| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10084789 |
| E.1.2 | Term | Homologous recombination deficiency positive advanced ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 evaluate the efficacy of neoadjuvant niraparib compared with neoadjuvant platinum-taxane doublet chemotherapy after 1 induction cycle of
carboplatin-paclitaxel per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in participants with confirmed HRd Stage III to IV OC |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate clinical benefit by Gynecological Cancer InterGroup (GCIG) cancer antigen 125 (CA-125) response criteria
• To evaluate clinical benefit as measured by progression-free survival (PFS) per RECIST v1.1 by investigator assessment
• To evaluate participants’ reported overall tolerability toward treatment, overall health status, OC-specific health-related quality of life (HRQoL) & symptoms, and work productivity
• To evaluate clinical benefit as measured by OS
• To evaluate clinical benefit as measured by time to first subsequent treatment (TFST)
• To evaluate the safety and tolerability of neoadjuvant niraparib and neoadjuvant platinum-taxane doublet chemotherapy
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
C1. Participant must be female ≥18 years of age, able to understand the study procedures, and agree to participate in the study by providing written informed consent.
C2. Participant must have measurable disease according to RECIST v1.1.
C3. Participant has an ECOG performance status of 0 to 2.
C4. Participant has adequate organ function, defined as follows:
a. Absolute neutrophil count ≥1500/μL, without growth factor support (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administration is not permitted within 2 weeks of Screening)
b. Platelets ≥100,000/μL without platelet transfusion support within 2 weeks prior to Screening
c. Hemoglobin ≥9 g/dL without transfusion or growth factor (recombinant erythropoietin) within 2 weeks of Screening
d. Serum creatinine ≤1.5× upper limit of normal (ULN) or calculated creatinine clearance ≥50 mL/min using Cockcroft-Gault equation
e. Total bilirubin ≤1.5× ULN, except in participants with Gilbert’s syndrome. Participants with Gilbert’s syndrome may enroll if direct bilirubin is ≤1.5× ULN.
f. Aspartate aminotransferase and alanine aminotransferase ≤2.5× ULN, unless liver metastases are present, in which case they must be ≤5× ULN
g. International normalized ratio or prothrombin time (PT) ≤1.5× ULN, unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
h. Activated PTT ≤1.5× ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Participants with known lupus anticoagulant and elevated PTT may be eligible on a case-by-case basis after discussion with the sponsor’s Medical Monitor.
C5. Participant is not pregnant or breastfeeding, and at least 1 of the following conditions apply:
- Is not a woman of childbearing potential (WOCBP), as defined in Appendix 1 in the master protocol.
OR
- Is a WOCBP using a contraceptive method that is highly effective (with a failure rate of <1% per year) with low user dependency, as described in Appendix 1 in the master protocol, during the treatment periods and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relation to the first dose of study treatment.
o A WOCBP must have a negative pregnancy test (highly sensitive urine test or serum test as required by local regulations) within 72 hours before the first dose of study treatment.
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
C6. Participant has newly diagnosed Stage III or IV ovarian, fallopian tube, or primary peritoneal cancer according to the International Federation of Gynecology and Obstetrics staging criteria.
C7. Participant must provide sufficient tumor tissue at Prescreening and agree to undergo a central HRD tumor testing using a fully validated assay. The tumor must be HRd as per central HRD tumor testing. If central testing does not confirm tumor HRd, the participant will not be eligible for the study.
a. Participants with documented germline BRCA1/2 deleterious or suspected deleterious mutations by approved test (e.g., BRACAnalysis CDx) will be eligible but will require central HRD testing. Participants with local, academic, or university-based germline BRCA1/2 testing will not be allowed to enroll without results of central HRD test.
b. All participants must agree to provide tumor tissue collected from IDS.
c. Participant must provide 2 formalin-fixed paraffin-embedded tissue blocks (or slides if blocks are not available) with sufficient tumor content (as confirmed by the sponsor’s designated central and/or testing laboratory) for central HRD testing at Prescreening and for exploratory biomarker testing at Prescreening or Screening. If sufficient tumor tissue is provided at Prescreening, participants do not need to provide additional tissue at Screening.
C8. Participant must have completed 1 run-in cycle of carboplatin-paclitaxel and not experienced disease progression after this treatment. Completion is defined as receiving ≥50% of the prescribed dose of therapy within 5 weeks.
C9. Participant must not have known contraindication or uncontrolled hypersensitivity to carboplatin and paclitaxel and their excipients and no known pre-existing conditions that would preclude treatment with these agents.
C10. Participant must not have known contraindication or uncontrolled hypersensitivity to niraparib and its excipients. |
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| E.4 | Principal exclusion criteria |
C1. Participant has not recovered (i.e., to Grade ≤1 or to Baseline) from prior chemotherapy induced AEs. Note: Participant with Grade ≤2 neuropathy or alopecia is an exception to this criterion and may qualify for the study.
C2. Participant has a known diagnosis of immunodeficiency or is receiving systemic steroid therapy exceeding an equivalent of prednisone 10 mg daily or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
C3. Participant is currently participating in a treatment study or has participated in a study of an investigational agent within 4 weeks of the first dose of treatment.
C4. Participant has received prior systemic anticancer therapy including cytotoxic chemotherapy, PARP inhibitor, immune checkpoint inhibitors, hormonal therapy given with the intention to treat cancer, or biological therapy within 3 weeks of the first dose of study treatment. This washout period is required to ensure prior therapy is not confounding the toxicity profile of the investigational study drug or study drug combinations in cohorts.
Note: For this cohort (Cohort C), this criterion will not apply because the population will include only participants who are eligible for neoadjuvant chemotherapy.
C5. Participant has received live vaccine within 14 days of planned start of study therapy.
C7. Participant had major surgery within 4 weeks of starting the study or participant has not recovered from any effects of any major surgery.
C8. Participant has a known additional malignancy that progressed or required active treatment within the last 2 years because reoccurrence of another malignancy would confound interpretation of ORR by RECIST v1.1 criteria. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer that is considered to be low risk for progression by the investigator.
C9. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. These include, but are not limited to, coronavirus disease 2019, significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, myocardial infarction, cardiac arrhythmia or unstable angina within 6 months prior to enrollment, New York Heart Association Grade ≥2 congestive heart failure, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, Grade ≥2 peripheral vascular disease, and history of cerebrovascular accident within 6 months prior to enrollment), uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, and any psychiatric disorder that prohibits obtaining informed consent.
C10. Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, might interfere with the participant’s participation for the full duration of the study treatment, or is not in the best interest of the participant to participate.
C11. Participant has known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative] is detected).
C12. Participant has low-grade or Grade 1 epithelial OC or mucinous, germ cell, transitional cell, carcinosarcoma, or undifferentiated tumor.
C13. Participant has contraindications to surgery.
C14. Participant has a bowel obstruction by clinical symptoms or CT scan, subocclusive mesenteric disease, abdominal or gastrointestinal fistula, gastrointestinal perforation, or intra-abdominal abscess.
C15. Participant has any known history or current diagnosis of MDS or AML.
C16. Participant is at increased bleeding risk due to concurrent conditions (e.g., major injuries or major surgery within the past 28 days prior to the start of study treatment and/or history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
C18. Participant received prior treatment for high-grade non-mucinous epithelial ovarian, fallopian tube, or peritoneal cancer (e.g., prior surgery, immunotherapy, anticancer therapy [with the exception of 1 run-in cycle of carboplatin-paclitaxel], or radiation therapy).
C19. Participant has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone or insulin).
C20. Participant is unable to swallow orally administered medication or has a gastrointestinal disorder likely to interfere with absorption of the study medication. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy analysis is pre-IDS overall response rate (ORR; defined as the percentage of participants with unconfirmed complete or partial response) per RECIST v1.1 by investigator assessment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| Secondary endpoints include CA-125 progression by GCIG CA-125 response criteria; PFS; patient-reported outcomes to evaluate overall tolerability to treatment, overall health status, OC-specific health-related quality of life and symptoms, and work productivity; OS; TFST; and safety and tolerability |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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