Phase 3 Pracinostat Trial Discontinued in Newly Diagnosed AML

An interim futility analysis of an ongoing phase 3 trial (NCT03151408), which is evaluating pracinostat in combination with azacitidine in patients with acute myeloid leukemia (AML) who are unfit to receive standard intensive chemotherapy, demonstrated that it is unlikely to meet the primary end point of overall survival (OS) compared with a control arm, according to Helsinn, the manufacturer of pracinostat. Based on these data, it has been decided that the trial will end and patient recruitment will be discontinued.¹

In the analysis, which was undertaken by the study Independent Data Monitoring Committee, the investigators made the decision to end the study based on a lack of efficacy, and not safety concerns.

“Pending further evaluation, patients currently enrolled in other pracinostat studies will continue treatment,” Helsinn stated in the press release.

Pracinostat is an investigational oral HDAC inhibitor that is being investigated in combination with azacitidine for the treatment of adults with newly diagnosed AML who are unfit for standard intensive chemotherapy.

Previously, the FDA and the European Medicines Agency have granted Orphan Drug Designations to pracinostat in combination with azacitidine for the treatment of patients with newly diagnosed AML who are 75 years or older or are unfit for intensive chemotherapy. The FDA also granted a breakthrough therapy designation in 2016 to the pracinostat combination for use in this setting.

The designation was 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% with the pracinostat combination in treatment-naïve elderly patients with AML.

In this phase 2 study, 50 patients who were considered unsuitable for intensive chemotherapy due to AML-related features, comorbidities, and/or high-risk cytogenetics were enrolled at 15 study locations between December 2013 and December 2015. Patients were at least 65 years old with newly diagnosed disease and were ineligible for standard induction chemotherapy.

The median age was 75 years (range, 66-84). Thirty-three patients had de novo AML, 12 had secondary AML, and 5 were treatment-related. The baseline median bone marrow blast count was 40% (range, 20-89). Additionally, 20 patients had high-risk cytogenetics, 28 had intermediate-risk cytogenetics, and the status was unknown for 2 patients.

Pracinostat was given at 60 mg orally on 3 alternating days each week for 3 weeks plus 75 mg/m² of azacitidine given intravenously or subcutaneously on days 1 to 7, or days 1 to 5 and 8 to 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.

Results that were published in Blood Advances in 2019 demonstrated that the CR rate was 42%, the CRi rate was 4, and the MLFS rate was 6%.² The median progression-free survival (PFS) was 12.6 months (95% CI, 10-17.7), and the median OS was 19.1 months (95% CI, 10-26.5). Additionally, the 1-year OS rate was 62%.

Grade 3 or high treatment-emergent adverse effects with the combination occurred in 43 patients (86%), with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively.

The agent is also being evaluated in a phase 2 trial of patients with high- or very high-risk myelodysplastic syndromes.

References:

1. Helsinn Group and MEI Pharma Discontinue the Phase 3 Study with Pracinostat in AML after Completing Interim Analysis [news release]; Lugano, Switzerland, and San Diego, CA. Helsinn. Published July 2, 2020. Accessed July 2, 2020.
2. Garcia-Manero G, Abaza Y, Takahashi K, et al. Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study. Blood Advances. 2019;3(4):508-519. doi:10.1182/bloodadvances.2018027409