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

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ClinicalTrials.gov Identifier: NCT04516447
Recruitment Status : Recruiting
First Posted : August 18, 2020
Last Update Posted : September 24, 2021
Sponsor:
Information provided by (Responsible Party):
K-Group Beta

Tracking Information
First Submitted Date  ICMJE August 11, 2020
First Posted Date  ICMJE August 18, 2020
Last Update Posted Date September 24, 2021
Actual Study Start Date  ICMJE October 26, 2020
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 17, 2021)
  • To investigate the safety and tolerability of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine [ Time Frame: Through completion, approximately 27 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  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 17, 2021)
  • 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 27 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 27 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 27 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 27 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 27 months ]
    Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable)
Original Secondary Outcome Measures  ICMJE
 (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: September 17, 2021)
  • To investigate the pharmacodynamics of ZN-c3 on the biological activity of γH2AX [ Time Frame: Through completion, approximately 27 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 27 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 27 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 27 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 27 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  ICMJE A Study of ZN-c3 in Patients With Platinum-Resistant Ovarian Cancer
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumor
  • Epithelial Ovarian Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
Intervention  ICMJE
  • 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  ICMJE
  • 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 50 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 15 minutes or longer every 3 weeks, on Day 1 of each 21-day cycle
    Interventions:
    • Drug: ZN-c3
    • Drug: Gemcitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 17, 2021)
140
Original Estimated Enrollment  ICMJE
 (submitted: August 14, 2020)
100
Estimated Study Completion Date  ICMJE January 1, 2023
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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.
    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.
  • 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 radiologically 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.
  • 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.
  • Taking medications that lead to significant QT prolongation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Project Director 8582634333 info@zenopharma.com
Listed Location Countries  ICMJE Australia,   Bosnia and Herzegovina,   Bulgaria,   Georgia,   Korea, Republic of,   Serbia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04516447
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party K-Group Beta
Study Sponsor  ICMJE K-Group Beta
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Philippe Pultar, MD K-Group Beta
PRS Account K-Group Beta
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP