Ovarian Cancer, Platinum-resistant Ovarian Cancer, Primary Peritoneal Carcinoma, Fallopian Tube Cancer
Conditions
Keywords
Wee1, Wee-1
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 and of ZN-c3 Monotherapy in subjects with platinum-resistant ovarian cancer.
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 and of ZN-c3 Monotherapy in subjects with platinum-resistant ovarian cancer who have failed Poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment.
Interventions
DRUGAzenosertib
Azenosertib
DRUGNiraparib
Niraparib
Sponsors
K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Histologically or cytologically confirmed recurrent high grade epithelial ovarian, primary peritoneal, or fallopian tube cancer with histologic subtypes of serous, clear cell or endometroid for which there is no known or established treatment available with curative intent. 2. Subjects must have platinum-resistant disease. 3. Must have evaluable or measurable disease according to RECIST v1.1 criterion: defined as at least one lesion that can be accurately measured. 4. Adequate hematologic and organ function. 5. Ability and willingness to take oral medication. 6. Subjects must provide formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer. Key
Exclusion criteria
1. 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). 2. A minimum of 10 days between termination of the prior PARPi and administration of ZN-c3 and niraparib treatment is required. 3. Any investigational drug therapy \<28 days. 4. Prior treatment with a WEE1 inhibitor. 5. Known hypersensitivity to any drugs similar to ZN-c3 and/or niraparib in class or its excipients. 6. Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). 7. Uncontrolled hypertension (Diastolic BP \> 90 mmHg or Systolic BP \> 140 mmHg). 8. 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). 9. 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. 10. 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. 11. History or current evidence of congenital or family history of long QT syndrome or Torsades de Pointes (TdP). 12. Taking medications with a known risk of TdP (according to current information provided at https://crediblemeds.org).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To determine the safety and tolerability of ZN-c3 monotherapy | 12 months | Frequency and severity of AEs and dose modifications |
| To investigate the antitumor activity of ZN-c3 monotherapy | 12 months | ORR as defined by the revised RECIST Guideline version 1.1 and assessed by ICR. |
| To investigate the safety and tolerability of ZN-c3 in combination with niraparib, including identification of the MTD and RP2D | 6 months | Incidence and severity of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects during Cycle 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To investigate the safety and tolerability of ZN-c3 in combination with niraparib and ZN-c3 monotherapy | 30 months | Frequency and severity of AEs and dose modifications |
| 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 - 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 - 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 - 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 |
| To further investigate the antitumor activity of ZN-c3 in combination with niraparib and ZN-c3 monotherapy | 30 months | Duration of response (DOR) as key secondary endpoint |
| To investigate the OS of subjects receiving ZN-c3 in combination with niraparib and ZN-c3 monotherapy | 30 months | OS (median and at 12 months) |
Countries
France, United States
Outcome results
None listed