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

Condition(s) studied

Investigational drug(s) / intervention(s)

Niraparib 200 mg: Participants will receive niraparib 200 mg orally.

Cetrelimab 240 mg: Participants will receive cetrelimab 240 mg IV every 2 weeks.

Cetrelimab 480 mg: Participants will receive cetrelimab 480 mg IV every 4 weeks.

Abiraterone acetate 1000 mg: Participants will receive AA 1000 mg orally.

Prednisone 5 mg: Participants will receive prednisone 5 mg orally.

Study 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).

Eligibility

Primary outcome measure(s)

• Combination 1: Part 1: Number of Participants With Specified Toxicity — Cycle 1 (28 days)
  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.
• Combination 1: Part 2: Objective Response Rate (ORR) — Up to 37 months
  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.
• Combination 2: Composite Response Rate (RR) — Up to 31 months
  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.
• Combination 1: Part 2: Number of Participants With Adverse Events (AEs) — Up to 37 months
  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.
• Combination 2: Number of Participants With Adverse Events (AEs) — Up to 31 months
  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.
• Combination 1: Part 2: Number of Participants With Adverse Events (AEs) of Grade >=3 Severity — Up to 37 months
  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).
• Combination 2: Number of Participants With Adverse Events (AEs) of Grade >=3 Severity — Up to 31 months
  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).
• Combination 3: Maximum Observed Plasma Concentration (Cmax) of Niraparib and Abiraterone Acetate 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
  Cmax is defined as maximum observed plasma concentration of niraparib and abiraterone acetate (AA) after a single dose.
• 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 — 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
  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.
• 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 — 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
  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.
• 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 — 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
  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.

Trial sites (50)

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