A First-in-human Phase I Study of JNJ-26481585, a Novel Oral Histone Deacetylase Inhibitor (hdaci), in Patients with Advanced Cancer with Evidence of Target Modulation and Antitumor Activity.

3024 Background: JNJ-26481585 is a potent, hydroxamate, pan-HDACi with broad activity in solid and hematologic tumor models. Methods: JNJ-26481585 was administered orally, once daily (QD) in 3-weekly cycles to advanced cancer patients (pts) using a 2-stage accelerated titration design. As QD dosing was poorly tolerated, three intermittent schedules were explored: 1) 4 days on, 3 days off; 2) every Mon, Wed, Fri (MWF); and 3) every Mon, Thurs (M-Th). Primary objectives were safety, maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives were pharmacodynamic (PD) effects in normal and tumor tissues (acetylated Histone H3, Ki67), PK food effect and anti-tumor activity. Results: 73 patients (37 M, median age 56 yr) received JNJ-26481585. Number of pts, dose-limiting toxicities (DLTs), and MTD for each cohort and schedule are shown in the Table. Common grade 1-2 toxicities were fatigue, anorexia, and nausea. PK was dose-proportional with high volume of distribution and AUC (range 11-20 h.ng/mL) consistent with the exposure required for activity in xenograft models. There was no food effect. PD data showed increased acetylated Histone H3 in hair follicles, skin biopsies and tumor, confirming proof of mechanism. A partial response lasting 5 months (mo) was seen in one patient with melanoma. Stable disease was seen in 8 pts (duration 4 – 10.5 mo). Conclusions: The adverse event profile of JNJ-26481585 is comparable to other HDACi. Intermittent administration is better tolerated than QD. The recommended dose for phase II trials is 12 mg on the MWF schedule, based on tolerability, anti-tumor activity, PK predictions, and PD activity. Schedule. 2 mg 4 mg 6 mg 8 mg 10 mg 12 mg 15 mg 16 mg 19 mg QD N=2 N=2 N=6 1 DLT (bilirubin↑) N=8 1 DLT (NSVT*) 0 MTD - N=2 2 DLTs (NSVT*, fatigue) - - - 4 days on, 3 days off - - N=3 N=3 N=6 0..DLTs MTD N=7 2 DLTs (NSVT*, infection) - - - MWF - - N=3 N=3 - N=7 1 DLT (hypertension + troponin↑) MTD - N=6 0..DLTs*** - M-Th - - - N=3 - N=3 N=6 0..DLTs MTD - N=3 2 DLTs (T-wave inversion, SVT**) *Nonsustained ventricular tachycardia. **Supraventricular tachycardia. ***Palpitations + ventricular extrasystoles in 2 pts in cycle 2.