c3 with either pegylated liposomal doxorubicin (PLD), carboplatin, paclitaxel, or gemcitabine.

Official Title
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A Phase 1b Study of ZN-c3 in Combination With Chemotherapy in Patients With Platinum-Resistant Ovarian, Peritoneal or Fallopian Tube Cancer

Conditions
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Solid Tumor, Epithelial Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Intervention / Treatment
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* Drug: ZN-c3
* Drug: Carboplatin
* Drug: Pegylated liposomal doxorubicin
* Drug: Paclitaxel
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent prior to initiation of any study-related procedures that are not considered standard of care. Females ≥ 18 years of age or the minimum legal adult age (whichever is greater) at the time of informed consent. ECOG performance status ≤ 2. Histologically or cytologically confirmed high-grade serous epithelial ovarian carcinoma, fallopian tube, or peritoneal carcinoma. Subjects must have received 1 or 2 prior therapeutic regimens/lines of therapy in the advanced or metastatic setting. The disease must be platinum-resistant, i.e., the Platinum-Free Interval (PFI) must have been < 6 months. Platinum refractory disease, i.e., PD during first-line platinum-based therapy is allowed. Measurable disease per RECIST version 1.1. Adequate hematologic and organ function as defined by the following criteria: ANC ≥ 1.5 × 10^9/L; excluding measurements obtained within 7 days after daily administration of filgrastim/sargramostim or within 3 weeks after administration of pegfilgrastim. Platelet count ≥ 100 × 10^9/L; excluding measurements obtained within 3 days after transfusion of platelets or within 3 weeks after administration of platelet growth factors. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × upper limit of normal (ULN). If liver function abnormalities are due to underlying liver metastases, AST and ALT ≤ 5 x ULN. Total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the case of Gilbert's disease. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min. Female subjects of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) test and agree to use an effective method of contraception per institutional standard. Left ventricular ejection fraction (LVEF) ≥ 50% or within normal limits of the institution (only for subjects treated with PLD). Exclusion Criteria: Histology of abdominal adenocarcinoma of unknown origin or diagnosis of a borderline ovarian tumor. Any of the following treatment interventions within the specified time frame prior to Cycle 1 Day 1: Major surgery within 28 days. Radiation therapy within 21 days. Autologous or allogeneic stem cell transplant within 3 months. Inability to discontinue treatment for 5 half-lives or 14 days (whichever is longer) prior to Cycle 1 Day 1 with prescription or non-prescription drugs, or to discontinue consumption of food and herbal supplements, that are: strong and moderate CYP3A inhibitors strong and moderate CYP3A inducers P-gp inhibitors A serious illness or medical condition(s) including, but not limited to, the following: Brain metastases that require immediate treatment or are clinically or radiographically unstable. Leptomeningeal disease that requires or is anticipated to require immediate treatment. Myocardial impairment of any cause. Significant gastrointestinal abnormalities. Active or uncontrolled infection. Any evidence of small bowel obstruction as determined by air/fluid levels on computed tomography (CT) scan, recent hospitalization for small bowel obstruction within 3 months prior to Cycle 1 Day 1, or recurrent paracentesis or thoracentesis within 6 weeks prior to Cycle 1 Day 1. 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 Cycle 1 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 > 480 msec, 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 long QT syndrome.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination with carboplatin<br>Participants will take: (1) ZN-c3 orally and continuously once daily (QD) in 21-day treatment cycles (± 3 days), and (2) carboplatin 5 mg/mL*min intravenously over 15 minutes or longer every 3 weeks, on Day 1 of each 21-day cycle (± 3 days) | Drug: ZN-c3<br>* Investigational drug<br>* Other names: Study drug;Drug: Carboplatin<br>* Carboplatin is an approved drug<br>|
| Experimental: Combination with PLD<br>Participants will take: (1) ZN-c3 orally and continuously once daily (QD) in 28-day treatment cycles (± 3 days), and (2) PLD 40 mg/m^2 intravenously over 60 minutes every 4 weeks, on Day 1 of each 28-day cycle | Drug: ZN-c3<br>* Investigational drug<br>* Other names: Study drug;Drug: Pegylated liposomal doxorubicin<br>* Pegylated liposomal doxorubicin (PLD) is an approved drug<br>|
| Experimental: Combination with paclitaxel<br>Participants will take: (1) ZN-c3 orally and continuously once daily (QD) in 28-day treatment cycles, and (2) paclitaxel 80 mg/m^2 administered intravenously over 60 minutes (± 10 minutes) on Days 1, 8, and 15 of each 28-day cycle | Drug: ZN-c3<br>* Investigational drug<br>* Other names: Study drug;Drug: Paclitaxel<br>* Paclitaxel is an approved drug<br>|
| Experimental: Combination with gemcitabine<br>Participants will take: (1) ZN-c3 orally and continuously once daily (QD) in 21-day treatment cycles, and (2) gemcitabine 1000 mg/m^2 intravenously over 30 minutes or longer every 3 weeks, on Day 1 of each 21-day cycle. If the dose of 1000 mg/m2 is deemed to have unacceptable toxicity in combination with ZN-c3, lower doses may be assessed. | Drug: ZN-c3<br>* Investigational drug<br>* Other names: Study drug;Drug: Gemcitabine<br>* Gemcitabine is an approved drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the safety and tolerability of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Incidence and severity of adverse events (AEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 | Through completion, approximately 40 months | 
| To identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Incidence and severity of dose-limiting toxicities (DLTs) in DLT-evaluable subjects during Cycle 1 | Through Cycle 1 (cycle is 28 days for PLD or paclitaxel, and 21 days for carboplatin or gemcitabine) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To obtain estimates of clinical activity by determining the objective response rate (ORR) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors RECIST version 1.1 | Through completion, approximately 40 months | 
| To obtain estimates of clinical activity by determining the duration of response (DOR) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Duration of response (DOR) as defined by Response Evaluation Criteria in Solid Tumors RECIST version 1.1 | Through completion, approximately 40 months | 
| To obtain estimates of clinical activity by determining the progression-free survival (PFS) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Progression-free survival (PFS) as defined by RECIST version 1.1 and clinical criteria | Through completion, approximately 40 months | 
| To obtain estimates of clinical activity by determining the time to CA125 progression of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Time to CA125 progression according to the Gynecologic Cancer Intergroup (GCIG) criteria | Through completion, approximately 40 months | 
| To investigate the plasma pharmacokinetics (PK) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine | Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable) | Through completion, approximately 40 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor