A Phase 3 Randomized Study (PRIMULA) of the Epigenetic Combination of Pracinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor, with Azacitidine (AZA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Unfit for Standard Intensive Chemotherapy (IC)
Authors: Garcia-Manero Guillermo , Kaźmierczak Maciej , Fong Chun Yew , Montesinos Pau , Venditti Adriano , Mappa Silvia , Spezia Riccardo , Ades Lionel 
Published: November 2019

Background:
AML is associated with poor survival rates in patients ineligible for IC or stem cell transplant due to advanced age, comorbidities, and/or disease and patient-specific risk factors. Non-intensive therapies, including the hypomethylating agent (HMA) AZA, have historically been used in this setting; however, response rates and survival remain dismal. Pre-clinical studies in myeloid malignancies indicate that the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes in a synergistic fashion. Pracinostat, an oral pan-HDAC (class I, II, and IV isoforms) inhibitor, has shown superior pharmacokinetic and pharmacodynamic properties compared with other HDAC inhibitors. The activity of pracinostat has been shown in xenograft tumor models of AML and synergistic interactions have been observed with multiple cytotoxic and targeted anti-cancer therapeutics, including AZA. In a Phase 2 study in AML patients ≥65 years not eligible for IC, the epigenetic combination of pracinostat and AZA showed promising efficacy (Garcia Manero, Blood 2016) with a 64% overall response rate and 19.1 months median overall survival. Favorable responses were also seen in patients with high risk molecular features and adverse prognostic factors. The safety profile of pracinostat/AZA is comparable to each administered as monotherapy, with no significant added toxicity.
Study Design and Methods:
The Phase 3, multicenter, double-blind, randomized PRIMULA study (NCT03151408) evaluates the efficacy and safety of pracinostat administered with AZA in adult patients with newly diagnosed AML who are ineligible to receive IC based on either 1) age ≥75 years or 2) age <75 years plus a protocol-defined comorbidity. A total of 500 patients (randomized 1:1 to either pracinostat/AZA or placebo/AZA) are planned to be enrolled at ~140 study centers worldwide. Randomization is stratified by cytogenetic risk (intermediate vs. unfavorable-risk) and ECOG Performance Status (0-1 vs. 2). Treatments are administered as 28-day cycles, with pracinostat given orally as a 60 mg capsule QD, 3x/week for 3 weeks followed by one week off, and AZA administered for 7 days of each cycle. Patients are to receive a minimum of 6 cycles as long as there is no evidence of disease progression or non-manageable toxicity. The primary endpoint is overall survival; secondary efficacy endpoints include morphologic and cytogenetic complete remission (CR) rates, CR without minimal residual disease and transfusion independence ≥8 weeks. Safety is assessed primarily through treatment-emergent adverse events. Overall survival will be tested for superiority of pracinostat/AZA over placebo/AZA using the stratified log-rank test at the alpha = 0.025 level of significance (one-sided). One interim analysis is planned when 260 events (i.e., deaths due to any cause) have occurred. Enrollment is open and as of July 8, 2019 257 patients have been randomized.

Disclosures
Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Fong:Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Montesinos:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Venditti:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mappa:Helsinn Healthcare SA: Employment; Helsinn Healthcare SA: Patents & Royalties. Spezia:Helsinn Healthcare: Employment. Ades:Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

OffLabel Disclosure:
Pracinostat is an HDAC inhibitor not yet approved by the FDA