FDA Grants Pracinostat Breakthrough Designation for AML

Daniel P. Gold, PhD

The FDA has granted pracinostat a breakthrough therapy designation for use in combination with azacitidine as a treatment for patients with newly diagnosed acute myeloid leukemia (AML) who are aged ≥75 years or ineligible for intensive chemotherapy, according to MEI Pharma, the company developing the HDAC inhibitor.

The designation, which will expedite the review and development of pracinostat, is based on a phase II trial in which the median overall survival (OS) was 19.1 months and the complete response (CR) rate was 42% with the pracinostat combination in treatment-naïve elderly patients with AML.

"This designation speaks to both the serious unmet need for AML patients unfit to receive intensive chemotherapy and the promise of pracinostat to address this need,” Daniel P. Gold, PhD, president and CEO of MEI Pharma, said in a statement.

“With this designation, the FDA recognizes that our preliminary clinical data demonstrate that pracinostat may result in a substantial improvement in the lives of AML patients over available therapy. We have worked closely with the FDA to get to this point and now focus on executing our phase III study and bringing pracinostat to market as quickly and efficiently as possible,” added Gold.

The phase II study on which the designation was based included 50 patients who were considered unsuitable for intensive chemotherapy due to AML-related features, comorbidities, and/or high-risk cytogenetics. Patients were enrolled at 15 study locations between December 2013 and December 2015.

The median patient age was 75 years (range, 66-84). Thirty-two patients had de novo AML, 13 evolved from an antecedent hematologic disorder, and 5 were treatment-related. At baseline, the median bone marrow blast count was 40% (range, 20-89). Twenty patients had high-risk cytogenetics, 28 had intermediate-risk cytogenetics, and the status was unknown for 2 patients.

Pracinostat was administered at 60 mg orally on 3 alternating days each week for 3 weeks plus 75 mg/m² of azacitidine (IV or subcutaneous on days 1-7, or days 1-5 and 8-9). Each cycle was 28 days and patients continued treatment until progressive disease, unacceptable toxicity, or nonresponse.

The primary endpoint of the trial was CR plus CR with incomplete blood count recovery (CRi) plus morphologic leukemia free state (MLFS). Secondary outcome measures included OS, overall response rate (ORR; CR + CRi + MLFS + partial response [PR] + PRi), and duration of response. Patients were assessed for response following cycles 1 and 2 and then after alternating cycles or when clinically indicated.

According to a press release from MEI Pharma, the 19.1-month median OS and 42% CR rate with the combination compared favorably with results from the phase III AZA-AML-0011 trial, which examined azacitidine alone in a similar population. In that study, the median OS with azacitidine was 10.4 months and the CR rate was 19.5%.

In data reported at the 2015 ASH Annual Meeting,¹ 54% (n = 27) of patients reached the primary endpoint of CR plus CRi plus MLFS. The estimated 1-year OS rate at the time was 60%.

The researchers considered the pracinostat combination to be well tolerated overall. The most common grade ≥3 adverse events (AEs) included febrile neutropenia (30%), thrombocytopenia (22%), neutropenia (10%), cellulitis (10%), anemia (8%), fatigue (8%), sepsis (6%), and pancytopenia 6%. AEs leading to treatment discontinuation included peripheral motor neuropathy (n = 1), parainfluenza (n = 1), atrial fibrillation/prolonged QTc (n = 1), subdural hematoma after a fall (n = 1), and sepsis (n = 3).

1. Garcia-Manero G, Atallah E, Khaled SK, et al. final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia (AML). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 453.