E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
mCRPC and DNA-repair anomalies |
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E.1.1.1 | Medical condition in easily understood language |
Prostate cancer in adult men that has spread to other parts of the body |
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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 assess the efficacy of niraparib in subjects with measurable mCRPC and who have either biallelic DNA-repair anomalies in BRCA (BRCA1 or BRCA2) or germline BRCA |
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E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of niraparib in subjects with measurable mCRPC and DNA-repair anomalies in biallelic non-BRCA (ATM FANCA, PALB2, CHEK2, BRIP1, or HDAC2) -To assess the efficacy of niraparib in subjects with mCRPC and DNA repair anomalies -To evaluate response outcomes of niraparib in subjects with mCRPC and DNA-repair anomalies. -To evaluate the safety and tolerability of niraparib. -To evaluate duration of tumor response. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male 2. >18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place). 3. Signed main study ICF indicating that the subject understands the purpose of, and procedures required for, the study and is willing to participate in the study. 4. Histologically confirmed prostate cancer (mixed histology is acceptable,with the exception of the small cell pure phenotype, which to be excluded). 5.3. Criterion modified per Amendment 6 5.4. Received a taxane-based chemotherapy for the treatment of metastatic prostate cancer with evidence of disease progression on or after treatment, or discontinued from a taxane-based chemotherapy due to an adverse event 6.4. Criterion modified per Amendment 7. 6.5. Received a second-generation or later AR-targeted therapy (for example, abiraterone acetate plus prednisone, enzalutamide, apalutamide) for the treatment of metastatic prostate cancer with evidence of disease progression or non-metastatic castration-resistant prostate cancer with evidence of subsequent metastasis. 7.1. Criterion modified per Amendment 7 7.2 Biomarker-positive by at least one of the following criteria: a. Biallelic DNA-repair anomaly (refer to Table 5) based on a sponsor-validated blood or tissue assay. b. Germline pathogenic BRCA1 or BRCA2 by any test (somatic local results must be confirmed as positive by the sponsor-validated assay before dosing). 8. Progression of metastatic prostate cancer in the setting of castrate levels of testosterone ≤50 ng/dL on a gonadotropin releasing hormone analog (GnRHa), or history of bilateral orchiectomy at study entry defined as having one or more of the following: a. PSA progression defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each determination (per Prostate Cancer Working Group 3 [PCWG3] criteria). The PSA level at the screening visit should be ≥1 μg/L (1 ng/mL). b. Radiographic progression of soft tissue by RECIST 1.1 or bone disease by PCWG3 criteria as defined below: I. Soft disease (measurable) by RECIST 1.1 defined as having one or more of the following: i. Nodal disease (pelvic or extrapelvic [retroperitoneal, mediastinal, thoracic, other]) with lesions ≥1.5 cm in the short axis. ii. Visceral disease (lung, liver, adrenal) with lesions ≥1 in the long axis. II. Bone disease (non-measurable) defined as having bone lesions in the absence of measurable soft tissue disease 9. Must be able to continue GnRHa during the course of the study if not surgically castrate. 10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤2. 11. Must be able to swallow whole capsules. 12. Subject must agree to use medically accepted and highly effective methods of contraception during the course of the study and for 3 months after the last dose of study drug. 13. To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must agree while on study drug and for 3 months following the last dose of study drug to: a. Use a condom during sexual activity. b. Not donate sperm. 14.3. Criterion modified per Amendment 6 14.4. At screening,the following laboratory parameters must be met: a. Absolute neutrophil count (ANC) ≥1.5 x 10^9/L b. Hemoglobin ≥9.0 g/dL c. Platelet count ≥100 x 10^9/L d. Serum albumin ≥3 g/dL e. Creatinine clearance ≥30 mL/min f. Criterion deleted per Amendment 5. 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 direct bilirubin is ≤1.5 x ULN, subject may be eligible) h. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x ULN i. CTC count of ≥1 cells /7.5 mL blood (required only for patients with non-measurable soft tissue disease by RECIST 1.1) |
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E.4 | Principal exclusion criteria |
1. Prior treatment with a PARP inhibitor. 2. Prior platinum-based chemotherapy for the treatment of prostrate cancer. 3. Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). 4. Symptomatic or impending cord compression, except if subject has received definitive treatment for this and demonstrates evidence of clinically stable disease. 5. Symptomatic brain metastases. 6. Known allergies, hypersensitivity, or intolerance to niraparib or its excipients (refer to Investigator's Brochure). 7. Any condition for which, in the opinion of the investigator or sponsor, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. 8. Known disorder affecting gastrointestinal absorption. 9. Active cancer (other than prostate cancer; or basal cell or squamous cell skin cancer, non-muscle invasive bladder cancer [stages pTaG1 and pTaG2], or any other cancer in situ currently in complete remission) within 2 years prior to Cycle 1 Day 1. 10.Prior palliative radiotherapy ≤7 days prior to Cycle 1 Day 1 Radiotherapy given >7 days prior to Cycle 1 Day 1 is permitted as long as any AEs associated with radiotherapy have resolved to Grade 1 or baseline. 11. Criterion deleted per Amendment 5 12. Criterion deleted per Amendment 3. 13. History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsades de pointes). 14. HIV positive subjects with 1 or more of the following: a. Not receiving highly active antiretroviral therapy b. A change in antiretroviral therapy within 6 months of the start of screening(except if, after consultation with the sponsor on exclusion criterion 14.c, a change is made to avoid a potential drug-drug interaction with the study drug) c. Receiving antiretroviral therapy that may interfere with the study drug consult the sponsor for review of medication prior to enrollment) d. CD4 count <350 at screening e. An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening 15.1. Criterion modified per Amendment 6. 15.1. ≤14 days prior to Cycle 1 Day 1 had: a. a transfusion (platelets or red blood cells) b. chemotherapy c. hematopoietic growth factors 16. Criterion deleted per Amendment 5. 17. Subjects with uncontrolled (persistent) hypertension defined as systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg despite medical management. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (ORR) or soft tissue (visceral or nodal disease) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with no evidence of bone progression according to the PCWG3 criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final analysis for the RR will occur approximately 30 months (approximately 6 months from last subject enrolled) |
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E.5.2 | Secondary end point(s) |
-Circulating tumor cell (CTC) response defined as CT=0 per 7.5 mL blood at 8 weeks post-baseline in subjects with baseline CTC >0 OS: time from enrollment to death from any cause - rPFS: time from enrollment to radiographic progression or death from any cause, whichever occurs first -Time to radiographic progression -Time to PSA progression -Time to symptomatic skeletal event (SSE) -Incidence of adverse events -Clinical laboratory test results -Duration of objective response: time from complete response (CR) or partial response (PR) to radiographic progression of disease, unequivocal clinical progression, or death, whichever occurs first |
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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 | Yes |
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 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Australia |
Belgium |
Brazil |
Canada |
France |
Israel |
Korea, Republic of |
Netherlands |
Russian Federation |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 13 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 26 |