A phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of the histone deacetylase (HDAC) inhibitor PXD101 in patients (pts) with advanced solid tumours

Abstract

3035 BackgroundPXD101 is a novel HDAC inhibitor with potent antiproliferative activity in vitro. PXD101 inhibits tumour growth in vivo in pre-clinical models. We present a phase 1 trial of PXD101 in pts with advanced solid tumours re fractory to standard therapy. Methods Sequential cohorts of 3–6 pts were recruited to this study to determine the maximum tolerated dose of PXD101 administered as a 30 minute IV infusion on days 1 - 5 of a 21 day cycle. The PK profile of PXD101 was calculated by non-compartmental analysis of plasma and urine from 2–4 pts at each dose level. Acetylation of histones extracted from PMN cells was measured by Western blotting. The PK profile of a single oral dose of PXD101 was evaluated in 3 pts. Results 21 pts (median age 58 years, range 39–72); 10M 11F; all ECOG PS ≤ 2) have been treated with a total of 57 cycles of PXD101 (median 2; range 1 to 7) at 5 escalating dose levels: 150mg/m2(4pts), 300 mg/m2(4pts), 600 mg/m2 (6pts), 900 mg/m2 (3pts) and 1200mg/m2 (3pts). No haematological toxicity was observed. Dose limiting toxicity was seen in 3 pts: G3 fatigue (1 pt) at 600 mg/m2, reversible atrial fibrillation (1 pt) at 1200 mg/m2and G3 diarrhoea and lethargy (1pt) at 1200mg/m2. All other adverse effects were ≤ G2. PXD101 displays linear kinetics. Dose-proportional Cmax (range 2.1 - 68.1μg/ml) was reached at the end of the infusion. The elimination half-life of 0.5–1 hr was independent of dose. PXD101 was detected in plasma at low levels after 10 hrs at 1200 mg/m2but undetectable after 8–10 hrs at lower doses. There was no drug accumulation on repeated dosing. Mean oral bioavailability of PXD101 was 33% (range 32–35%). Histone H4 hyperacetylation was observed at the end of each infusion and was sustained for 4–24 hrs in a dose-dependent manner. PXD101 induced p21, p19 and Apaf-1 expression in PMN cells. To date, stable disease has been achieved in 3pts for 2 cycles; 2pts for 4 cycles and 2 pts for 6 cycles. ConclusionsThe novel HDAC inhibitor PXD101 is well tolerated and exhibits dose-dependent PD effects. 1200mg/m2 was the maximally administered dose and dose escalation has ceased. Recruitment to a 1000mg/m2 dose level continues. Further studies of oral PXD101 are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Topotarget Topotarget Topotarget