A Study of ZN-c3 and Niraparib in Subjects With Platinum-Resistant Ovarian Cancer
Study Details
Study Description
Brief Summary
This is a Phase 1/2 study to evaluate the safety, clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD) of ZN-c3 in combination with niraparib in subjects with platinum-resistant ovarian cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
This is a Phase 1/2 open-label, multicenter study to evaluate the safety, clinical activity, PK, and PD of ZN-c3 in combination with niraparib in subjects with platinum-resistant ovarian cancer who have failed Poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ZN-c3 and Niraparib ZN-c3 in combination with Niraparib |
Drug: ZN-c3
ZN-c3 will be administered.
Drug: Niraparib
Niraparib will be administered.
|
Outcome Measures
Primary Outcome Measures
- Phase 1: Incidence and severity of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects during Cycle 1 [6 months]
Phase 1: To investigate the safety and tolerability of ZN-c3 in combination with niraparib, including identification of the MTD and RP2D
- Phase 2: To investigate the antitumor activity of ZN-c3 in combination with niraparib - Progression Free Survival at 4 months [12 months]
Stage 1 (Futility): Progression-Free Survival at 4 months (PFS@4) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.1
- Phase 2: To investigate the antitumor activity of ZN-c3 in combination with niraparib - Objective Response Rate [18 months]
Stage 2 (Promising Clinical Activity): Objective response rate (ORR) as defined by the revised RECIST Guideline version 1.1 and assessed by Independent Central Review (ICR)
Secondary Outcome Measures
- To further investigate the antitumor activity of ZN-c3 in combination with niraparib - Duration of response [30 months]
Duration of response (DOR) as key secondary endpoint
- To further investigate the antitumor activity of ZN-c3 in combination with niraparib - Clinical Benefit Rate [30 months]
Clinical Benefit Rate (CBR), Progression Free Survival (PFS) (median and 4-month rate), as defined by the revised RECIST version 1.1
- To further investigate the antitumor activity of ZN-c3 in combination with niraparib - Objective Response Rate [30 months]
Objective Response Rate (ORR) based on investigator assessment
- To investigate the OS of subjects receiving ZN-c3 in combination with niraparib [30 months]
OS (median and at 12 months)
- To investigate the safety and tolerability of ZN-c3 in combination with niraparib [30 months]
Frequency and severity of AEs, including laboratory abnormalities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0
- To evaluate changes in Patient Reported Outcomes (PROs) and quality of life [30 months]
Ongoing measurement of subject-reported symptomatic toxicity according to the PRO-CTCAE, and determination of change from Baseline in self-reported quality of life using EQ-5D-5L
- To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Maximum Plasma Concentration [30 months]
The maximum plasma concentration (Cmax) of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined
- To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Area under the plasma concentration-time curve from 0 to 24h [30 months]
Area under the plasma concentration-time curve from 0 to 24h [AUC0-24h] of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined
- To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Trough concentration [30 months]
Trough concentration [Ctrough] of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined
- To investigate the plasma PK of ZN-c3 and niraparib when given in combination - Time to maximum plasma concentration [30 months]
Time to maximum plasma concentration (Tmax) of ZN-c3 (and its potential metabolites, as applicable) and niraparib (and their potential metabolites, as applicable) will be determined
Other Outcome Measures
- To investigate the PD and downstream effects of ZN-c3 when given in combination with niraparib - Baseline Cyclin E expression [30 months]
Baseline Cyclin E expression in pre-dose tumor tissue
- To investigate the PD and downstream effects of ZN-c3 when given in combination with niraparib - Molecular determinants of sensitivity to ZN-c3 [30 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 investigate the PD and downstream effects of ZN-c3 when given in combination with niraparib - Changes in genomic or protein biomarkers [30 months]
Changes in genomic or protein biomarkers in peripheral blood samples
Eligibility Criteria
Criteria
Key Inclusion Criteria:
-
Female and at least 18 years old.
-
Histologically or cytologically confirmed recurrent high grade epithelial ovarian, primary peritoneal, or fallopian tube cancer with histologic subtypes of serous, clear cell or endometrial for which there is no known or established treatment available with curative intent.
-
Have demonstrated relapse within 6 months of platinum therapy (platinum-free interval <6 months).
-
Must have evaluable or measurable disease according to RECIST v1.1 criterion: defined as at least one lesion that can be accurately measured.
-
Adequate hematologic and organ function.
-
Ability and willingness to take oral medication.
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If unknown homologous recombination deficiency (HRD) status, subjects must provide formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy prior to study treatment initiation.
-
Willingness to release archival tissue for research purposes or to undergo a tumor tissue biopsy prior to dosing on Cycle 1 Day 1.
Additional Key Inclusion Criteria for Phase II:
-
This supersedes inclusion criterion 3 (above). Demonstrated relapse within 6 months of platinum therapy, while taking a PARPi as maintenance: a minimum of 3 months is required if the participant received PARPi maintenance following first-line chemotherapy.
-
Must have measurable disease according to RECIST V1.1 criterion: defined as at least one lesion that can be accurately measured.
Key Exclusion Criteria:
-
Prior therapy directed at the malignant tumor within the last four weeks prior to Cycle 1 Day 1 (6 weeks for nitrosoureas or mitomycin C).
-
A minimum of 10 days between termination of the prior PARPi and administration of ZN-c3 and niraparib treatment is required.
-
Any investigational drug therapy <28 days.
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Prior treatment with a WEE1 inhibitor.
-
Known hypersensitivity to any drugs similar to ZN-c3 and/or niraparib in class or its excipients.
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Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
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Uncontrolled hypertension (Diastolic BP > 90 mmHg or Systolic BP > 140 mmHg).
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Myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV).
-
Significant gastrointestinal abnormalities, requirement for IV alimentation, active peptic ulcer, chronic diarrhea, or vomiting considered to be clinically significant in the judgment of the Investigator, or prior surgical procedures affecting absorption.
-
12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of
480 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 (according to current information provided at https://crediblemeds.org).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Site 0136 | Tucson | Arizona | United States | 85711 |
| 2 | Site 0135 | Aurora | Colorado | United States | 80012 |
| 3 | Site 0152 | Albuquerque | New Mexico | United States | 87109 |
| 4 | Site 0201 | Eugene | Oregon | United States | 97401 |
| 5 | Site 0191 | Providence | Rhode Island | United States | 02905 |
| 6 | Site 0130 | Charlottesville | Virginia | United States | 22908 |
| 7 | Site 0194 | Fairfax | Virginia | United States | 22031 |
Sponsors and Collaborators
- K-Group Beta
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ZN-c3-006
- GOG-3067
- 2021-004161-13