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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Fallopian Tube Cancer; Solid Tumor; Epithelial Ovarian Cancer; Peritoneal Cancer
• Intervention / Treatment: Drug: Gemcitabine; Drug: ZN-c3; Drug: Carboplatin; Drug: Pegylated liposomal doxorubicin; Drug: Paclitaxel

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: K-Group, Beta, Inc., a subsidiary of Zentalis Pharmaceuticals; Phone Number: 8582634333; Email: medicalaffairs@zentalis.com

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Recruiting
      • Site 2707
    • Sunshine Coast, Queensland, Australia, 4556
      • Recruiting
      • Site 2708
  • Victoria
    • Melbourne, Victoria, Australia, 3144
      • Recruiting
      • Site 2706
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Recruiting
      • Site 2705
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78000
    • Recruiting
    • Site 1001
  • Sarajevo, Bosnia and Herzegovina, 71000
    • Completed
    • Site 1002
  • Tuzla, Bosnia and Herzegovina, 75000
    • Recruiting
    • Site 1003
• Bulgaria
  • Panagyurishte, Bulgaria, 4500
    • Completed
    • Site 1202
  • Sofia, Bulgaria, 1632
    • Terminated
    • Site 1201
• Georgia
  • Tbilisi, Georgia, 0112
    • Recruiting
    • Site 1401
• Korea, Republic of
  • Busan, Korea, Republic of
    • Recruiting
    • Site 2901
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Site 2903
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Site 2904
• Serbia
  • Belgrade, Serbia, 11080
    • Recruiting
    • Site 1902
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Site 0264
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Site 0104
  • Missouri
    • Saint Louis, Missouri, United States, 53110
      • Recruiting
      • Site 0111
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Site 0173
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Site 0259
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Recruiting
      • Site 0191
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Site 0196
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Site 0103

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. 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.
  2. 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.
  3. 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.
  4. Total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the case of Gilbert's disease.
  5. 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:

  1. Major surgery within 28 days.
  2. Radiation therapy within 21 days.
  3. Autologous or allogeneic stem cell transplant within 3 months.

  4. 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:

  1. Brain metastases that require immediate treatment or are clinically or radiographically unstable.
  2. Leptomeningeal disease that requires or is anticipated to require immediate treatment.
  3. Myocardial impairment of any cause.
  4. Significant gastrointestinal abnormalities.
  5. Active or uncontrolled infection.
  6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination with carboplatin; 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; Investigational drug; Other Names: Study drug; Drug: Carboplatin; Carboplatin is an approved drug
Experimental: Combination with paclitaxel; 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; Investigational drug; Other Names: Study drug; Drug: Paclitaxel; Paclitaxel is an approved drug
Experimental: Combination with PLD; 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; Investigational drug; Other Names: Study drug; Drug: Pegylated liposomal doxorubicin; Pegylated liposomal doxorubicin (PLD) is an approved drug
Experimental: Combination with gemcitabine; 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: Gemcitabine; Gemcitabine is an approved drug; Drug: ZN-c3; Investigational drug; Other Names: Study drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To characterize the PK of ZN-c3 in tumor tissue	ZN-c3 concentrations (and its potential metabolites as applicable) in tumor tissue	At Cycle 1 Day 1 and Cycle 2 Day 1 (pre-dose) (each cycle is 28 days for PLD or paclitaxel, and 21 days for carboplatin or gemcitabine)
To investigate the pharmacodynamics of ZN-c3 on the biological activity of γH2AX	Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of γH2AX	Through completion, approximately 40 months
To investigate the pharmacodynamics of ZN-c3 on the biological activity of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1)	Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1)	Through completion, approximately 40 months
To investigate the pharmacodynamics of ZN-c3 on the biological activity of Ki-67	Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of Ki-67	Through completion, approximately 40 months
To investigate the pharmacodynamics of ZN-c3 on Baseline Cyclin E expression	Including, but not limited to, Baseline Cyclin E expression in pre-dose tumor tissue	Through completion, approximately 40 months
To investigate the pharmacodynamics of ZN-c3 on 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)	Through completion, approximately 40 months

Collaborators and Investigators

• Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Investigators: Study Director: Philippe Pultar, MD, K-Group Beta

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2020
• Primary Completion (Estimated): January 31, 2024
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 14, 2020
• First Posted (Actual): August 18, 2020

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 15, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Solid Tumor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Carboplatin; Paclitaxel; Doxorubicin; Liposomal doxorubicin; Gemcitabine
• Other Study ID Numbers: ZN-c3-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No