A Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to: a) establish the recommended phase 2 dose (RP2D) and to evaluate the antitumor activity and safety of niraparib combination therapies (Combinations 1 and 2) and b) to determine the relative bioavailability of niraparib and abiraterone acetate (AA) in combination (Combination 3) in participants with metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description
-----------------
This multicenter study will evaluate safety and efficacy of niraparib in combination with other anti-cancer agents. Combination 1 will combine niraparib with the anti-programmed cell death protein (PD)-1 monoclonal antibody cetrelimab, in participants with mCRPC. Combination 1 has 2 parts: in Part 1 (dose selection), participants will be enrolled to establish RP2D doses of niraparib and cetrelimab; and Part 2 (dose expansion) will evaluate the combination therapy in an expanded number of participants into 2 cohorts (biomarker positive or biomarker negative). Combination 2 will combine niraparib with abiraterone acetate plus prednisone (AA-P) in mCRPC participants with DNA-repair gene defects (DRD). Combination 3 will evaluate the relative bioavailability (BA) of niraparib and AA in combination. In a pharmacokinetics (PK) assessment phase, niraparib and AA will be administered, and in an extension phase, niraparib and AA-P will be administered. Combinations 1 and 2 will have 5 phases: A Pre-screening Phase, a Screening Phase, a Treatment Phase, a Follow-up Phase, and a Long-term Extension (LTE) Phase; Combination 3 has 3 phases: A Screening Phase, A PK Assessment Phase, an Extension Phase (including LTE phase). Study evaluations will include efficacy, PK, PK/pharmacodynamics, biomarkers, safety and tolerability.

Official Title
-----------------
A Phase 1b-2 Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Conditions
-----------------
Prostatic Neoplasms, Castration-Resistant

Intervention / Treatment
-----------------
* Drug: Niraparib 200 mg
* Drug: Cetrelimab 240 mg
* Drug: Cetrelimab 480 mg
* Drug: Abiraterone acetate 1000 mg
* Drug: Prednisone 5 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for Combination 3: Diagnosed with mCRPC, who in the opinion of the investigator may benefit from treatment in Combination 3 of this study Able to continue gonadotropin releasing hormone analogue (GnRHa) therapy during the study if not surgically castrate (that is, subjects who has not undergone bilateral orchiectomy). Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to (<=) 1 Toxicity associated with prior chemotherapy or radiotherapy has resolved to Grade <= 1 (except alopecia or Grade <= 2 neuropathy) at screening Participant must agree not to donate sperm while on study treatment, and for 3 months following the last dose of study treatment Exclusion Criteria: History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) Active malignancies (that is, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are: non-muscle invasive bladder cancer; skin cancer (non-melanoma or melanoma); breast cancer; malignancy that is considered cured with minimal risk of recurrence Active infection requiring systemic therapy Allergies, hypersensitivity, or intolerance to niraparib or the corresponding excipients Combination 3: Symptomatic brain metastases Prior disease progression during combination treatment with AA and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitor (PARPi). Prior discontinuation of treatment with AA or PARPi due to AA- or PARPi-related toxicity

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination 1:Dose Selection: Niraparib + cetrelimab (Part 1)<br>Dose regimen 1: The participants will receive niraparib 200 milligram (mg) orally once daily in combination with cetrelimab 240 mg intravenously (IV) once every 2 weeks. Dose regimen 2: The participants will receive niraparib 200 mg orally once daily in combination with cetrelimab 480 mg IV once every 4 weeks in 28-day treatment cycles until disease progression, unacceptable toxicity, death, or the sponsor terminates the study. The safety evaluation team (SET) will determine if an additional cohort is necessary, based on the data from dose regimens 1 and 2. Participants in the Treatment Phase of this combination will be offered the option to enter the Long-term Extension Phase of the study. | Drug: Niraparib 200 mg<br>* Participants will receive niraparib 200 mg orally.<br>Drug: Cetrelimab 240 mg<br>* Participants will receive cetrelimab 240 mg IV every 2 weeks.<br>* Other names: JNJ-63723283;Drug: Cetrelimab 480 mg<br>* Participants will receive cetrelimab 480 mg IV every 4 weeks.<br>* Other names: JNJ-63723283;|
| Experimental: Combination 1:Dose Expansion: Niraparib + cetrelimab (Part 2)<br>Participants will be assigned to either Cohort 1A (Biomarker [BM] positive [+]) or Cohort 1B (BM negative [-]) and will receive established RP2D of cetrelimab and niraparib, in Part 2 until disease progression, unacceptable toxicity, death, or the sponsor terminates the study. A futility analysis will be performed for the Cohort 1B after 10 BM- participants are enrolled in Part 2. This cohort will be closed if the response is less than predetermined response rate as outlined in the protocol. Participants in the Treatment Phase of this combination will be offered the option to enter the Long-term Extension Phase of the study. | Drug: Niraparib 200 mg<br>* Participants will receive niraparib 200 mg orally.<br>Drug: Cetrelimab 480 mg<br>* Participants will receive cetrelimab 480 mg IV every 4 weeks.<br>* Other names: JNJ-63723283;|
| Experimental: Combination 2: Dose Expansion: Niraparib + AA-P (Part 2)<br>Participants will be assigned to one of 4 cohorts based on biomarker status - Cohort 2A (BRCA biallelic loss), 2B (other DRD biallelic loss), 2C (BRCA monoallelic loss), or 2D (other DRD monoallelic loss), and will receive niraparib 200 mg once daily in combination with abiraterone acetate 1000 mg (4*250 mg) plus 10 mg prednisone (5 mg twice daily) throughout treatment phase. Participants in the Treatment Phase of this combination will be offered the option to enter the Long-term Extension Phase of the study. | Drug: Niraparib 200 mg<br>* Participants will receive niraparib 200 mg orally.<br>Drug: Abiraterone acetate 1000 mg<br>* Participants will receive AA 1000 mg orally.<br>Drug: Prednisone 5 mg<br>* Participants will receive prednisone 5 mg orally.<br>|
| Experimental: Combination 3: Niraparib + AA-P<br>Participants will be assigned to one of three cohorts to receive AA-P with or without niraparib. Participants in the Treatment Phase of this combination will be offered the option to enter the Long-term Extension Phase of the study. | Drug: Niraparib 200 mg<br>* Participants will receive niraparib 200 mg orally.<br>Drug: Abiraterone acetate 1000 mg<br>* Participants will receive AA 1000 mg orally.<br>Drug: Prednisone 5 mg<br>* Participants will receive prednisone 5 mg orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combination 1: Part 1: Number of Participants With Specified Toxicity | Number of participants with specified toxicity during Cycle 1 was reported. Only toxicities that occurred during safety evaluation period(defined as first 28 days of treatment-Cycle 1 of Part 1) was used for analysis of specified toxicities and for dose reduction decisions. Toxicities were graded for severity as per NCI-CTCAE, version 4.03. Safety evaluation criteria were: Any Grade(G) >=3 non-hematological toxicity without anorexia, or constipation, fatigue improved to G<=2 in <7 days, vomiting and diarrhea resolved in <=3 days, laboratory abnormalities with hospitalization, tumor flare improved to G<=2 in <=7 days, elevation in AST/ALT for <=7 days and G3 hypertension controlled by medical therapy; any treatment-related(TR)G4 or G>=3 thrombocytopenia required platelet transfusion; Any TR G4 neutropenia >=7 days or G3 or 4 neutropenia with infection/fever >38.5 degrees Celsius; Any TR SAE or intolerable toxicity. | Cycle 1 (28 days) | 
| Combination 1: Part 2: Objective Response Rate (ORR) | ORR of soft tissue (visceral or nodal disease) was defined as percentage of participants with measurable disease who achieved a best response of either complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with no evidence of bone progression according to prostate cancer working group 3 (PCWG3) criteria. | Up to 37 months | 
| Combination 2: Composite Response Rate (RR) | Composite response rate was defined as the percentage of participants who had a composite response which is defined as one of the following PCWG3 criteria: Objective response (percentage of participants with measurable disease who achieved a best response of either CR or PR as assessed by RECIST 1.1 with no evidence of bone progression according to PCWG3 criteria) (confirmed per RECIST 1.1), or; circulating tumor cells (CTC) response: defined as CTC=0 per 7.5 milliliters (mL) of blood at 8 weeks for participants who had CTC greater than or equal to (>=) 1 at baseline or CTC less than (<) 5 per 7.5 mL with CTC >=5 at baseline, confirmed by a second consecutive value obtained 4 or more weeks later, or prostate-specific antigen (PSA) declined of >=50 percentage (%), measured twice 3 to 4 weeks apart. This outcome measure was analyzed for specified arms only as pre-planned in the protocol. | Up to 31 months | 
| Combination 1: Part 2: Number of Participants With Adverse Events (AEs) | AE was defined as an any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. | Up to 37 months | 
| Combination 2: Number of Participants With Adverse Events (AEs) | AE was defined as an any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. | Up to 31 months | 
| Combination 1: Part 2: Number of Participants With Adverse Events (AEs) of Grade >=3 Severity | AE was defined as an any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An assessment of severity grade was made using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) as Grade 1 (mild): awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with everyday activities; Grade 2 (moderate): sufficient discomfort is present to cause interference with normal activity; Grade 3 (severe): extreme distress, causing significant impairment of functioning or incapacitation, prevents normal everyday activities; Grade 4 (Life-threatening): urgent intervention indicated; and Grade 5 (death). | Up to 37 months | 
| Combination 2: Number of Participants With Adverse Events (AEs) of Grade >=3 Severity | AE was defined as an any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An assessment of severity grade was made using the NCI-CTCAE as Grade 1 (mild): awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with everyday activities; Grade 2 (moderate): sufficient discomfort is present to cause interference with normal activity; Grade 3 (severe): extreme distress, causing significant impairment of functioning or incapacitation, prevents normal everyday activities; Grade 4 (Life-threatening): urgent intervention indicated; and Grade 5 (death). | Up to 31 months | 
| Combination 3: Maximum Observed Plasma Concentration (Cmax) of Niraparib and Abiraterone Acetate After a Single Dose | Cmax is defined as maximum observed plasma concentration of niraparib and abiraterone acetate (AA) after a single dose. | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Maximum Observed Plasma Concentration (Cmax) of Niraparib Normalized by the Dose(Niraparib) (Cmax/Dose) of Niraparib Administered With AA After a Single Dose | Cmax/dose of niraparib was defined as maximum observed plasma concentration of niraparib Cmax normalized by the dose of niraparib administered with AA after a single dose. | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC [0-168hr]) of Niraparib Administered With AA After a Single Dose | AUC(0-168 hours) was defined as area under the plasma concentration-time curve from time zero to 168 hours of Niraparib administered with AA After a single dose. | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Area Under the Plasma Concentration-Time Curve for Niraparib From Time Zero to 168 Hours (AUC [0-168 Hours]/Dose) of Niraparib Administered With AA After a Single Dose | AUC0(168 hours)/dose was defined as area under the plasma concentration-time curve for niraparib from time 0 to 168 hours of niraparib administered with AA after a single dose. | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combination 1: Parts 1 and 2: Plasma Concentrations of Niraparib |  | Day 1 | 
| Combination 1: Parts 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Niraparib |  | Day 1 | 
| Combination 1: Parts 1 and 2: Time to Reach the Maximum Plasma Concentration (Tmax) of Niraparib |  | Day 1 | 
| Combination 1: Parts 1 and 2: Minimum Observed (Predose) Concentration Following Multiple Dosing (Ctrough) of Niraparib |  | Day 1 | 
| Combination 1: Parts 1 and 2: Number of Participants With Anti-drug Antibodies of Niraparib |  | From baseline up to end of study (6 years 10 months) | 
| Combination 1: Part 2 and Combination 2: Circulating Tumor Cells (CTC) Response |  | From baseline up to end of study (6 years 10 months) | 
| Combination 1: Part 2: Composite Response Rate |  | From baseline up to end of study (6 years 10 months) | 
| Combination 2: Objective Response Rate (ORR) |  | From baseline up to end of study (6 years 10 months) | 
| Combination 1: Part 2 and Combination 2: Duration of Objective Response |  | From baseline up to end of study (6 years 10 months) | 
| Combination 1: Part 2 and Combination 2: Overall Survival |  | From baseline up to end of study (6 years 10 months) | 
| Combination 3: Cmax of Niraparib and Abiraterone Acetate After a Single Dose For Low-strength FDC |  | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Maximum Observed Plasma Concentration (Cmax) of Niraparib Normalized by the Dose(Niraparib) (Cmax/Dose) of Niraparib Administered With AA After a Single Dose for Low-strength FDC |  | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC [0-168hr]) of Niraparib Administered With AA After a Single Dose For Low-strength FDC |  | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Area Under the Plasma Concentration-Time Curve for Niraparib From Time Zero to 168 Hours (AUC [0-168 Hours]/Dose) of Niraparib Administered With AA After a Single Dose For Low-strength FDC |  | Pre-dose, 30 min, 1 hour (hr), 1.5 hr, 2hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 24 hr, 48 hr, 72 hr, and 168 hr post dose on Day 1 | 
| Combination 3: Number of Participants With Adverse Events |  | From baseline up to end of study (6 years 10 months) | 
| Combination 3: Number of Participants With Clinical Laboratory Parameters |  | From baseline up to end of study (6 years 10 months) |