A Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer
- Conditions
- Prostatic Neoplasms, Castration-Resistant
- Interventions
- Registration Number
- NCT03431350
- Lead Sponsor
- Janssen Research & Development, LLC
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Male
- Target Recruitment
- 136
Not provided
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Combination 1:Dose Selection: Niraparib + cetrelimab (Part 1) Cetrelimab 240 mg 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. Combination 1:Dose Expansion: Niraparib + cetrelimab (Part 2) Cetrelimab 480 mg 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. Combination 1:Dose Selection: Niraparib + cetrelimab (Part 1) Cetrelimab 480 mg 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. Combination 1:Dose Expansion: Niraparib + cetrelimab (Part 2) Niraparib 200 mg 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. Combination 2: Dose Expansion: Niraparib + AA-P (Part 2) Abiraterone acetate 1000 mg 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. Combination 3: Niraparib + AA-P Niraparib 200 mg 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. Combination 2: Dose Expansion: Niraparib + AA-P (Part 2) Niraparib 200 mg 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. Combination 3: Niraparib + AA-P Prednisone 5 mg 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. Combination 1:Dose Selection: Niraparib + cetrelimab (Part 1) Niraparib 200 mg 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. Combination 2: Dose Expansion: Niraparib + AA-P (Part 2) Prednisone 5 mg 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. Combination 3: Niraparib + AA-P Abiraterone acetate 1000 mg 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.
- Primary Outcome Measures
Name Time Method 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.
- Secondary Outcome Measures
Name Time Method 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) 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
Trial Locations
- Locations (49)
Princess Margaret Cancer Centre University Health Network
🇨🇦Toronto, Ontario, Canada
Urological Associates of Southern Arizona, P.C.
🇺🇸Tucson, Arizona, United States
The Urology Center of Colorado
🇺🇸Denver, Colorado, United States
Mayo Clinic - Division Of Hematology/oncology
🇺🇸Jacksonville, Florida, United States
First Urology, PSC
🇺🇸Jeffersonville, Indiana, United States
Chesapeake Urology Research Associates
🇺🇸Towson, Maryland, United States
Michigan Institute of Urology
🇺🇸Troy, Michigan, United States
New York Oncology Hematology
🇺🇸Albany, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center (UPMC)
🇺🇸Pittsburgh, Pennsylvania, United States
Carolina Urologic Research Center
🇺🇸Myrtle Beach, South Carolina, United States
MUSC-Hollings Cancer Center
🇺🇸Charleston, South Carolina, United States
Urology Associates
🇺🇸Nashville, Tennessee, United States
Azienda Ospedaliera Universitaria Careggi di Firenze
🇮🇹Firenze, Italy
Houston Metro Urology
🇺🇸Houston, Texas, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Utah Cancer Specialists
🇺🇸Salt Lake City, Utah, United States
Urology of Virginia, PLCC
🇺🇸Virginia Beach, Virginia, United States
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States
OLV Ziekenhuis Aalst
🇧🇪Aalst, Belgium
ZNA Middelheim
🇧🇪Antwerpen, Belgium
ULB Hôpital Erasme
🇧🇪Brussels, Belgium
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Az Groeninge
🇧🇪Kortrijk, Belgium
Centre Hospitalier Universitaire de Liege Domaine Universitaire du Sart Tilman
🇧🇪Liege, Belgium
Southern Alberta Institute of Urology / Prostate Cancer Centre
🇨🇦Calgary, Alberta, Canada
British Columbia Cancer Agency
🇨🇦Vancouver, British Columbia, Canada
Centre de Recherche du CHUM
🇨🇦Montreal, Quebec, Canada
Asaf Harofe Medical Center
🇮🇱Beer Yaakov, Israel
Soroka Hospital
🇮🇱Beer-Sheva, Israel
Rambam Medical Center
🇮🇱Haifa, Israel
Azienda Ospedaliera ''Vito Fazzi''
🇮🇹Lecce, Italy
Rabin Medical Center
🇮🇱Petach Tikva, Israel
Sheba Medical Center Tel Hashomer
🇮🇱Ramat Gan, Israel
UOC Oncologia Ospedale Provinciale di Macerata
🇮🇹Macerata, Italy
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Italy
IRCCS-Fondazione Pascale
🇮🇹Napoli, Italy
Hosp. de La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hospital Vall D'Hebron
🇪🇸Barcelona, Spain
Hosp. Univ. de La Princesa
🇪🇸Madrid, Spain
Hosp Univ Fund Jimenez Diaz
🇪🇸Madrid, Spain
Hosp Univ Hm Sanchinarro
🇪🇸Madrid, Spain
Hosp Virgen de La Victoria
🇪🇸Malaga, Spain
Royal United Hospital
🇬🇧Bath, United Kingdom
University College London Hospitals
🇬🇧London, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
The Royal Marsden NHS Trust Sutton
🇬🇧Sutton, United Kingdom
Royal Cornwall Hospitals NHS Trust - Royal Cornwall Hospital
🇬🇧Truro, United Kingdom