Phase Ib dose finding trial of intravenous panobinostat with docetaxel in patients with castration-resistant prostate cancer (CRPC)
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abstract
5064 Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor that has demonstrated activity in both in vivo and in vitro prostate cancer models. Methods: An open-label, multicenter, dose-finding trial of i.v. panobinostat given on Days 1 and 8 (10, 15, and 20 mg/m2) with fixed-dose docetaxel on Day 1 (75 mg/m2) and prednisone (5 mg bid) in a 21-day cycle is being conducted in chemotherapy-naïve patients (pts) with CRPC. All pts have adequate organ function and ECOG performance status (PS) < 1. Pts with significant cardiovascular abnormalities or QTcF >450 msec on screening ECG are excluded. This treatment is continued until disease progression or intolerability. The primary endpoint is determination of the maximum tolerated dose (MTD) of i.v. panobinostat in combination with docetaxel using the Bayesian logistic regression model. Dose-limiting toxicities (DLTs) are defined in first cycle. Results: Twenty-one pts (Cohort 1, n = 8; Cohort 2, n = 10; Cohort 3, n = 3) have been treated, with a median age of 66 yrs (range 50–88), median Gleason score of 9 (range 7–9), and median entry PSA of 67.1 (range 1.3–7920). DLTs include: Gr 4 bradycardia in Cohort 1 (n = 1) and Gr 4 neutropenia, resulting in Day 8 panobinostat dose omission (Cohort 2, n = 2; Cohort 3, n = 1). Gr 3/4 adverse events (AEs) include: neutropenia (n = 12), febrile neutropenia (n = 3), dizziness (n = 2), DVT (n = 1). Other Gr 1 or 2 AEs include: thrombocytopenia (n = 4), fatigue (n = 10), alopecia (n = 7), diarrhea, nausea, and rash (n = 5). Among the 599 ECGs, there was 1 QTcF increase of >60 ms from baseline and no QTcF >480 ms. Preliminary Cohort 1 pharmacokinetic (PK) data shows the mean panobinostat AUC0-inf does not differ between Day 1 (239 ng*hr/mL ) and Day 8 (254 ng*hr/mL), and the mean clearance value appeared to be similar between Days 1 and 8. In Cohort 1, the median number of cycles was 6. Four of 8 pts received >6 cycles. Five and four pts had >30% and >50% PSA reduction from baseline, respectively. In Cohort 2, 9 of 10 pts are still on treatment after 3 cycles. Conclusions: The combination of panobinostat at 10 or 15 mg/m2 with docetaxel is feasible and to date no PK interaction is apparent. Full safety, efficacy, and PK results will be presented. Under DOD PCCTC. [Table: see text]
