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

Janssen (J&J Innovative Medicine)

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Prostatic Neoplasms, Castration-Resistant

Treatments: Drug: Niraparib 200 mg; Drug: Cetrelimab 480 mg; Drug: Prednisone 5 mg; Drug: Cetrelimab 240 mg; Drug: Abiraterone acetate 1000 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT03431350

CR108406

2017-003552-23 (EudraCT Number)

64091742PCR2002 (Other Identifier)

Details and patient eligibility

About

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).

Full 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.

Enrollment: 136 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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136 participants in 4 patient groups

Combination 1:Dose Selection: Niraparib + cetrelimab (Part 1)

Experimental group

Description:

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.

Treatment:

Drug: Cetrelimab 240 mg

Drug: Cetrelimab 480 mg

Drug: Niraparib 200 mg

Combination 1:Dose Expansion: Niraparib + cetrelimab (Part 2)

Experimental group

Description:

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.

Treatment:

Drug: Cetrelimab 480 mg

Drug: Niraparib 200 mg

Combination 2: Dose Expansion: Niraparib + AA-P (Part 2)

Experimental group

Description:

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.

Treatment:

Drug: Abiraterone acetate 1000 mg

Drug: Prednisone 5 mg

Drug: Niraparib 200 mg

Combination 3: Niraparib + AA-P

Experimental group

Description:

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.

Treatment:

Drug: Abiraterone acetate 1000 mg

Drug: Prednisone 5 mg

Drug: Niraparib 200 mg