Pracinostat was granted a breakthrough therapy designation by the FDA for use in some patients with AML.
The U.S. Food and Drug Administration granted pracinostat a breakthrough therapy designation when used in combination with azacitidine for patients with newly diagnosed acute myeloid leukemia (AML) who are aged 75 or older 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 2 trial in which the median overall survival (OS) was 19.1 months and the complete response (CR) rate was 42 percent 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, 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 3 study and bringing pracinostat to market as quickly and efficiently as possible,” added Gold.
The phase 2 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 five were treatment-related. At baseline, the median bone marrow blast count was 40 percent (range, 20-89). Twenty patients had high-risk cytogenetics, 28 had intermediate-risk cytogenetics and the status was unknown for two patients.
Pracinostat was administered at 60 mg orally on three alternating days each week for three weeks plus 75 mg/m2 of azacitidine (IV or subcutaneous on days one to seven, or days one to five and eight and nine). 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 one and two 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 percent CR rate with the combination compared favorably with results from the phase 3 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 percent.
In data reported at the 2015 ASH Annual Meeting, 54 percent (27 patients) of patients reached the primary endpoint of CR plus CRi plus MLFS. The estimated one-year OS rate at the time was 60 percent.
The researchers considered the pracinostat combination to be well tolerated overall. The most common grade 3 or higher adverse events (AEs) included febrile neutropenia (30 percent), thrombocytopenia (22 percent), neutropenia (10 percent), cellulitis (10 percent), anemia (8 percent), fatigue (8 percent), sepsis (6 percent) and pancytopenia 6 percent. AEs leading to treatment discontinuation included peripheral motor neuropathy (one patient), parainfluenza (one patient), atrial fibrillation/prolonged QTc (one patient), subdural hematoma after a fall (one patient) and sepsis (one patient).