Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase inhibitor (HDACi), in patients (pts) with advanced, previously treated soft tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French Sarcoma Group.

Abstract

10027 Background: Treatment options are limited for pts with advanced pretreated STS. HDACi have shown activity in preclinical models of STS and SCT Methods: Pts with advanced pretreated STS and SCT were enrolled in this open label, single arm, multicenter phase II study. Panobinostat was given orally, 40 mg thrice per week. The primary end-point was 3-month progression-free rate according to RECIST 1.1 using central review. Fleming-A’Hern single-stage design for phase II trials was used, and assuming a type I error alpha of 5% with 90% power, 15/47 pts were needed to be progression free at 3 months to reject a rate of 20%. Results: Fifty three pts were enrolled between January 2010 and January 2011. Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had metastatic disease. The most common sites were the lung and the liver. All but one pt had documented disease progression prior to study entry. The median number of prior lines of therapy was 2 (range 1-7). Panobinostat dose was lowered to 20 mg thrice a week after 11 pts were enrolled based on the recommendation of an independent safety committee. Fifty-two pts were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) reported at least one adverse event (AE) and 22 (42%) reported at least one treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited although some patients had prolonged SD. Activity in pts with SCT warrants further investigation.