| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum-resistant Ovarian Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the ovaries that has failed to respond to previous platinum therapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-To investigate the safety and tolerability of ZN-c3 in combination with Niraparib, including identification of the MTD and RP2D.
-To investigate the antitumor activity of ZN-c3 in combination with Niraparib. |
|
| E.2.2 | Secondary objectives of the trial |
-To further investigate the antitumor activity of ZN-c3 in combination with Niraparib.
-To investigate the overall survival (OS) of subjects receiving ZN-c3 in combination with Niraparib.
-To investigate the safety and tolerability of ZN-c3 in combination with Niraparib.
-To evaluate changes in patient-reported outcomes (PRO) and quality of life.
-To investigate the plasma PK of ZN-c3 and Niraparib when given in combination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent by subjects or their legally authorized representatives prior to initiation of any study-related procedures; assent, when appropriate, will be obtained according to institutional guidelines.
2. Female and at least 18 years old at the time of informed consent.
3. 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.
4. Have demonstrated relapse within 6 months of platinum therapy (platinum-free interval <6 months).
5. Must have evaluable or measurable disease according to RECIST Guideline version 1.1 criteria: defined as at least one lesion that can be accurately measured.
6. ECOG performance status (PS) of 0 or 1.
7. Adequate hematologic and organ function as defined by the following criteria:
a. Absolute neutrophil count (ANC) ≥1.5 x 109/L.
b. Platelet count ≥100 × 109/L.
c. Hemoglobin ≥9 g/dL without blood transfusion within the last 14 days.
d. Creatinine clearance (CrCl) ≥60 mL/min based on Cockroft-Gault method.
e. Total bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN in the case of Gilbert’s disease.
f. ALT and AST ≤2.5 × ULN. If liver function abnormalities are due to underlying liver metastases: AST and ALT ≤5 × ULN.
8. Ability and willingness to take oral medication.
9. 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 for myChoice® CDx testing retrospectively.
10. Willingness to release archival tissue (less than 1 year old) for research purposes or to undergo a tumor tissue biopsy prior to dosing on Cycle 1 Day 1. Note: If, in the opinion of the Investigator, obtaining a tumor tissue biopsy would expose the subject to unacceptable risk, otherwise eligible subjects may be permitted to enroll on a case-by-case basis after consultation with the Sponsor.
11. Female subjects of childbearing potential must agree to use a highly effective method of contraception prior to the first dose and for 180 days after the last dose of study drug treatment (per Appendix 1).
12. Willingness to practice adequate sun protection (use of sunscreen or sun-protective clothing or limitation of sun exposure) for the duration of the study and for 48 hours following the last dose.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
14. Toxicity of any previous chemotherapy has returned to ≤CTCAE 1 or baseline level, except for sensory neuropathy or alopecia with stable symptoms ≤CTCAE grade 2.
Additional Inclusion Criteria for Phase 2
1. This supersedes inclusion criterion 4 (above). Demonstrated relapse within 6 months of platinum therapy, while taking a PARPi as maintenance: a minimum of 3 months is required if the subject received PARPi maintenance following first-line chemotherapy.
2. Must have measurable disease according to RECIST Guideline version 1.1 criteria: defined as at least one lesion that can be accurately measured. |
|
| E.4 | Principal exclusion criteria |
1. Any of the following treatment interventions within the specified time frame prior to Cycle 1 Day 1:
a. Major surgery <28 days (the surgical incision should be fully healed prior to study drug administration).
b. Any other prior therapy directed at the malignant tumor, including immunologic agents, must be discontinued at least four weeks prior to Cycle 1 Day 1 (6 weeks for nitrosoureas or mitomycin C).
c. A minimum of 10 days between termination of the prior PARPi and administration of ZN-c3 and niraparib treatment is required. In the event the previously administered PARPi has a half-life ≥21 days, treatment with ZN-c3 and niraparib should not begin for at least 21 days.
d. Prior radiotherapy <14 days.
e. Any investigational drug therapy <28 days or 5 half-lives (whichever is shorter).
f. Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment, as well as P-gp inhibitors (see Appendix 3 Section 12.3).
g. Any hormonal therapy directed at the malignant tumor must be discontinued at least a month prior to Cycle 1 Day 1. Continuation of hormone replacement therapy is permitted.
h. Herbal medications 7 days prior to first dose of study treatment.
i. Treatment with a WEE1 inhibitor.
2. Unresolved toxicity of Grade >1 attributed to any prior therapies (excluding Grade ≤2 neuropathy, alopecia or skin pigmentation).
3. Known hypersensitivity to any drugs similar to ZN-c3 and/or niraparib in class or its excipients.
4. A serious illness or medical condition(s) including, but not limited to, the following:
a. Brain metastases that require immediate treatment or are clinically or radiologically unstable (i.e., have been stable for <1 month). If receiving corticosteroids for treatment of brain metastases, subjects must be receiving a stable dose or a decreasing corticosteroid dose during at least 1 week before enrollment.
b. Leptomeningeal disease that requires or is anticipated to require immediate treatment.
c. Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
d. 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).
e. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the subject inappropriate for entry into this study.
f. 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.
g. Active or uncontrolled infection. Subjects with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) must have completed such treatment and the infection must be considered controlled/resolved by the investigator before enrollment.
h. Uncontrolled hypertension (diastolic blood pressure >90 mmHg or systolic blood pressure >140 mmHg)
i. Known or current diagnosis of myelodysplastic syndrome or acute myeloid leukemia, or prior diagnosis of posterior reversible encephalopathy syndrome.
5. 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.
6. Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy.
7. Individuals who are considered by the Investigator to be unsuitable as study subjects.
8. 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.
9. 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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Incidence and severity of dose-limiting toxicities (DLTs) in DLTevaluable subjects during Cycle 1 (C1).
Phase 2:
− 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.
− 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1: After 20 subjects are enrolled the determination of the MTD will be consistent with that of a typical 3+3 dose escalation, safety lead-in design.
Phase 2: The primary clinical activity evaluation at the end of the study . |
|
| E.5.2 | Secondary end point(s) |
-Duration of response (DOR) as key secondary endpoint.
-Clinical Benefit Rate (CBR), Progression Free Survival (PFS) (median and 4-month rate), as defined by the revised RECIST version 1.1.
-Objective Response Rate (ORR) based on investigator assessment.
-Overall Survival (OS) (median and @12 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.
-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.
-Plasma PK parameters of ZN-c3 (and its potential metabolites, as applicable) and Niraparib. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| In Stage 1 (Total N=50 for each HRD cohort), clinical activity in each cohort is monitored at frequent 10-subject intervals |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the time when the last subject in the study completes 12 months after the last subject receives the first dose of study medication. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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