A Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer (QUEST)
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| ClinicalTrials.gov Identifier: NCT03431350 |
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Recruitment Status :
Active, not recruiting
First Posted : February 13, 2018
Last Update Posted : January 19, 2023
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Sponsor:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Janssen Research & Development, LLC
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Prostatic Neoplasms, Castration-Resistant | Drug: Niraparib 200 mg Drug: Cetrelimab 240 mg Drug: Cetrelimab 480 mg Drug: Abiraterone acetate 1000 mg Drug: Prednisone 5 mg | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 136 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 |
| Actual Primary Completion Date : | August 31, 2021 |
| Estimated Study Completion Date : | July 31, 2023 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Prostate cancer
MedlinePlus related topics:
Prostate Cancer
| Arm | Intervention/treatment |
|---|---|
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Experimental: Combination 1:Dose Selection: Niraparib + cetrelimab (Part 1)
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.
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Drug: Niraparib 200 mg
Participants will receive niraparib 200 mg orally. Drug: Cetrelimab 240 mg Participants will receive cetrelimab 240 mg IV every 2 weeks.
Other Name: JNJ-63723283 Drug: Cetrelimab 480 mg Participants will receive cetrelimab 480 mg IV every 4 weeks.
Other Name: JNJ-63723283 |
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Experimental: Combination 1:Dose Expansion: Niraparib + cetrelimab (Part 2)
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.
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Drug: Niraparib 200 mg
Participants will receive niraparib 200 mg orally. Drug: Cetrelimab 480 mg Participants will receive cetrelimab 480 mg IV every 4 weeks.
Other Name: JNJ-63723283 |
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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 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.
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Drug: Niraparib 200 mg
Participants will receive niraparib 200 mg orally. Drug: Abiraterone acetate 1000 mg Participants will receive AA 1000 mg orally. Drug: Prednisone 5 mg Participants will receive prednisone 5 mg orally. |
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Experimental: Combination 3: Niraparib + AA-P
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.
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Drug: Niraparib 200 mg
Participants will receive niraparib 200 mg orally. Drug: Abiraterone acetate 1000 mg Participants will receive AA 1000 mg orally. Drug: Prednisone 5 mg Participants will receive prednisone 5 mg orally. |
Primary Outcome Measures :
- Part 1: Combination 1: Incidence of Specified Toxicities [ Time Frame: Up to Day 28 ]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.
- Part 2: Combination 1: Objective Response Rate (ORR) [ Time Frame: Up to 42 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.
- Part 2: Combinations 1: Incidence of Adverse Events (AEs) [ Time Frame: Up to 42 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.
- Part 2: Combinations 1: Severity of Adverse Events [ Time Frame: Up to 42 months ]Any AE not listed in the NCI-CTCAE will be graded according to the investigator's clinical judgment using the standard grades.
- Part 2: Combination 2: Composite Response Rate (RR) [ Time Frame: Up to 42 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.
- Combination 3: Maximum Observed Analyte Plasma Concentration (Cmax) of Niraparib and AA After a Single Dose [ Time Frame: Up to 168 hours postdose ]Cmax is defined as the maximum observed plasma concentration.
- Combination 3: Maximum Observed Analyte Plasma Concentration for Niraparib Normalized by the Dose (Cmax/dose) of Niraparib and AA After a Single Dose [ Time Frame: Up to 168 hours postdose ]Cmax/dose is defined as maximum observed analyte plasma concentration for niraparib normalized by the dose.
- Combination 3: Area Under the Plasma Concentration-Time Curve from Time Zero to 168 Hours (AUC [0-168]) of Niraparib and AA After a Single Dose [ Time Frame: Up to 168 hours postdose ]AUC (0-168) is defined as area under plasma concentration-time curve from time 0 to time 168 hours post dosing.
- Combination 3: Area Under the Plasma Concentration-Time Curve for Niraparib from Time Zero to 168 Hours (AUC [0-168]/dose) of Niraparib and AA After a Single Dose [ Time Frame: Up to 168 hours postdose ]AUC (0-168)/dose is defined as area under plasma concentration-time curve for niraparib from time 0 to time 168 hours post dosing.
Secondary Outcome Measures :
- Part 2: Combination 1: Number of Participants with Circulating Tumor Cell (CTC) Response [ Time Frame: Up to 42 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.
- Part 2: Combination 1: Composite Response Rate (RR) [ Time Frame: Up to 42 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.
- Part 2: Combination 1: Duration of Objective Response [ Time Frame: Up to 42 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.
- Part 2: Combination 1: Overall Survival (OS) [ Time Frame: Up to 46 months ]OS is defined as time from start of treatment to death from any cause.
- Part 2: Combination 2: Objective Response Rate (ORR) [ Time Frame: Up to 42 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.
- Combination 3: Number of Participants with Adverse Events [ Time Frame: Up to 46 months ]Number of participants with adverse events will be reported.
- Combination 3: Number of Participants with Abnormal Clinical Laboratory Findings [ Time Frame: Up to 46 months ]Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) will be reported.
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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 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03431350
Locations
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Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
| Study Director: | Janssen Research & Development, LLC Clinical Trial | Janssen Research & Development, LLC |
| Responsible Party: | Janssen Research & Development, LLC |
| ClinicalTrials.gov Identifier: | NCT03431350 |
| Other Study ID Numbers: |
CR108406 64091742PCR2002 ( Other Identifier: Janssen Research & Development, LLC ) 2017-003552-23 ( EudraCT Number ) |
| First Posted: | February 13, 2018 Key Record Dates |
| Last Update Posted: | January 19, 2023 |
| Last Verified: | January 2023 |
| 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 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 |