Very High Rates of Clinical and Cytogenetic Response with the Combination of the Histone Deacetylase Inhibitor Pracinostat (SB939) and 5-Azacitidine in High-Risk Myelodysplastic Syndrome

Pracinostat (SB939) is a dialkyl benzimidazole competitive inhibitor of histone deacetylase (HDACi) that has >1000-fold selectivity for HDAC Class 1 and 2 versus Class 3. Antitumor activity has been demonstrated in xenograft models of AML (MV4–11). We conducted a phase I study with pracinostat in patients with advanced myelodysplastic syndrome (MDS; n=11), acute myeloid leukemia (AML; n=12), and lymphoma (n=1). Pracinostat demonstrated excellent PK properties and target inhibition and was generally well tolerated. The MTD was not reached. Activity was documented in 9 patients (1 CR, 1 PR, 7 SD), which encouraged further exploration of pracinostat-based combinations. The recommended phase II dose was 100 mg daily. The combination of 5-azacitidine and HDACi is known to be safe and active in MDS and AML.

Ñ This is a pilot phase II study conducted as an extension study in the context of a phase I trial of pracinostat in hematological malignancies to determine the efficacy and safety of the combination of pracinostat (60 mg orally every other day 3 times a week for 3 consecutive weeks) and 5-azacitidine (75 mg/m² IV daily × 5 every 3 to 6 weeks) given in 4-week cycles to patients with intermediate-2 or high risk MDS.

Nine patients (6 women) were accrued between May 2011 and September 2011. Median age was 64 years (range, 22–73), WBC 2.4×10⁹/dL (0.7–9.3), Hg 10g/dL (8.2–11), platelets 31×10⁹/dL (14–269), and bone marrow blasts 7% (0%-18%). Seven (78%) patients had therapy related MDS with history of prior chemotherapy/radiotherapy exposure (3 breast cancer, 2 non-Hodgkin's lymphoma, 1 breast and ovarian cancer, and 1 melanoma). Three patients had failed prior therapy: decitabine and haploidentical stem cell transplantation (SCT; n=1), lenalidomide (n=1), and decitabine and TXA-127 (n=1). All patients carried cytogenetic abnormalities: complex (n=4, 3 including −7 and 1 with −5), −7 (n=3, one of them with +8), t(6;9) (n=1), and t(14;16) and del(20) (n=1). Two patients with −7 also carried gene mutations: 1 in CEBPa and 1 IDH2^R140Q. Patients received a median of 4 cycles. All 9 patients are evaluable. The overall response rate (ORR; defined as CR+CRi+PR) is 8/9 (89%) and the CR+CRi rate is 7/9 (78%). Five (56%) patients achieved a complete cytogenetic response, including the patient carrying IDH2R140Q, in whom such mutation became undetectable. Eight-week mortality was 0%. Only 1 (11%) patient has died, unrelated to study drug (after allogeneic-SCT). The median duration of response was 45 days (0–229). Reasons for discontinuation were: transition to allogeneic-SCT (n=5), no pracinostat availability by sponsor (n=2), no response (n=1), and progression to AML (n=1). The combination was well tolerated. All toxicities were grade 1 or 2. The most frequent toxicities were fatigue and nausea (56% each).

The combination of pracinostat and 5-azacitidine was very well tolerated in patients with MDS. The preliminary ORR of 89% is very encouraging, considering that most patients in this study had high-risk cytogenetics and/or had treatment related MDS, both subsets of MDS with very poor prognosis.

Ravandi:Celgene: Honoraria, Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:SBIO: Research Funding.