A study to understand the effect of Niraparib in men with end-stage PCA+

Phase 1

Conditions: mCRPC and DNA-repair anomalies
Therapeutic area: Diseases [C] - Cancer [C04]
MedDRA version: 21.1Level: PTClassification code 10036909Term: Prostate cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Registration Number: EUCTR2016-002057-38-IT

Lead Sponsor: JANSSEN CILAG INTERNATIONAL NV

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Male

Target Recruitment: 160

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 is be excluded).
5. Documented evidence of disease progression while on treatment with at least 1 taxane-based chemotherapy for prostate cancer
6. Documented evidence of disease progression while on treatment with at least 1 AR-targeted therapy (eg, abiraterone acetate, enzalutamide, apalutamide) for prostate cancer.
7. Tumor that is biomarker- positive for DNA-repair anomalies.
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 =2 µg/L (2 ng/mL).
b. Radiographic progression of soft tissue by RECIST 1.1 or bone disease by PCWG3 criteria as defined below:
I. Soft tissue 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 cm 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. 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. Serum creatinine =1.5 × upper limit of normal (ULN), or a calculated creatinine clearance =60 mL/min using the Cockcroft-Gault equation
f. Serum potassium =3.5 mmol/L
g. Serum total bilirubin =1.5 × ULN or direct bilirubin =1 x ULN (Note: in subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin, and if direct bilirubin is =1.5 × ULN, subject may be eligible)
h. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =3.0 × ULN or =5 x ULN in the presence of liver metastases i. i CTC count of =1 cells/7.5 mL blood
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 64
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 96

Exclusion Criteria

1. Prior treatment with a PARP inhibitor.
2. Prior platinum-based chemotherapy for the treatment of prostate cancer.
3. Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).
4. Known symptomatic or impending cord compression, except if subject has received definitive treatment for this and demonstrates evidence of clinically stable disease.
5. Known symptomatic uncontrolled brain or leptomeningeal metastases (controlled is defined as CNS disease which has undergone treatment
[eg, radiation or surgery] at least 15 days prior to Cycle 1 Day 1).
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, 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 radiotherapy =15 days prior to Cycle 1 Day 1, with the exception of a single fraction of radiotherapy for the purposes of palliation, which is permitted.
11. Corrected QT interval by the Fridericia correction formula (QTcF) on the screening ECG >450 msec.
12. Receiving concomitant medications that prolong QTc and are unable to discontinue use while receiving study drug.
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. =30 days prior to Cycle 1 Day 1 had:
a. a transfusion (platelets or red blood cells)
b. chemotherapy
c. hematopoietic growth factors
d. an investigational agent for prostate cancer
e. major surgery

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the efficacy of niraparib in subjects with measurable mCRPC and DNA-repair anomalies.;Secondary Objective: -To assess the efficacy of niraparib in subjects with mCRPC and DNArepair anomalies<br>-To evaluate response outcomes of niraparib in subjects with mCRPC and DNA-repair anomalies.<br>-To evaluate the safety and tolerability of niraparib.<br>-To evaluate duration of tumor response.;Primary end point(s): Objective response rate (ORR) of soft tissue (visceral or nodal disease) as defined by RECIST 1.1 with no evidence of bone progression according to the PCWG3 criteria;Timepoint(s) of evaluation of this end point: l'analisi finale di ORR avrà luogo a circa 26 mesi (approssimativamente 6 mesi dopo l’ultimo paziente arruolato).

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): -CTC response defined as CTC=0 per 7.5 mL blood at 8 weeks postbaseline<br>-OS: time from enrollment to death from any cause<br>- rPFS: time from enrollment to radiographic progression or death from<br>any cause, whichever occurs first<br>-Time to radiographic progression<br>-Time to PSA progression<br>-Time to symptomatic skeletal event (SSE)<br>-Duration of objective response: time from complete response (CR) or<br>partial response (PR) to radiographic progression of disease;Timepoint(s) of evaluation of this end point: Nap

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