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

• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

The purpose of this study is to establish the recommended phase 2 dose (RP2D) of niraparib combination therapies of Part 1 and to evaluate the antitumor activity and safety of niraparib combination therapies of Part 2.

Condition or disease	Intervention/treatment	Phase
Prostatic Neoplasms, Castration-Resistant	Drug: Niraparib 200 mg; Drug: JNJ-63723283 240 mg; Drug: JNJ-63723283 480 mg; Drug: Abiraterone Acetate; Drug: Prednisone	Phase 1; Phase 2

Detailed Description:

This multicenter study will evaluate safety and efficacy of niraparib in combination with other anti-cancer agents. Two combinations are being studied: the first combination study will combine niraparib with the anti-programmed cell death protein (PD)-1 monoclonal antibody, JNJ-63723283 in participants with metastatic castration-resistant prostate cancer (mCRPC). The second combination will combine niraparib with abiraterone acetate plus prednisone (AA-P) in mCRPC participants with DNA-repair gene defects (DRD). Combination 1 has 2 parts: in Part 1 (dose selection), participants will be enrolled to explore 2 doses of niraparib and JNJ-63723283; and Part 2 (dose expansion) will evaluate the combination therapy in an expanded number of participants. In Part 2, participants will be enrolled into 2 cohorts based on biomarker status. Combination 2 has only 1 part (Part 2) and no Part 1. In Part 2, participants will be enrolled into 4 cohorts (breast cancer gene [BRCA] biallelic loss [2A], other DRD biallelic loss [2B], BRCA monoallelic loss [2C], and other DRD monoallelic loss [2D]). Each combination in the study will have 4 phases: A Prescreening Phase, a Screening Phase, a Treatment Phase, and a Follow-up Phase. Study evaluations will include efficacy, pharmacokinetic (PK), PK/pharmacodynamics, biomarkers, safety and tolerability.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	150 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1b-2 Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer
Actual Study Start Date :	March 2, 2018
Estimated Primary Completion Date :	July 31, 2019
Estimated Study Completion Date :	August 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combination 1:Dose Selection: Niraparib + JNJ-63723283(Part 1); Dose regimen 1: The participants will receive niraparib 200 milligram (mg) orally once daily in combination with JNJ-63723283 240 mg intravenously (IV) once every 2 weeks. Dose regimen 2: The participants will receive niraparib 200 mg orally once daily in combination with JNJ-63723283 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.	Drug: Niraparib 200 mg; Participant will receive niraparib 200 mg orally once daily.; Drug: JNJ-63723283 240 mg; Participants will receive JNJ-63723283 240 mg IV every 2 weeks.; Drug: JNJ-63723283 480 mg; Participants will receive JNJ-63723283 480 mg IV every 4 weeks.
Experimental: Combination 1:Dose Expansion: Niraparib + JNJ-63723283(Part 2); Participants will be assigned to either Cohort 1A (Biomarker [BM] positive [+]) or Cohort 1B (BM negative [-]) and will receive 480 mg of JNJ-63723283 IV once every 4 weeks and niraparib 200 mg once daily as RP2D, in Part 2. 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 rate is 13 percent (%) or less for the participants.	Drug: Niraparib 200 mg; Participant will receive niraparib 200 mg orally once daily.; Drug: JNJ-63723283 480 mg; Participants will receive JNJ-63723283 480 mg IV every 4 weeks.
Experimental: Combination 2: Dose Expansion: Niraparib + AA-P (Part 2); 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 as RP2D in combination with abiraterone acetate 1000 mg (4*250 mg) plus 10 mg prednisone (5 mg twice daily) throughout treatment phase.	Drug: Niraparib 200 mg; Participant will receive niraparib 200 mg orally once daily.; Drug: Abiraterone Acetate; Participants will receive 1000 mg (4*250 mg tablets) once daily orally.; Other Name: Zytiga; Drug: Prednisone; Participants will receive 10 mg (2*5 mg tablets twice daily).

Outcome Measures

Primary Outcome Measures :

1. Part 1: Combination 1: Incidence of Specified Toxicities [ Time Frame: Up to 28 days ]
   Incidence defined as number of participants with specified toxicities will be reported. The dose will be considered intolerable if a participant developed Grade greater than or equal to (>=) 3 non-hematological toxicity (with exceptions including anorexia, fever, constipation, fatigue that improves to Grade less than or equal to (<=) 2 in <=7 days, vomiting and diarrhea that resolves in <=3 days with best supportive care), treatment-related Grade 4 thrombocytopenia or Grade >= 3 thrombocytopenia, treatment-related Grade 4 neutropenia >= 7 days, or Grade 3 or 4 neutropenia, treatment-related serious adverse events.
2. Part 2: Combination 1: Objective Response Rate (ORR) [ Time Frame: Approximately 24 months ]
   Objective response rate is defined as the percentage of participants who achieve complete response (CR) or partial response (PR), as assessed by response evaluation criteria in solid tumors (RECIST) 1.1 criteria with no evidence of bone progression according to prostate cancer working group 3 (PCWG3) criteria. CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the baseline sum diameters.
3. Part 2: Combination 2: Composite Response Rate (RR) [ Time Frame: Approximately 24 months ]
   Composite response rate (RR) is defined as percentage of participants who have 1 of the following by PCWG3 criteria: Objective response (confirmed per RECIST 1.1), or circulating tumor cells (CTC) response: defined as CTC=0 per 7.5 milliliter (mL) of blood at 8 weeks for participants who have 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) decline of >=50%, measured twice 3 to 4 weeks apart.
4. Part 2: Combinations 1 and 2: Incidence of Adverse Events (AEs) [ Time Frame: Approximately 24 months ]
   Incidence defined as number of participants with AEs will be reported. An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
5. Part 2: Combinations 1 and 2: Severity of Adverse Events [ Time Frame: Approximately 24 months ]
   An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Severity of AEs will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Any AE not listed in the NCI-CTCAE will be graded according to the investigator's clinical judgment using the standard grades as follows: 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; Grade 5, Death: Death.

Secondary Outcome Measures :

1. Part 1 and Part 2 (Combination 1): Plasma Concentrations of Niraparib and JNJ-63723283 [ Time Frame: Cycle 1 up to 12 (each cycle is of 28 days) ]
   Plasma concentrations of niraparib and JNJ-63723283 will be assessed.
2. Part 1 and Part 2 (Combination 1): Number of participants with Anti-Drug Antibodies [ Time Frame: Approximately 24 months ]
   Number of participants with Anti-Drug Antibodies will be reported.
3. Part 2: Combinations 1 and 2: Number of Participants with Circulating Tumor Cell (CTC) Response [ Time Frame: From screening up to end of treatment (30 days of last dose) (approximately up to 24 months) ]
   CTC response is defined as CTC=0 per 7.5 milliliter (mL) of blood at 8 weeks for participants who have CTC >= 1 at baseline or CTC<5 per 7.5 mL with CTC >=5 at baseline, confirmed by a second consecutive value obtained 4 or more weeks later.
4. Part 2: Combination 1: Composite Response Rate (RR) [ Time Frame: Screening, Cycle 1 (each cycle of 28 days) Day 1 (every 8 weeks for the first 6 months and then every 12 weeks thereafter) until follow-up phase (for 3 months) (approximately up to 24 months) ]
   Composite RR is defined as percentage of participants who have 1 of the following by PCWG3: Objective response (confirmed per RECIST 1.1), or CTC response: defined as CTC=0 per 7.5 mL of blood at 8 weeks for participants who have CTC >=1 at baseline or CTC <5 baseline per 7.5 mL with CTC>5 at baseline, confirmed by a second consecutive value obtained 4 or more weeks later, or PSA decline of >= 50%, measured twice 3 to 4 weeks apart.
5. Part 2: Combination 2: Objective Response Rate (ORR) [ Time Frame: Approximately 24 months ]
   ORR of soft tissue (visceral or nodal disease) as defined by RECIST 1.1 with no evidence of bone progression according to PCWG3 criteria. As per RECIST 1.1 criteria, ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR), as assessed by response evaluation criteria in solid tumors (RECIST) 1.1 criteria with no evidence of bone progression according to prostate cancer working group 3 (PCWG3) criteria. CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the baseline sum diameters.
6. Part 2: Combinations 1 and 2: Duration of Objective Response [ Time Frame: Screening, Cycle 1 (each cycle of 28 days) Day 1 (every 8 weeks for the first 6 months and then every 12 weeks thereafter) until follow-up phase (approximately up to 24 months) ]
   Duration of objective response is defined as time from complete response (CR) or partial response (PR) to radiographic progression of disease (PD), unequivocal clinical progression, or death, whichever occurs first. CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 % decrease in sum of the diameters of the target lesions taking as reference the baseline sum diameters. PD is defined as a 20% increase in the sum of diameters of all target lesions and a minimum absolute increase of 5 mm in the sum.
7. Part 2: Combinations 1 and 2: Overall Survival (OS) [ Time Frame: Up to follow-up (approximately up to 24 months) ]
   OS is defined as time from start of treatment to death from any cause.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Participants willing to undergo all protocol-specified biopsies
• Diagnosis of prostate adenocarcinoma as confirmed by the investigator

Combination 1:

• Must have determination of biomarker (BM) status for DNA-repair gene defects (DRD) (either BM positive [+] or BM negative [-]) by the sponsor's blood or tissue assay
• Participants must have measurable disease as defined by response evaluation criteria in solid tumors (RECIST) 1.1 (soft tissue lesion of greater than or equal to (>=) 10 millimeter (mm) in the long axis or extrapelvic lymph node of >=15 mm in the short axis)
• Must have previously received at least 1, but no more than 2, lines of novel androgen receptor (AR)-targeted therapy (that is, abiraterone acetate with prednisone, enzalutamide) for metastatic castration-resistant prostate cancer (mCRPC). Participants must have had at least 4 weeks of AR-targeted therapy

Combination 2:

• Must be biomarker positive for DRD by either the sponsor's blood or tissue assay
• Must have progressed on 1 prior line of novel AR-targeted therapy (that is, abiraterone acetate with prednisone, enzalutamide) for mCRPC. Prior treatment with taxane-based therapy and AR-targeted therapy outside of the mCRPC setting is allowed

Exclusion Criteria:

• Prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor
• History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Active malignancy (exceptions: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently remission) less than or equal to (<=) 2 years prior to enrollment
• Active infection requiring systemic therapy
• Allergies, hypersensitivity, or intolerance to niraparib or the corresponding excipients

Contacts and Locations

Contacts

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

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Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

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

More Information

Additional Information:

To learn how to participate in this trial please click here. 

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Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT03431350 History of Changes
Other Study ID Numbers:	CR108406; 64091742PCR2002 ( Other Identifier: Janssen Research & Development, LLC ); 2017-003552-23 ( EudraCT Number )
First Posted:	February 13, 2018
Last Update Posted:	February 28, 2019
Last Verified:	February 2019

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

Additional relevant MeSH terms:

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Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Prednisone; Abiraterone Acetate; Niraparib; Anti-Inflammatory Agents	Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors