A Randomized, Placebo-Controlled, Phase II Study of Pracinostat in Combination with Azacitidine (AZA) in Patients with Previously Untreated Myelodysplastic Syndrome (MDS)

Background: Pracinostat (PR) is a potent oral inhibitor of histone deacetylases (HDAC's), selective for class I, II and IV isoforms. A pilot phase Ib study of pracinostat in combination with AZA in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). The current study was designed to rigorously assess the clinical activity of this combination in a multi-center environment, including a placebo-controlled comparator group.

Methods: Eligibility includes age ≥18 years, previously untreated intermediate risk-2 or high-risk MDS by IPSS, >5% and <30% marrow blasts, PS≤2, and adequate organ function. Treatment is AZA, 75 mg/m² days 1-7 or days 1-5/days 8-9 plus PR or placebo (PL), 60 mg 3 days/week for 3 weeks. Cycles are repeated every 28 days until disease progression lack of benefit, or intolerance. Randomization was stratified by IPSS risk group with a planned sample size of 100. The primary endpoint is confirmed CR within 6 cycles, based on IWG criteria (Cheson, 2006). CR rates are calculated for each group with 95% CI's and compared using Chi-square testing. Time-to-event secondary endpoints (PFS, EFS, OS) are analyzed by Kaplan-Meier and hazard ratios calculated. The primary analysis population is defined as all randomized and treated patients.

Results: Between June 2013 and August 2014, 102 patients were randomized and treated at 24 U.S sites. Baseline characteristics: median age 69 (26-90), 69% M:31% F, PS 36% 0/58% 1/6% 2. IPSS Risk categories, 67% INT2/33% High risk. Treatment-related 12%, median blasts 13% (2.2 - 27). Efficacy (PR vs. PL): As of June 30, 2015, CR within 6 cycles was 18% vs. 31%; hematologic improvement was 35% vs. 55%; PFS was 10.7 vs. 9.2 mo. (HR=0.93, p=NS); EFS was 8.6 vs. 9.0 mo. (HR=0.82, p=NS); OS was 15.7 vs. 18.8 mo (HR=1.21, p=NS). Pracinostat resulted in a higher rate of discontinuations for adverse events (AE's), 26% vs. 10%, predominantly within the first 2 cycles of treatment. Notable grade ≥3 AE's: thrombocytopenia, 47% vs. 26%; febrile neutropenia 33% vs. 18%; fatigue, 24% vs. 0%. Exploratory sensitivity analyses, censoring patients not starting cycle 5 (n=54), showed the following HR's all favoring Pracinostat: PFS=0.37, EFS=0.33, OS=0.59.

Conclusions: Pracinostat failed to improve the clinical effectiveness of AZA in this population of higher risk MDS. This appears related to a higher rate of early study discontinuation in the PR group, primarily due to AE's. Exploratory analyses suggest that patients able to tolerate PR for at least 4 cycles may derive benefit.