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

• ClinicalTrials.gov Identifier: NCT04516447
• Recruitment Status: Recruiting
• First Posted: August 18, 2020
• Last Update Posted: September 21, 2023
• Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Information provided by (Responsible Party): K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Tracking Information

• First Submitted Date: August 11, 2020
• First Posted Date: August 18, 2020
• Last Update Posted Date: September 21, 2023
• Actual Study Start Date: October 26, 2020
• Estimated Primary Completion Date: January 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 28, 2023)

• To investigate the safety and tolerability of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine [ Time Frame: Through completion, approximately 40 months ]
  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
• To identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine [ Time Frame: Through Cycle 1 (cycle is 28 days for PLD or paclitaxel, and 21 days for carboplatin or gemcitabine) ]
  Incidence and severity of dose-limiting toxicities (DLTs) in DLT-evaluable subjects during Cycle 1

Original Primary Outcome Measures (submitted: August 14, 2020)

• To investigate the safety and tolerability of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through completion, approximately 24 months ]
  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
• To identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through Cycle 1 (cycle is 28 days for PLD, and 21 days for carboplatin) ]
  Incidence and severity of dose-limiting toxicities (DLTs) in DLT-evaluable subjects during Cycle 1

Current Secondary Outcome Measures (submitted: March 28, 2023)

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

Original Secondary Outcome Measures (submitted: August 14, 2020)

• To obtain estimates of clinical activity by determining the objective response rate (ORR) of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through completion, approximately 24 months ]
  Objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors RECIST version 1.1
• To obtain estimates of clinical activity by determining the duration of response (DOR) of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through completion, approximately 24 months ]
  Duration of response (DOR) as defined by Response Evaluation Criteria in Solid Tumors RECIST version 1.1
• To obtain estimates of clinical activity by determining the progression-free survival (PFS) of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through completion, approximately 24 months ]
  Progression-free survival (PFS) as defined by RECIST version 1.1 and clinical criteria
• To obtain estimates of clinical activity by determining the time to CA125 progression of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through completion, approximately 24 months ]
  Time to CA125 progression according to the Gynecologic Cancer Intergroup (GCIG) criteria
• To investigate the plasma pharmacokinetics (PK) of ZN-c3 in combination with PLD and with carboplatin, respectively [ Time Frame: Through completion, approximately 24 months ]
  Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable)

Current Other Pre-specified Outcome Measures (submitted: March 28, 2023)

• To investigate the pharmacodynamics of ZN-c3 on the biological activity of γH2AX [ Time Frame: Through completion, approximately 40 months ]
  Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of γH2AX
• To investigate the pharmacodynamics of ZN-c3 on the biological activity of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1) [ Time Frame: Through completion, approximately 40 months ]
  Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1)
• To investigate the pharmacodynamics of ZN-c3 on the biological activity of Ki-67 [ Time Frame: Through completion, approximately 40 months ]
  Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of Ki-67
• To investigate the pharmacodynamics of ZN-c3 on Baseline Cyclin E expression [ Time Frame: Through completion, approximately 40 months ]
  Including, but not limited to, Baseline Cyclin E expression in pre-dose tumor tissue
• To investigate the pharmacodynamics of ZN-c3 on molecular determinants of sensitivity to ZN-c3 [ Time Frame: Through completion, approximately 40 months ]
  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)
• To characterize the PK of ZN-c3 in tumor tissue [ Time Frame: 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) ]
  ZN-c3 concentrations (and its potential metabolites as applicable) in tumor tissue

Original Other Pre-specified Outcome Measures (submitted: August 14, 2020)

• To investigate the pharmacodynamics of ZN-c3 on the biological activity of γH2AX [ Time Frame: Through completion, approximately 24 months ]
  Biological activity in pre- versus post-dose tumor tissue, hair follicle samples and peripheral blood mononuclear cell (PBMC) samples of γH2AX
• To investigate the pharmacodynamics of ZN-c3 on the biological activity of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1) [ Time Frame: Through completion, approximately 24 months ]
  Biological activity in pre- versus post-dose tumor tissue, hair follicle samples and peripheral blood mononuclear cell (PBMC) samples of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1)
• To investigate the pharmacodynamics of ZN-c3 on the biological activity of Ki-67 [ Time Frame: Through completion, approximately 24 months ]
  Biological activity in pre- versus post-dose tumor tissue, hair follicle samples and peripheral blood mononuclear cell (PBMC) samples of Ki-67
• To investigate the pharmacodynamics of ZN-c3 on Baseline Cyclin E expression [ Time Frame: Through completion, approximately 24 months ]
  Including, but not limited to, Baseline Cyclin E expression in pre-dose tumor tissue
• To investigate the pharmacodynamics of ZN-c3 on molecular determinants of sensitivity to ZN-c3 [ Time Frame: Through completion, approximately 24 months ]
  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)
• To characterize the PK of ZN-c3 in tumor tissue [ Time Frame: At Cycle 1 Day 1 and Cycle 2 Day 1 (pre-dose) (each cycle is 28 days for PLD, and 21 days for carboplatin) ]
  ZN-c3 concentrations (and its potential metabolites as applicable) in tumor tissue

Descriptive Information

• Brief Title: A Study of ZN-c3 in Patients With Platinum-Resistant Ovarian Cancer
• Official Title: A Phase 1b Study of ZN-c3 in Combination With Chemotherapy in Patients With Platinum-Resistant Ovarian, Peritoneal or Fallopian Tube Cancer
• Brief Summary: 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: 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
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor
• Epithelial Ovarian Cancer
• Fallopian Tube Cancer
• Peritoneal Cancer

Intervention

• Drug: ZN-c3
  Investigational drug
  Other Name: Study drug
• Drug: Carboplatin
  Carboplatin is an approved drug
• Drug: Pegylated liposomal doxorubicin
  Pegylated liposomal doxorubicin (PLD) is an approved drug
• Drug: Paclitaxel
  Paclitaxel is an approved drug
• Drug: Gemcitabine
  Gemcitabine is an approved drug

Study Arms

• 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)
  Interventions:

  • Drug: ZN-c3
  • Drug: Carboplatin
• 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
  Interventions:

  • Drug: ZN-c3
  • Drug: Pegylated liposomal doxorubicin
• 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
  Interventions:

  • Drug: ZN-c3
  • Drug: Paclitaxel
• 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.
  Interventions:

  • Drug: ZN-c3
  • Drug: Gemcitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 17, 2021): 140
• Original Estimated Enrollment (submitted: August 14, 2020): 100
• Estimated Study Completion Date: August 31, 2024
• Estimated Primary Completion Date: January 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: K-Group, Beta, Inc., a subsidiary of Zentalis Pharmaceuticals; 8582634333; medicalaffairs@zentalis.com

• Listed Location Countries: Australia, Bosnia and Herzegovina, Bulgaria, Georgia, Korea, Republic of, Serbia, United States

Administrative Information

• NCT Number: NCT04516447
• Other Study ID Numbers: ZN-c3-002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Verification Date: September 2023