| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration-resistant prostate cancer (mCRPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic castration-resistant prostate cancer (mCRPC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (ie,
abiraterone acetate with prednisone, enzalutamide) for mCRPC. Prior
treatment with taxane-based therapy and AR-targeted therapy outside
of the mCRPC setting are allowed.
Combination 3:
In the protocol please See Attachment 6 for the Inclusion Criteria for Combination 3. |
|
| E.4 | Principal 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 <350 cells/mm^3 at screening.
e. An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening.
7. Active hepatitis B virus (eg, hepatitis B surface antigen reactive) or active hepatitis C virus (HCV) (eg, HCV ribonucleic acid [RNA] [qualitative] is detected).
8. If a subject has undergone major surgery, they must have recovered adequately from the toxicities or complications from the intervention prior to starting therapy.
9. Criterion deleted per Amendment 2.
10. Any of the following ≤30 days prior to planned Cycle 1 Day 1:
a.A transfusion (platelets or red blood cells).
b.Hematopoietic growth factors.
c.An investigational agent for prostate cancer.
d.Major surgery (sponsor's medical monitor should be consulted regarding what constitutes major surgery).
e.Radiation therapy
11. Symptomatic brain metastasis from prostate cancer.
12. Symptomatic congestive heart failure (New York Heart Association
Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or uncontrolled hypertension defined as systolic blood pressure [BP] >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 prior to treatment allocation. The use of physiologic doses of corticosteroids may be approved after consultation with the
sponsor.
7. Active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
treatment.
8. Received a live vaccine within 30 days of the first dose of study drugs.
9.History of organ transplant, including allogeneic stem cell transplantation.
Combination 2: Niraparib and AAP
1. Allergies, hypersensitivity, or intolerance to abiraterone acetate or prednisone or the corresponding excipients (refer to the Investigator's Brochure)
2. Current evidence of any of the following:
a. Any medical condition that would make prednisone use contraindicated.
b. Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone (or equivalent) once daily
Lifestyle Considerations
Potential subjects must be willing and able to adhere to the following lifestyle restrictions during the course of the study to be eligible for participation: For remainder text refer to protocol
Combination 3:
In the protocol please See Attachment 6 for the Inclusion Criteria for Combination 3. |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. First 28 days of treatment (Cycle 1)
2. From Cycle (C) 1 Day (D) 1, imaging will be performed every 8 weeks for the first 6 months and then every 12 weeks thereafter
3.
a.At the discretion of the investigator according to routine practice.
b.At the discretion of the investigator according to routine practice.
c.At the discretion of the investigator according to routine practice.
4. Day 0 to until the End-of-treatment (EOT) visit
Combination 3:
1.PK samples will be taken at Predose,30 min, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6hrs, 8 hr, 10 hr, 24 hrs, 48 hrs, 72 hrs, 168 hrs after administration. |
|
| E.5.2 | 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 |
|
| E.5.2.1 | 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 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity and Biomarker Analyses |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1b-2:The primary objective of the study is to establish the RP2D of niraparib with JNJ63723283 |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Israel |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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