Planned Interim Analysis of a Phase 2 Study Evaluating the Combination of Pracinostat, a Histone Deacetylase Inhibitor (HDACi), and Azacitidine in Patients with High/Very High-Risk Myelodysplastic Syndrome (MDS)
Authors: Keng Michael K , Khaled Samer K. , Cooper Brenda , Warlick Erica D. , Ramies David , Mappa Silvia , Atallah Ehab L. 
Published: October 2019

Abstract
Introduction:
Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes.
Methods:
The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation (<6 months) due to lack of response. Response evaluation is performed after 2 and 6 cycles of therapy, and then every 6 months or as clinically indicated; analyses are descriptive. At a planned interim analysis, a pre-defined discontinuation rate due to adverse events (AEs) of ≤10% in the first 3 cycles ("early discontinuations"), a rate comparable to that observed with azacitidine alone in the prior study, and an overall response rate (ORR) of ≥20% were deemed desirable and would support expansion into Stage 2, wherein approximately 20 additional patients will be treated for a total of 60 evaluable patients. The study Independent Data Monitoring Committee (IDMC) in conjunction with the study Sponsor was to determine whether the study would expand based on the discontinuation rate.
Results:
At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study.
Conclusions:
The interim analysis of this study evaluating the efficacy and safety of pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented.

Disclosures
Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.