A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer (MAGNITUDE)

• ClinicalTrials.gov Identifier: NCT03748641
• Recruitment Status: Recruiting
• First Posted: November 21, 2018
• Last Update Posted: October 9, 2020
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: November 19, 2018
• First Posted Date: November 21, 2018
• Last Update Posted Date: October 9, 2020
• Actual Study Start Date: January 25, 2019
• Estimated Primary Completion Date: July 21, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 17, 2020)

Cohort 1 and 3: Radiographic Progression Free Survival (rPFS) [ Time Frame: Up to 28 months ]

As per blinded independent central review, rPFS is defined as time from randomization date to date of radiographic progression or death, whichever occurs first. Radiographic progression will be evaluated by Prostate Cancer Working Group 3 (PCWG3) as follows: progression of soft tissue lesions measured by computed tomography/magnetic resonance imaging as per response evaluation criteria in solid tumors (RECIST) 1.1; progression by bone lesions observed by bone scan and based on PCWG3. As per criteria, any bone progression must be confirmed by a subsequent scan greater than or equal to (>=) 6 weeks later. Week 8 scan will be baseline to which all subsequent scans will be compared to determine progression. Participants whose confirmatory scan shows >=2 new lesions will be considered to have bone scan progression and participants whose confirmatory scans did not show >= 2 new lesions will not be considered to have bone scan progression when compared to Week 8 scan.

Original Primary Outcome Measures (submitted: November 19, 2018)

Radiographic Progression Free Survival (rPFS) [ Time Frame: Approximately 40 months ]

rPFS is defined as time from date of randomization to date of radiographic progression or death, whichever occurs first. Radiographic progression will be evaluated by Prostate Cancer Working Group 3 (PCWG3) as follows: progression of soft tissue lesions measured by computed tomography/magnetic resonance imaging as per response evaluation criteria in solid tumors (RECIST) 1.1; progression by bone lesions observed by bone scan and based on PCWG3. As per criteria, any bone progression must be confirmed by a subsequent scan greater than or equal to (>=) 6 weeks later. Week 8 scan will be baseline to which all subsequent scans will be compared to determine progression. Bone progression is defined as one of the following: participants whose confirmatory scan shows >=2 new lesions will be considered to have bone scan progression and who did not show >= 2 new lesions will not be considered to have bone scan progression when compared to Week 8 scan.

Current Secondary Outcome Measures (submitted: August 17, 2020)

• Cohort 1: Overall survival (OS) [ Time Frame: Up to 66 months ]
  OS is defined as the time from date of randomization to date of death from any cause.
• Cohort 1: Time to Symptomatic Progression [ Time Frame: Up to 28 months ]
  Time to symptomatic progression is defined as the need to initiate/record any of the following; a. the use of external beam radiation therapy (EBRT) for skeletal symptoms; b. the need for tumor-related orthopedic surgical intervention; c. other cancer-related procedures (for example: nephrostomy insertion, bladder catheter insertion, EBRT, or surgery for tumor symptoms other than skeletal); d. cancer-related morbid events (for example: fracture [symptomatic and/or pathologic, cord compression, urinary obstructive events); e. initiation of new systemic anti-cancer therapy because of cancer pain.
• Cohort 1: Time to Initiation of Cytotoxic Chemotherapy [ Time Frame: Up to 28 months ]
  Time to initiation of cytotoxic chemotherapy is defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
• Cohort 1: Observed Plasma Concentrations of Niraparib [ Time Frame: Cycle 2 to 7; Each Cycle is of 28 days (Up to 7 months) ]
  Observed plasma concentrations of niraparib with descriptive statistics will be reported.
• Cohort 1: Observed Trough Plasma Concentrations of Abiraterone [ Time Frame: Cycles 2 and 3; Each Cycle is of 28 days (Up to 3 months) ]
  Observed trough plasma concentrations of abiraterone with descriptive statistics will be reported.
• Cohort 1: Number of Participants with Treatment-Emergent Adverse events (TEAEs) [ Time Frame: Up to 66 months ]
  An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. AE does not necessarily have a causal relationship with intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. TEAEs are those events that occur or worsen on or after first dose of study drug through 30 days after last dose of study drug.
• Cohort 1: Number of Participants with Treatment-Emergent Adverse events by Severity [ Time Frame: Up to 66 months ]
  Adverse event is any untoward medical occurrence in clinical study participant administered a medicinal (investigational or non-investigational) product. AE does not necessarily have causal relationship with intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. TEAEs are those events that occur or worsen on or after first dose of study drug through 30 days after last dose of study drug. Severity criteria includes grades: 1) Mild: easily tolerated, causing minimal discomfort and no interference with everyday activities; 2) Moderate: sufficient discomfort to cause interference with normal activity; 3) Severe: extreme distress, significant impairment of functioning/incapacitation. Prevents everyday activities; 4) Life-threatening: urgent intervention indicated and 5) Death.
• Cohort 1: Number of Participants with Laboratory Abnormalities as Measure of Safety [ Time Frame: Up to 66 months ]
  Number of participants with laboratory abnormalities (hematology, serum chemistry and liver function test) will be determined.

Original Secondary Outcome Measures (submitted: November 19, 2018)

• Overall survival (OS) [ Time Frame: Approximately up to 73 months ]
  OS is defined as the time from date of randomization to date of death from any cause.
• Time to Chronic Opioid Use [ Time Frame: Approximately up to 73 months ]
  Time to chronic opioid use (oral opioid use for >=3 weeks; parenteral opioid use for >=7 days) is defined as the time from date of randomization to the first date of chronic opioid use.
• Time to Pain Progression [ Time Frame: Approximately up to 73 months ]
  Time to pain progression is defined as the time from date of randomization to the date of the first observation of pain progression. Pain progression is defined as an increase by at least 2 points from baseline in the brief pain inventory-short form (BPI-SF) worst pain intensity (item 3) observed at 2 consecutive evaluations >= 3 weeks apart, or Initiation of short or long-acting opioids for pain.
• Time to Initiation of Cytotoxic Chemotherapy [ Time Frame: Approximately up to 73 months ]
  Time to initiation of cytotoxic chemotherapy is defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
• Observed Plasma Concentrations of Niraparib [ Time Frame: Cycle 2: Day 1 (Predose, between 1 to 3 and 3 to 6 hours postdose); Cycle 3: Day 1 (Predose); Cycles 4 to 7: Day 1 (Predose or at least 3 hours postdose); each Cycle of 28 days ]
  Observed plasma concentrations of niraparib with descriptive statistics will be reported.
• Observed Trough Plasma Concentrations of Abiraterone [ Time Frame: Cycles 2 and 3 (Each Cycle of 28 days): Day 1 (Predose) ]
  Observed trough plasma concentrations of abiraterone with descriptive statistics will be reported.
• Number of Participants with Treatment-Emergent Adverse events (TEAEs) [ Time Frame: Approximately up to 73 months ]
  An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. AE does not necessarily have a causal relationship with intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. TEAEs are those events that occur or worsen on or after first dose of study drug through 30 days after last dose of study drug.
• Number of Participants with Treatment-Emergent Adverse events by Severity [ Time Frame: Approximately up to 73 months ]
  An adverse event is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. AE does not necessarily have a causal relationship with intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. TEAEs are those events that occur or worsen on or after first dose of study drug through 30 days after last dose of study drug. Severity criteria includes grades:1) Mild: easily tolerated, causing minimal discomfort and no interference with everyday activities 2) Moderate: sufficient discomfort to cause interference with normal activity 3) Severe: extreme distress, significant impairment of functioning/incapacitation. Prevents everyday activities 4) Life-threatening: urgent intervention indicated 5) Death
• Number of Participants with Laboratory Abnormalities as Measure of Safety [ Time Frame: Approximately up to 73 months ]
  Number of participants with laboratory abnormalities (hematology, serum chemistry and liver function test) will be determined.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer
• Official Title: A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Metastatic Prostate Cancer
• Brief Summary: The purpose of this study is to evaluate the effectiveness of niraparib in combination with abiraterone acetate plus prednisone (AAP) compared to AAP plus placebo.
• Detailed Description: This study will assess efficacy and safety of niraparib in combination with AAP for the treatment of participants with metastatic castration resistant prostate cancer. Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. AA is a pro-drug of abiraterone and selectively inhibits the enzyme 17 alpha-hydroxylase/C17,20-lyase (CYP17), which is found in the testes and adrenals, as well as in prostate tissues and tumors. In participants with metastatic prostate cancer, DNA-repair anomalies are identified in approximately 15 percent (%) to 20% of tumors. The study will consist of 4 phases: a prescreening phase for biomarker evaluation only, a screening phase, a treatment phase, and a follow up phase. During the prescreening phase participants will be evaluated for homologous recombination repair (HRR) gene alteration status and then will be assigned to one of the 2 cohorts based on their biomarker status. Treatment will be administered daily and is planned to be continuous until disease progression, unacceptable toxicity, death, or the sponsor terminates the study. Efficacy, pharmacokinetics, biomarkers, participants reported outcomes and safety will be assessed. The total duration of study will be approximately 66 months.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Castration-Resistant Prostatic Cancer

Intervention

• Drug: Niraparib
  Participants will receive niraparib 200 mg capsules once daily.
  Other Name: JNJ-64091742
• Drug: Abiraterone Acetate
  Participants will receive AA 1000 mg tablets once daily.
• Drug: Prednisone
  Participants will receive prednisone 10 mg tablets daily.
• Drug: Placebo
  Participants will receive matching placebo once daily.
• Drug: New Formulation of Niraparib and Abiraterone Acetate (AA)
  Participants will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets once daily.

Study Arms

• Experimental: Cohort 1: Participants with mCRPC and HRR gene alteration
  Participants with L1 metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alteration will receive combination of niraparib 200 milligrams (mg) or matching placebo and abiraterone acetate (AA) 1000 mg plus prednisone 10 mg.
  Interventions:

  • Drug: Niraparib
  • Drug: Abiraterone Acetate
  • Drug: Prednisone
  • Drug: Placebo
• Experimental: Cohort 2: Participants with mCRPC and No HRR Gene alteration
  Participants with L1 mCRPC and no HRR Gene alteration will receive combination of niraparib 200 mg or matching placebo and AA 1000 mg plus prednisone 10 mg.
  Interventions:

  • Drug: Niraparib
  • Drug: Abiraterone Acetate
  • Drug: Prednisone
  • Drug: Placebo
• Experimental: Cohort 3 (Open-label): Participants with mCRPC
  Participants with mCRPC will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets plus prednisone 10 mg.
  Interventions:

  • Drug: Prednisone
  • Drug: New Formulation of Niraparib and Abiraterone Acetate (AA)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 19, 2018): 1000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 25, 2025
• Estimated Primary Completion Date: July 21, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• HRR gene alteration (as identified by the sponsor's required assays) as follows:

  1. Cohort 1: positive for HRR gene alteration
  2. Cohort 2: not positive for DRD (that is, HRR gene alteration)
• Metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI)
• Metastatic prostate cancer in the setting of castrate levels of testosterone less than or equal to (<=) 50 nanogram per deciliter (ng/dL) on a gonadotropin releasing hormone analog (GnRHa) or bilateral orchiectomy
• Able to continue GnRHa during the study if not surgically castrate
• Score of <= 3 on the brief pain inventory-short form (BPI-SF) question number 3 (worst pain in last 24 hours)

Exclusion Criteria:

• Prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor
• Systemic therapy (that is, novel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or more than 4 months of abiraterone acetate plus prednisone [AAP] prior to randomization) in the metastatic castration-resistant prostate cancer (mCRPC) setting; or AAP outside of the mCRPC setting
• Symptomatic brain metastases
• History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Other prior malignancy (exceptions: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) <= 2 years prior to randomization, or malignancy that currently requires active systemic therapy

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Contact; 844-434-4210; JNJ.CT@sylogent.com

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Russian Federation, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03748641
• Other Study ID Numbers: CR108534; 2017-003364-12 ( EudraCT Number ); 64091742PCR3001 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Janssen Research & Development, LLC
• Study Sponsor: Janssen Research & Development, LLC
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: October 2020