The purpose of this study is to understand if a new treatment for prostate cancer (niraparib) added to a standard treatment (abiraterone acetate plus prednisone) will work better than the standard treatment alone.Cohort 3: the purpose is to evaluate…
ID
Source
Brief title
Condition
- Prostatic disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Radiographic progression-free survival (rPFS)
Secondary outcome
-Overall Survival
-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
Background summary
In patients with metastatic prostate cancer, DNA-repair anomalies are
identified in approximately 15% to 20% of tumors. PARP inhibition leads to an
accumulation of unrepaired single-strand breaks, which result in stalling and
collapse of replication forks and, consequently, to double-strand breaks
(DSBs). Normally, DSBs are repaired through homologous recombination. If not
repaired, DSBs result in cell death.
In addition to facilitating DNA-repair, dual roles for PARP in supporting AR
activity have been observed in the preclinical setting.In the clinical setting,
recent data have shown the efficacy of combining AR-targeted therapy and a PARP
inhibitor in patients with metastatic prostate cancer.8 The patients treated
with a combination of olaparib and AA-P had improved rPFS compared with those
treated with AA-P alone. This benefit was seen in both patients with and
without HRR.
Cohort 3: the fixed dose combination tablet would reduce the number of pills to
2 tablets per day plus prednisone. Reducing the pill burden for patients with
cancer may improve compliance. In cohort 3 the sponsor will evaluate the safety
and efficacy of the regular-strength FDC tablet formulation in the same patient
population as cohort 1+2. The sponsor is also developing a low-strength FDC
tablet formulation to allow dose modications to address the need for patients
with toxicities.
Study objective
The purpose of this study is to understand if a new treatment for prostate
cancer (niraparib) added to a standard treatment (abiraterone acetate plus
prednisone) will work better than the standard treatment alone.
Cohort 3: the purpose is to evaluate the efficacy and safety of the FDC tablet
formulation of Niraparib and AA, plus prednisone.
Study design
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter
study to assess the
efficacy and safety of niraparib 200 mg once daily in combination with AA 1,000
mg once daily
and prednisone 10 mg (2 x 5 mg), compared to AA-P plus placebo in subjects with
metastatic
prostate cancer. Subjects in each cohort will be randomized in a 1:1 ratio to
receive either
niraparib plus AA-P or placebo plus AA-P.
The study will consist of 4 phases:
• Prescreening Phase for biomarker evaluation only
• Screening Phase of up to 28 days to establish study eligibility
• Treatment Phase
• Follow-up Phase of up to 60 months to monitor survival status and other
information
The biomarker status for all subjects will be assessed using the sponsor*s
required assays during the Prescreening Phase. Subjects will be assigned to a
cohort based on their biomarker status. A treatment cycle is defined as 28
days. Imaging will be performed
very 8 weeks for the first 6 months and then every 12 weeks thereafter.
Subjects must discontinue study medication in the event of documented
unequivocal clinical progression. If the subject has radiographic progression,
but not unequivocal clinical progression, and alternate treatment is not
initiated, the subject may continue study treatment at the investigator*s
discretion. After discontinuing study drug, subjects will be contacted every 3
months for survival follow-up. Selected patient-reported outcomes (PROs)
questionnaires will also be administered every 3 months for up to 2 years after
treatment discontinuation.
Cohort 1: Subjects with mCRPC and DNA Repair Defects (DRD)
Cohort 1 will evaluate the combination of niraparib and AA-P versus placebo and
AA-P in subjects with mCRPC (ie, have not been treated with any therapy in the
metastatic castrate-resistant setting, except for ADT and a limited exposure to
AA-P) and DRD. The cohort will enroll approximately 400 subjects (per protocol
amendment 3 50% of patients in cohort 1 need to have a BRCA mutation, stop
enrollment of patient with an ATM mutation in cohort 1).
Cohort 2: Subjects with mCRPC and No DRD
Cohort 2 will evaluate the combination of niraparib and AA-P versus placebo and
AA-P in subjects with mCRPC (ie, have not been treated with any therapy in the
metastatic castrate-resistant setting, except for ADT and a limited exposure to
AA-P) and who do not have DRD. The cohort will enroll approximately 600
subjects.
Groep 3: patients with mCRPC that will receive a FDC tablet formulation of
niraparib and abiraterone
Cohort 3 will be an open label cohort that will start after cohort 1 and 2 are
completed. If futility analysis of cohort 2 is not met, then approximately 100
patients will be enrolled in cohort 3; approximately 60 patients without HRR
gene alterations and approximately 40 patients with HRR gene alterations
(approximately 20 of whom should have BRCA mutation). If futility analysis of
cohort 2 is met, then approximately 40 patients with HRR gene alterations
(approximately 20 of whom should have BRCA mutation) will be enrolled.
Intervention
Cohort 1+2
Abiraterone acetate 1,000 mg (four 250 mg tablets) will be taken orally once
daily continuously,
concomitantly with oral prednisone 5 mg twice a day.
Niraparib 200 mg (two 100 mg capsules) or placebo should be taken daily around
the same time as AA-P.
Cohort 3
Regular strength FDC niraparib/AA (2 tablets of 100mg/500mg) will be taken
orally once daily continuously,
concomitantly with oral prednisone 5 mg twice a day.
Low strength FDC niraparib/AA (2tablets of 50mg/500mg) will be taken orally
once daily continuously,
concomitantly with oral prednisone 5 mg twice a day. This is to be able to
lower the dose of niraparib in case of toxicities.
Study burden and risks
The procedures required in the trial are also done in the standard treatment
setting, although certain procedures (eg.
blooddraws for pharmacokinetics, pharmacodynamics and biomarkers as well as the
number of CT/MRI and bone scans)
are done more often than in the standard treatment. The trial medication can
lead to side effects. The extra trial procedures
and possible side effects observed until now are considered to be acceptable,
taken into account the expected therapeutic
benefit of the trial medication.
The procedures for cohort 3 are the same as for cohort 1+2 except for the dose
modifications.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed metastatic prostate cancer with no prior systemic
therapy in the
mCRPC setting
2. Can provide blood sample for determination of HRR
3. Willing to provide a fresh or archival tumor tissue sample for determination
of HRR
4. HRR status (as identified by the sponsor*s required assays or positive BRCA1
or BRCA2 germline testing results from certified laboratories as acceptable for
screening.) as follows:
a. Cohort 1: positive for HRR (per protocol amendment 3: stop enrollment of
subjects with ATM mutations into Cohort 1 and to ensure at least 50% of Cohort
1 are subjects with BRCA mutations)
b. Cohort 2: not positive for HRR (ie, no HRR)
c. Cohort 3: positive or not positive for HRR gene alterations
5. Must be able to continue GnRHa during the study if not surgically castrate
6. ECOG PS grade of 0 or 1
7. Adequate hematologic and metabolic values at screening
Exclusion criteria
1. Prior treatment with a PARP inhibitor
2.Systemic therapy in the mCRPC setting; or AA-P outside of the mCRPC setting.
3.For subjects who received 2 to 4 months of AA-P prior to randomization for
the treatment of mCRPC, evidence of progression by PSA (per PCWG3) during
screening.
4.. Severe or unstable angina, myocardial infarction, symptomatic congestive
heart failure,
arterial or venous thromboembolic events (e.g, pulmonary embolism,
cerebrovascular
accident including transient ischemic attacks), or clinically significant
ventricular
arrhythmias within 6 months prior to randomization or New York Heart Association
(NYHA) Class II to IV heart disease.
5.. Presence of uncontrolled hypertension (systolic blood pressure [BP] >160
mmHg or
diastolic BP >100 mmHg). Subjects with a history of hypertension are allowed,
provided
that BP is controlled to within these limits by anti-hypertensive treatment.
6. Active or symptomatic viral hepatitis or chronic liver disease (as evidenced
by ascites or
bleeding disorders secondary to hepatic dysfunction)
7. Subjects who have had the following <=30 days prior to planned Cycle 1 Day 1:
a. a transfusion (platelets or red blood cells)
b. hematopoietic growth factors
c. an investigational agent for prostate cancer
d. major surgery
e. radiation therapy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003364-12-NL |
| ClinicalTrials.gov | NCT03748641 |
| CCMO | NL67657.056.18 |