A phase I study of oral belinostat (PXD101) in patients with advanced solid tumors.

B134

Background: Belinostat (PXD101) is a pan hydroxamate histone deacetylase (HDAC) inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. In Phase I studies in patients (pts) with advanced cancer, IV belinostat is well-tolerated up to 1000 mg/m² days (d) 1-5, q21d.
 Methods: Pts with advanced solid tumors refractory to standard therapy, or for which no standard therapy exists, adequate renal and hepatic function and Karnofsky PS ≥60 were eligible. Primary objectives were to evaluate safety and tolerability, and secondary objectives, to determine pharmacokinetics (PK) and explore anti-tumor efficacy of oral belinostat. Pts were dosed in sequential cohorts of 3-6 pts on 1 of 4 schedules: once (QD) or twice (BID) daily in 28d cycles (continuous schedule), or QD or BID d1-14 q21d (discontinuous schedule). The dose was escalated in 250mg increments. Fasting and non-fasting PK studies were performed on all pts along with serial ECGs to evaluate effects on QTc interval.
 Results: Sixty pts, median age 60 (range 32-80) have been treated: 46 pts on continuous schedules at 250mg QD (20 pts), 500mg QD (6 pts) and 250mg BID (20 pts), and 14 pts on discontinuous schedules at 500mg QD (3 pts), 750mg QD (7 pts) and 500mg AM/250mg PM (4 pts). Median number of cycles is 2 (range 1-11); 15 pts continue on study. Two of 6 pts on continuous schedule of 500mg QD developed dose limiting toxicity (DLT) of grade (gr) 3 dehydration and gr 3 fatigue, and thus the MTD was set at 250mg QD. Dose escalation from 250mg to 500mg BID was deferred and the MTD set at 250mg BID. One of 6 pts each at 750mg QD and 500mg AM/250mg PM discontinuous schedule developed DLT of gr 3 fatigue. In available safety data from 41 pts, the most frequent adverse events (AE) occurring in >25% of pts included fatigue, anorexia, nausea, constipation and weight loss. Fatigue is the only drug-related grade 3 / 4 AE in >1 pt, occurring in 9 pts. Symptoms usually resolved after drug was withheld. In >2400 ECGs collected, no QTcF >500ms or QTcF increase >60ms above baseline was seen. Most common tumor types treated are colorectal (n=15), prostate (n=10), bladder (n=6) and lung (n=5). To date, 7 pts have SD lasting ≥ 4 months (one pt each with adenoid carcinoma, chondrosarcoma, renal, rectal, lung, prostate, thyroid). PK studies detected belinostat in serum, with exposure generally correlating with either dose, or frequency of dose (i.e., QD vs. BID). The apparent t_1/2 of QD oral belinostat ranged from 1.16 - 1.59 hrs and did not appear to be influenced by food. T_max ranged from 1.26- 3.68 hrs.
 Conclusions: Oral belinostat at 250mg QD and 250mg BID continuous, and 750mg d1-14 in a 21d cycle is tolerated. Dose escalation on discontinuous schedules continues.