Metastatic castration-resistant prostate cancer (mCRPC) MedDRA version: 21.1 Level: LLT Classification code 10076506 Term: Castration-resistant prostate cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10036909 Term: Prostate cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Janssen-Cilag International NV
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. 18 years of age or older 2. Willing to undergo all protocol-specified biopsies 3. Diagnosis of prostate adenocarcinoma as confirmed by the investigator. 4. Criterion moved per Amendment 3. 5. Criterion moved per Amendment 3 6. Criterion moved per Amendment 3 7. Must have castrate levels of testosterone =50 ng/dL on a gonadotropin releasing hormone analogue (GnRHa), or history of bilateral orchiectomy at study entry 8. Progression of metastatic prostate cancer at study entry defined as having one or more of the following: a. PSA progression defined by a minimum of 2 rising PSA levels with an interval of =1 week between each determination (per Prostate Cancer Working Group 3 [PCWG3] criteria). The PSA level at the screening visit should be =2 µg/L (2 ng/mL). b. Radiographic progression by bone scan per PCWG3 or by soft tissue per RECIST 1.1. 9. Must be willing to continue GnRHa during the study if not surgically castrate. 10. Eastern Cooperative Oncology Group Performance Score (ECOG PS) Grade of 0 or 1 11. Subjects who received prior therapy with an anti-androgen (eg, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide) must have at least a 4-week wash-out prior to enrollment. 12.Criterion modified per Amendment 6. 12.1 While on study medication and for 3 months (Combination 2) or 5 months (Combination 1) following the last dose of study medication, a male subject must agree to use an adequate contraception method as deemed appropriate by the investigator and as specified in Section 4.4 Lifestyle Considerations. 13. Clinical laboratory values at Screening: a.Absolute neutrophil count (ANC) =1.5 x 10^9/L, independent of growth factors for 30 days b.Hemoglobin =9.0 g/dL, independent of growth factors or transfusions for 30 days c.Platelet count =100 x 10^9/L, independent of growth factors or transfusions for 30 days d.Serum albumin =3.0 g/dL e.Creatinine clearance =30 mL/min/1.73 m^2 either calculated or directly measured via 24-hour urine collection f.Serum total bilirubin =1.5 x upper limit of normal (ULN) or direct bilirubin =1 x ULN (Note: in subjects with Gilbert’s syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is =1.5 x ULN, subject may be eligible as determined by the medical monitor) g.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3 x ULN h.Fasting glucose =250 mg/dL 14.A male subject must agree not to donate sperm while on study treatment and for 3 months (Combination 2) or 5 months (Combination 1)following the last dose of study medication. Combination 1: Niraparib and Cetrelimab. 1.Criterion modified per Amendment 4. 1.1 Must have determination of biomarker positive for DRD OR CDK12(biallelic) by the sponsor's blood or tissue assay. For Part 1 of the study, subjects can be dosed prior to assay results becoming available. Results are required prior to dosing for Part 2. 2. Subjects must have measurable disease as defined by RECIST 1.1 (soft tissue lesion of =10mm in the long axis or extrapelvic lymph node of =15mm in the short axis). 3. Must have previously received at least 1, but no more than 2, lines of novel AR-targeted therapy (ie, abiraterone acetate with prednisone, enzalutamide) for mCRPC. Subjects must have had at least 4 weeks of AR-targeted therapy. Combination 2: Niraparib and AAP 1. Must be biomarker positive for DRD by either blood or tissue assay 2. Must have progressed on 1 prior line of novel AR-targeted therapy
Exclusion criteria
Exclusion criteria: 1. Prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. 2. History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). 3. Criterion modified per Amendment 5. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions please refer to protocol. 4. Active infection requiring systemic therapy. 5. Allergies, hypersensitivity, or intolerance to niraparib or the corresponding excipients (refer to the Investigator’s Brochures). 6. Human immunodeficiency virus (HIV)-positive subjects with 1 or more of the following: a. Not receiving highly active antiretroviral therapy. b. A change in antiretroviral therapy within 6 months of the start of screening (except if, after consultation with the sponsor on exclusion criterion 11.c, a change is made to avoid a potential drug-drug interaction with the study drug). c. Receiving antiretroviral therapy that may interfere with the study drug (consult the sponsor for review of medication prior to enrollment). d. CD4 count 160 mmHg or diastolic BP >100 mmHg). Note that subjects with a history of hypertension are allowed, if BP is controlled to within these limits by anti-hypertensive treatment. 13. Any condition for which, in the opinion of the investigator or medical monitor, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. For excl.criteria to combination 1: Niraparib and Cetrelimab: 1. Criterion deleted per Amendment 2. 2. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (including any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 3. Subjects with a history of allergy to protein-based therapies or any significant drug allergy (ie, anaphylaxis, heptatotoxicity, or immune-mediated thrombocytopenia or anemia). 4. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis. 5. Allergies, hypersensitivity, or intolerance to Cetrelimab or the corresponding excipients (refer to the Investigator’s Brochure). 6. Immunodeficiency or receiving systemic corticosteroid therapy or immunosuppressive therapy (eg, cyclosporine) within 7 days
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1: - To evaluate the tolerability of niraparib combination therapies for the treatment of mCRPC - Determine the recommended Phase 2 dose (RP2D) of niraparib combination therapies Part 2 (Dose Expansion): - To evaluate the antitumor effect of the RP2D of niraparib combination therapies for treatment of mCRPC - To evaluate the safety of the RP2D of niraparib combination therapies for the treatment of mCRPC For Combination 3: -To determine the relative bioavailability of 2 regular strength FDC tablet formulations of niraparib and AA with respect to niraparib and AA co-administered as SA under fasted conditions in subjects with mCRPC ;Secondary Objective: Part 1: - To characterize the pharmacokinetics (PK) and immunogenicity (if applicable) of niraparib combination therapies Part 2: - To evaluate other response outcomes of niraparib combination therapies for the treatment of mCRPC - To evaluate duration of response - To characterize the PK and immunogenicity (if applicable) of niraparib combination therapies through sparse sampling For Combination 3: -To evaluate the PK of a low-strength FDC tablet formulations of niraparib and AA under fasted conditions in subjects with mCRPC -To assess the safety of niraparib in combination with AA in subjects with mCRPC ;Primary end point(s): Part 1: 1. Incidence of specified toxicities Part 2: Combination 1 2. Objective response rate (ORR) of soft tissue (visceral or nodal disease) Combination 2 3. Composite response rate (RR) defined as 1 of the following by PCWG3 a. Objective Response b. Circulating tumor cells (CTC) response c. Prostate-specific antigen (PSA) decline of =50%, measured twice 3 to 4 weeks apart Combinations 1 and 2 4. Incidence and severity of Adverse events (AEs) For Combination 3: 1.PK parameters (Cmax, [Cmax/dose]niraparib, AUC0-168h, [AUC0 168h/dose]niraparib) of niraparib and AA after a single dose;Timepoint(s) of evaluation of this end point: 1. First 28 days of treatment (Cycle | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part 1: 1. Plasma concentrations of niraparib and, if performed, its major metabolite (M1), and plasma or serum concentrations of the combination agent 2. Population PK parameters and derived exposure of niraparib and combination agent 3. Anti-drug antibodies (if applicable) Part 2: Combination 1 and 2 4. Circulating tumor cell (CTC) response Combination 1 only 5. Composite Response rate (RR) Combination 1 and 2 6. Duration of objective response 7. Overall survival (OS) Combination 1 only 8. Plasma concentrations of niraparib and, if performed, its major metabolite (M1) when dosed with combination agent 9. Population PK parameters and derived exposure of niraparib and combination agent 10. Anti-drug antibodies (if applicable) Combination 2 only 11. Objective response rate (ORR) of soft tissue (visceral or nodal disease) For Combination 3: 1.PK parameters (Cmax, [Cmax/dose]niraparib, AUC0-168h, [AUC0 168h/dose]niraparib) of niraparib and AA after a single dose 2.Adverse events and clinical laboratory safety;Timepoint(s) of evaluation of this end point: 1, 2, 8 and 9. Cycle (C) 1 Day (D) 1, C2 D1, C3 D1, C6 D1 and C12 D1 3 and 10. Cycle 1 (D1, 15), C2 (D1, 15), C3 (D1, 15), C4 (D1, 15), C5 (D1, 15), C6 (D1, 15), C7 (D1, 15), C9 D1, C10 D1, C12 (D1, 15), at end of treatment (EoT) visit and follow-up 4. Combination 1: At Screening and At every cycle from C 2 D 1 through C 12 D 1, and at the EoT visit Combination 2:At the discretion of the investigator according to routine practice 5 & 7. Day 1 to until death. 6.Combination 1:Day 1 to until death 11. At the discretion of the investigator according to routine practice. For Combination 3: 1.PK samples will be taken as per protocol 2.Day 0 to until the End-of-Treatment (EoT) visit | — |
Countries
Australia, Belgium, Canada, Israel, Spain, United Kingdom, United States
Contacts
Public ContactClinical Registry group
Janssen-Cilag International N.V.
Outcome results
None listed