A Phase I Study of Histone Deacetylase Inhibitor, Pracinostat (SB939), in Pediatric Patients With Refractory Solid Tumors: IND203 a Trial of the NCIC IND Program/C17 Pediatric Phase I Consortium

作者：Zorzi Alexandra P; Bernstein Mark; Samson Yvan; Wall Donna A; Desai Sunil; Nicksy Darcy; Wainman Nancy; Eisenhauer Elizabeth; Baruchel Sylvain^*

来源：Pediatric Blood and Cancer, 2013, 60(11): 1868-1874.

DOI：10.1002/pbc.24694

• histone deacetylase inhibitor
• pediatric cancer
• phase I trial
• pracinostat
• solid tumor

BackgroundPracinostat (SB939) is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDAC). The adult recommended phase II dose (RP2D) is 60mg po three times per week (t.i.w.) for 3 weeks every 4 weeks. This study assessed the toxicities and pharmacokinetics of pracinostat and determined the RP2D in children with refractory solid tumors.
MethodsPediatric patients with refractory solid tumors were treated with oral pracinostat t.i.w. for 3 consecutive weeks, followed by 1 week off dosing. Three dose levels25, 35, and 45mg/m(2) were evaluated using a standard 3+3 cohort design. Pharmacokinetic (PK) studies were optional.
ResultsTwelve patients were enrolled. The most common diagnosis was Ewing sarcoma. Most adverse events (AEs) were hematological with five (40%) patients experiencing grade 3 neutropenia. Non-hematological AEs were generally grade 1. No dose limiting toxicities occurred. More hematological and non-hematological AEs occurred at 45mg/m(2): Two of five patients experienced Grade 3 neutropenia and one each Grade 3 thrombocytopenia and leucopenia, Grade 1 fatigue and anorexia occurred in three. The RP2D was declared to be 45mg/m(2) (comparable to an adult dose of 80mg). One patient had a best response of stable disease (duration of 2.9 months). Three patients on 25mg/m(2) and one each on 35 and 45mg/m(2) participated in the PK study. No dose related changes in C-max or AUC occurred.
ConclusionsPracinostat is reasonably well tolerated in children with refractory solid tumors. The RP2D is 45mg/m(2). Pediatr Blood Cancer 2013;60:1868-1874.

• 出版日期2013-11