A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group

Abstract

Background:Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS.Methods:We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate.Results:Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21–79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10–35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months.Conclusion:Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

“…HDAC inhibitors represent the first generation of approved epigenetic therapy agents, although their use as monotherapy in advanced sarcomas has had disappointing results beyond some prolongation of stable disease (41,42). Like other drugs tested in advanced tumors, HDAC inhibitors may be more effective in combination with other agents and/or when tested against timeto-event rather than objective response endpoints.…”

Panobinostat: First Global Approval

“…Several noncomparative, phase II studies (n = 7-47) of single-agent [50][51][52][53] or combination treatment [54, 55] with oral [50,[52][53][54][55] or intravenous [51] panobinostat in solid tumours (previously treated, extensive-or limitedstage small-cell lung cancer [50], previously treated, castration-resistant prostate cancer [51], previously gemcitabine-treated, progressing, advanced pancreatic cancer [54], refractory metastatic renal cell carcinoma [52], advanced, pretreated soft-tissue sarcoma [53], and recurrent glioblastoma [55]) indicate that it is unlikely to be effective in these indications.…”

Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: Systematic review of 62 studies and new hypotheses for future research

“…1 and Table 1). The included studies examining the different HDACi were divided as follows: 22 studies for Romidepsin , 14 for Panobinostat [33][34][35][36][37][38][39][40][41][42][43][44][45][46], 14 for Vorinostat [47][48][49][50][51][52][53][54][55][56][57][58][59][60], 7 for Belinostat [61][62][63][64][65][66][67], 4 for Valproate [68][69][70][71] and 1 for Entinostat [6]. A total of 3268 patients were identified from 62 studies, and were subsequently divided into six HDACi specific groups for subgroup analyses.…”