This study has been transitioned to CTIS with ID 2023-508150-26-00 check the CTIS register for the current data. Primary Objectives:- To determine the BE of a RS FDC tablet formulation of niraparib and Abiraterone Acetate with respect to niraparib…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
- PK parameters (Cmax,ss, AUC0-24h,ss, and test-to reference ratios for these
parameters) of niraparib and Abiraterone Acetate at steady state.
Secondary outcome
Secondary Endpoints:
- PK parameters (Cmax, AUC0-168h and test-to reference ratios for these
parameters) of niraparib and Abiraterone Acetate after a single dose.
- PD parameter (serum testosterone levels and test to-reference ratio) at
steady state.
- Incidence and severity of AEs and clinical laboratory safety.
Background summary
The sponsor is currently investigating the combination of niraparib and
Abiraterone Acetate plus prednisone, in 3 clinical trials: Phase 1b study of
subjects with mCRPC, irrespective of DNA-repair gene defects (DRD) status
(Study 64091742PCR1001, BEDIVERE, completed study), Phase 2 study of subjects
with mCRPC with DRD (Study 64091742PCR2002, QUEST, ongoing study), and a Phase
3 randomized, placebo-controlled, double-blind study of niraparib in
combination with Abiraterone Acetate plus prednison versus Abiraterone Acetate
plus prednison alone in subjects with first-line (L1) mCRPC with or without DRD
(Study 64091742PCR3001, MAGNITUDE, ongoing study). Niraparib is also being
evaluated as monotherapy in Study 64091742PCR2001 (GALAHAD) for the treatment
of subjects with mCRPC and DNA-repair anomalies.
In order to decrease the pill burden and aid in treatment compliance, the
sponsor is developing a fixed dose combination (FDC) formulations of niraparib
and Abiraterone Acetate for future clinical/commercial use. The approved
Abiraterone Acetate dose for clinical use is 1000 mg (2x500 mg tablets or 4x250
mg tablets) administered orally once daily on an empty stomach (no Abiraterone
Acetate intake at least one hour before or at least two hours after a meal) in
combination with prednisone 5 mg administered orally twice daily (BID).
Niraparib is approved for the treatment of ovarian cancer (monotherapy 300 mg
once daily) and is an investigational compound in the mCRPC setting.
Based on data from the Phase 1b study, 64091742PCR1001 (BEDIVERE), which
evaluated the recommended Phase 2 dose (RP2D) for the combination of niraparib
with abiraterone acetate plus prednisone, and based on supportive data from
TESARO-GSK Study TAPACIO, a dose of 200 mg niraparib once daily (2 x 100 mg
capsules) was selected form the combination Phase 3 MAGNITUDE study of
niraparib with 1000 mg abiraterone acetate once daily (4 x 250 mg tablets) plus
10 mg prednisone daily (5 mg tablets for BID oral administration) in mCRPC.
Thus, the selected doses of niraparib and abiraterone acetate in the
combination, when administered as individual single agents, would require
subjects to be treated with up to 6 capsules/tablets per day.
By developing an FDC formulation, the sponsor plans to reduce the number of
tablets required for the niraparib + Abiraterone Acetate combination regimen to
2 tablets per day, which may improve compliance with the regimen. The FDC
tablets to be evaluated in this study include two different dose ratios of
niraparib/Abiraterone Acetate:
100 mg niraparib/500 mg Abiraterone Acetate (regular-strength FDC tablet) and
50 mg niraparib/500 mg Abiraterone Acetate (low-strength FDC tablet). These FDC
formulations will be compared with the commercial tablets of Abiraterone
Acetate 250 mg and commercial capsules of niraparib 100 mg.
Study objective
This study has been transitioned to CTIS with ID 2023-508150-26-00 check the CTIS register for the current data.
Primary Objectives:
- To determine the BE of a RS FDC tablet formulation of niraparib and
Abiraterone Acetate with respect to niraparib and Abiraterone Acetate
co-administered as single agents at steady state under modified fasted
conditions in participants with mCRPC.
Secundary Objectives:
- To determine the relative BA of a LS FDC tablet formulation of niraparib and
Abiraterone Acetate with respect to niraparib and Abiraterone Acetate
co-administered as single agents after a single dose administration under
modified fasted conditions in participants with mCRPC.
- To compare the PD of Abiraterone Acetate (serum testosterone levels)
following multiple dose administration of a RS FDC tablet formulation of
niraparib and Abiraterone Acetate to the PD of Abiraterone Acetate following
niraparib and AA co-administered as single agents.
- To assess the safety of niraparib in combination with Abiraterone Acetate
plus prednison in participants with mCRPC.
Abbreviations: AE=adverse events;
BA=bioavailability; BE=bioequivalence; FDC=fixed-dose combination;
LS=low-strength; mCRPC=metastatic castration-resistant
prostate cancer; P=prednisone; PD=pharmacodynamics; PK=pharmacokinetics;
RS=regular-strength.
Study design
This is an open-label, multicenter, randomized study with a sequential design
to (1) assess the relative BA of a low-strength FDC tablet formulation of
niraparib and AA compared to niraparib and AA co-administered as single agents
after single-dose administration; and (2) assess BE of a regular-strength FDC
tablet formulation of niraparib and AA compared to niraparib and AA
co-administered as single agents at steady state in participants with mCRPC.
Approximately 120 participants with mCRPC are planned to be enrolled in this
trial.
The study will consist of up to a 21-day Screening Phase to determine
eligibility; an open-label Treatment Phase consisting of a PK Assessment Phase
including 3 periods (Period 1: 1-week run-in (Study days -7 to -1), Period 2:
Cycle 1 Day 1 to Day 11 (Study Days 1-11), and Period 3: Cycle 1 Day 12 to
Cycle 1 Day 22 (Study Days 12-22); followed by the Extension Phase during which
treatment with both niraparib and AA or AA alone, administered as single agents
will be continued from Cycle 1 Day 23 (Study Day 23) onwards until
discontinuation; and a 30-day Posttreatment Follow-up Phase.
Repeated dosing with regular-strength FDC tablets or single agents during the
PK Assessment Phase and the Extension Phase will be combined with
prednisone/prednisolone 5 mg twice a day (BID).
Participants will be randomly assigned to one of the four treatment sequences
(ABD, ADB, CBD, CDB), each containing three treatment periods which may include
Treatments A, B, C or D, as shown in the protocol Table 1, page 30.
Intervention
there will be 4 different groups:
1.
Period 1: 100mg Niraparib/1000mg Abiraterone Acetate as single agents (+5mg
prednison 2dd)
Period 2: 200mg Niraparib/1000mg Abiraterone Acetate as single agents (+5mg
prednison 2dd)
Period 3: 200mg Niraparib/1000mg Abiraterone Acetate as fixed dose combination
(+5mg prednison 2dd)
Extension Phase: chronische behandeling met 200mg Niraparib/1000mg Abiraterone
Acetate as single agents (+5mg prednison 2dd)
2.
Period 1: 100mg Niraparib/1000mg Abiraterone Acetatet as single agents (+5mg
prednison 2dd)
Period 2: 200mg Niraparib/1000mg Abiraterone Acetate as fixed dose combination
(+5mg prednison 2dd)
Period 3: 200mg Niraparib/1000mg Abiraterone Acetate as single agents (+5mg
prednison 2dd)
Extension Phase: chronische behandeling met 200mg Niraparib/1000mg Abiraterone
Acetate as single agents (+5mg prednison 2dd)
3.
Period 1: 100mg Niraparib/1000mg Abiraterone Acetatet as fixed dose combination
(+5mg prednison 2dd)
Period 2: 200mg Niraparib/1000mg Abiraterone Acetate as single agents (+5mg
prednison 2dd)
Period 3: 200mg Niraparib/1000mg Abiraterone Acetate as fixed dose combination
(+5mg prednison 2dd)
Extension Phase: chronische behandeling met 200mg Niraparib/1000mg Abiraterone
Acetate as single agents (+5mg prednison 2dd)
4.
Period 1: 100mg Niraparib/1000mg Abiraterone Acetate as fixed dose combination
(+5mg prednison 2dd)
Period 2: 200mg Niraparib/1000mg Abiraterone Acetate as fixed dose combination
(+5mg prednison 2dd)
Period 3: 200mg Niraparib/1000mg Abiraterone Acetate as single agents (+5mg
prednison 2dd)
Extension Phase: chronische behandeling met 200mg Niraparib/1000mg Abiraterone
Acetate as single agents (+5mg prednison 2dd)
Study burden and risks
Given that the anticipated toxicities of both Abiraterone Acetate plus
prednison and niraparib are recognizable through medical oversight and
laboratory monitoring and are able to be managed medically, and that there is a
potential for increased efficacy of the combination for patients with incurable
metastatic prostate cancer, the
sponsor considers that there is a positive benefit/risk profile and a strong
rationale for evaluating niraparib with Abiraterone Acetate plus prednison for
the treatment of patients with metastatic prostate cancer.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
1.Male
2. >/= 18 years or older
3. Signed ICF, documenting that purpose and procedures are understood and
patient is willing to participate in study.
4. Histologically or cytologically confirmed adenocarcinoma of the prostate.
5.Diagnosed with mCRPC, who in the opinion of the investigator may benefit from
treatment in this study.
6.Able to continue gonadotropin-releasing hormone analogues (GnRHa) therapy
during the study if not surgically castrate (ie, participants who have not
undergone bilateral orchiectomy).
7.Criterion modified per Amendment 1.
7.1 Participants who received prior therapy with enzalutamide or apalutamide
must have at least an 8-week or a 6-week washout, respectively, before the
first dose of study treatment. Participants who received prior therapy with
other anti-androgens (eg, bicalutamide, flutamide, nilutamide) must have at
least a 2-week washout before the first dose of the study treatment.
8.Eastern Cooperative Oncology Group Performance Status (ECOG PS) of <=1.
9.Toxicity associated with prior chemotherapy or radiotherapy has resolved to
Grade <=1 (except alopecia, local skin fibrosis/reaction or Grade <=2 neuropathy)
at screening.
10.At screening, the following laboratory parameters must be met:
a.Absolute neutrophil count (ANC) >=1.5x109/L
b.Hemoglobin >=9.0 g/dL independent of transfusion within the last 4 weeks
c.Platelet count >=100x109/L independent of transfusion within the last 4 weeks
d.Serum albumin >=3.0 g/dL
e.Serum creatinine <=1.5×upper limit of normal (ULN), or a calculated creatinine
clearance >=60 mL/min/1.73 m2 using the MDRD or Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation
f.Serum potassium >=3.5 mmol/L
g.Serum total bilirubin <=1.5×ULN (Note: In participants with Gilbert*s
syndrome, if total bilirubin is >1.5×ULN, measure direct and indirect
bilirubin, and if direct bilirubin is <=1.5×ULN, participant may be eligible)
h.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <=3xULN
11. Criterion modified per Amendment 1.
11.1 While on study medication and for 3 months following the last dose of
study medication, a male participant must agree to use an adequate
contraception method as deemed appropriate by the investigator and as specified
in Protocol Section 5.3. Lifestyle Considerations.
12. Ability to provide a blood sample for determination of HRR gene alteration
status.
13. Willing to provide a tumor sample (archival) for determination of HRR gene
alteration
status.
Exclusion criteria
1.Symptomatic brain metastases.
2. Criterion modified per Amendment 1.
2.1 Prior disease progression during treatment with AA alone or when combined
with a PARP inhibitor (PARPi). Prior discontinuation of treatment with AA or
PARPi
due to AA- or PARPi-related toxicity.
3.History or current diagnosis of MDS/AML.
4.Active malignancies (ie, progressing or requiring treatment change in the
last 24 months) other than the disease being treated under study. The only
allowed exceptions are:
a.non-muscle invasive bladder cancer.
b.skin cancer (non-melanoma or melanoma) treated within the last 24 months that
is considered completely cured.
c.Malignancy that is considered cured with minimal risk of recurrence.
5.Known allergies, hypersensitivity, or intolerance to niraparib or AA or the
corresponding excipients of niraparib/AA.
6. Any medical condition that would make prednisone use contraindicated.
7.Active hepatitis B virus (eg, hepatitis B surface antigen [HBsAg] reactive)
or active hepatitis C virus (HCV) (eg, HCV ribonucleic acid [RNA] [qualitative]
is detected).
8.Human immunodeficiency virus (HIV)-positive participants 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 15.c, a
change is made to avoid a potential drug-drug interaction with the study drug)
c.Receiving antiretroviral therapy that may interfere with study treatment
(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
9 .<=21 days prior to Study Day 1 received or had
a. chemotherapy or immunotherapy for treatment of prostate cancer
b. investigational agent for treatment of prostate cancer
10. Active or symptomatic viral hepatitis or chronic liver disease; ascites or
bleeding disorders secondary to hepatic dysfunction.
11. Moderate or Severe hepatic impairment Class B or C per Child-Pugh
classification system.
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 |
|---|---|
| EU-CTR | CTIS2023-508150-26-00 |
| EudraCT | EUCTR2019-000137-39-NL |
| ClinicalTrials.gov | NCT04577833 |
| CCMO | NL74660.056.20 |