E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Prostate Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic Prostate Cancer |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036909 |
E.1.2 | Term | Prostate cancer metastatic |
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 effectiveness of niraparib and AAP compared to AAP and placebo. |
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E.2.2 | Secondary objectives of the trial |
* To assess the clinical benefit of niraparib and AAP compared to AAP and placebo * To characterize the pharmacokinetics (PK) of niraparib when given with AAP and abiraterone trough levels * To characterize the safety profile of niraparib when given with AAP compared to AAP with placebo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Criterion modified per Amendment 3 1.1 Criterion modified per Amendment 4 1.2 Criterion modified per Amendment 5 1.3 HRR gene alteration status (as identified by the sponsor's required assays or local testing for HRR gene alteration) as follows: a. Cohort 1: positive for HRR gene alteration b. Cohort 2: not positive for HRR gene alteration (ie, no HRR gene alteration) c. Cohort 3: positive for HRR gene alteration, see Attachment 4 2. Metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI). 3. Criterion modified per Amendment 2 3.1 Metastatic prostate cancer in the setting of castrate levels of testosterone ≤50 ng/dL on a GnRHa or bilateral orchiectomy as evidenced by prostate-specific antigen (PSA) progression or radiographic progression 4. Able to continue GnRHa during the study if not surgically castrate 5. ECOG PS Grade of 0 or 1 6 Score of ≤3 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours). 7. Criterion modified per Amendment 2 7.1 Clinical laboratory values at Screening: a. Absolute neutrophil count (ANC) ≥1.5 x 10^9/L. b. Hemoglobin ≥9.0 g/dL, independent of transfusions for at least 30 days. c. Platelet count ≥100 x 10^9/L. d. Serum albumin ≥3.0 g/dL. e. Creatinine clearance ≥30 mL/min either calculated or directly measured via 24-hour urine collection. f. Serum potassium ≥3.5 mmol/L. g. Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤1 x ULN (Note: in subjects with Gilbert's syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is ≤1.5 x ULN, subject may be eligible as determined by the medical monitor). h. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN. 8. Able to swallow the study drug tablets and capsules whole. 9. Criterion modified per Amendment 5 9.1 While on study drug and for 3 months following the last dose of study drug, a male subject must agree to use an adequate contraception method as deemed appropriate by the investigator (specified in Section 4.4 Lifestyle Considerations) and agree not to donate sperm. 10. Willing and able to adhere to the prohibitions and restrictions specified in the protocol. |
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E.4 | Principal exclusion criteria |
1. Prior treatment with a PARP inhibitor 2. 2. Criterion modified per Amendment 2 2.1 Systemic therapy (ie, novel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or more than 4 months of AAP prior to randomization) in the mCRPC setting; or AAP outside of the mCRPC setting. 3. Criterion modified per Amendment 2 3.1 For subjects who received 2 to 4 months of AAP prior to randomization for the treatment of mCRPC, evidence of progression by PSA (per PCWG3) during screening. These potential subjects are required to have 2 PSA values during the Prescreening and Screening Phases. The second PSA value should be within 2 weeks of randomization. If PSA rise is thought to be due to flare, the investigator should confirm that there is no radiographic progression. 4. Symptomatic brain metastases 5. History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) 6. Other prior malignancy ≤2 years prior to randomization, or malignancy that currently requires active systemic therapy 7. Severe or unstable angina, myocardial infarction or ischemia requiring coronary artery bypass graft or stent within the previous 6 months, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g. adequate cardiac function), or clinically significant ventricular arrhythmias within 6 months prior to randomization or New York Heart Association (NYHA) Class II to IV heart disease 8. Presence of uncontrolled hypertension 9. Current evidence of any of the following: a. Any medical condition that would make prednisone use contraindicated b. Any chronic medical condition requiring a higher equivalent dose of corticosteroid than 10 mg prednisone (or equivalent) once daily. 10. Criterion modified per Amendment 5 10.1 Active or symptomatic viral hepatitis or chronic liver disease (as evidenced by ascites, encephalopathy or bleeding disorders secondary to hepatic dysfunction). 11. History of adrenal dysfunction 13. Subjects who are receiving opioid analgesics at the time of screening 14. Active human immunodeficiency virus (HIV) infection |
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E.5 End points |
E.5.1 | Primary end point(s) |
Radiographic progression-free survival (rPFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
While on study treatment, radiographic imaging will be performed at Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, and then every 12 weeks |
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E.5.2 | Secondary end point(s) |
* OS * Time-to-symptomatic progression * Time-to-initiation of cytotoxic chemotherapy * Observed plasma concentrations of niraparib and abiraterone and estimated population PK and exposure parameters for niraparib * Incidence and severity of AEs * Clinical laboratory test results |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessments of the secondary endpoints are variable but carried out on a regular basis from C1D1 through the follow up as described in the endpoint requirements |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker evaluations, PRO |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Czechia |
France |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Sweden |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 24 |