Conditions: Metastatic Prostate Cancer
Keywords: Enzalutamide Niraparib PARP-1 inhibitor PARP-2 inhibitor Castrate-Resistant Prostate Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This is a phase I study to determine the safety and feasibility of the combination of enzalutamide and niraparib in subjects with metastatic castration-resistant prostate cancer (CRPC).

Detailed description:
OUTLINE: This is a multi-center trial.

INVESTIGATIONAL TREATMENT:

Each eligible subject will begin treatment with a 28-day enzalutamide 160 mg/day lead-in cycle. If a subject is able to tolerate the lead-in enzalutamide cycle without Grade 2 or Grade 2-4 drug-related toxicity, dose reduction, or missed doses due to toxicity, cycle 1 of combined enzalutamide and niraparib will commence. Enzalutamide will continue at 160 mg daily.

Niraparib will be dosed daily starting at 100mg (dose level 1). Six subjects will be enrolled per dose level. If less than 33% of the subjects experience a dose-limiting toxicity (DLT) at the beginning of cycle 2, then the daily dose of niraparib will escalate to 200mg (dose level 2). If dose level 2 is similarly tolerated, then the daily dose of niraparib escalate to 300mg (dose level 3).

The following required laboratory values must be obtained within 14 days prior to registration for protocol therapy:

Hematopoietic:

* White blood cell count (WBC) ≥ 1500/mm3
* Hemoglobin (Hgb) ≥ 9 g/dL
* Platelets ≥ 150,000/µL
* Absolute neutrophil count (ANC) ≥ 1500/mm3

Renal:

* Calculated creatinine clearance of ≥ 40 cc/min using the Cockcroft-Gault formula

Hepatic:

* Bilirubin ≤ 1.5 × upper limit of normal (ULN)
* Aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN

Arms:
arm 1: Subjects will receive enzalutamide 160 mg/day PO in a 28-day lead-in cycle to assess tolerability. If well-tolerated, cycle 1 of combined enzalutamide and niraparib will commence. Enzalutamide will continue at 160 mg PO daily. Niraparib will be administered in three dose-escalation cohorts of 100mg PO, 200mg PO or 300 mg PO daily. Six subjects will be enrolled at each dose level. Each cycle will be 28 days. Combination treatment will continue until documented progression, unmanageable toxicity, or subject or treating investigator decision to discontinue for any reason.

Interventions: intervention 1: Enzalutamide intervention 2: Niraparib
Intervention descriptions: intervention 1: Following completion of 28-day lead-in cycle, enzalutamide 160 mg PO daily will continue to be administered in 28-day cycles until documented progression, unmanageable toxicity, or decision to discontinue for any reason. intervention 2: Niraparib will be administered daily in three dose-escalation cohorts of 6 subjects per dose levels of 100mg PO, 200mg PO or 300mg PO in 28-day cycles until documented progression, unmanageable toxicity, or decision to discontinue for any reason.

Protocol document: