Phase II Study of Vorinostat in Combination with Idarubicin (Ida) and Cytarabine (ara-C) as Front Line Therapy in Acute Myelogenous Leukemia (AML) or Higher Risk Myelodysplastic Syndrome (MDS).

Abstract 1055 Poster Board I-77 The combination of the histone deacetylase inhibitor vorinostat with Ida and ara-C has synergistic antileukemia activity in a sequence dependent fashion (Blood 2006;108:1174-82; CCR 2009;15:1698-707). The combination of high-dose vorinostat and Ida is safe and active in patients (pts) with relapsed/refractory AML (Kadia et al, submitted). Based on this, we designed a phase II study of vorinostat followed by Ida and ara-C in pts with AML or MDS. Eligibility criteria included previously untreated AML (excluding pts with APL), or int-2 or high risk MDS, age > 65 years, and adequate renal, hepatic and cardiac functions as well as performance status. Schedule for induction therapy is vorinostat 500 mg orally (po) three times a day (TID) for 3 days (days 1 to 3), Ida 12 mg/m2 IV daily x 3 (days 4 to 6) and ara-C (1.5 gm/m2 as a continuous (CI) 24 hours infusion on days 4 to 7). Five cycles of consolidation therapy are planned with same dases of vorinostat (days 1 to 3) but decreased doses of Ida (8 mg/m2 days 4 and 5) and ara-C (0.75 gm/m2 CI x 24 hours on days 4 to 6). Maintenance therapy consists of vorinostat 200 mg po TID daily x 14 days every 28 days for 12 cycles. The study is designed to stop early based on a composite endpoint and predefined stopping rules of progression free survival (PFS) (the study is to stop if a PFS of at least 7 months is not expected to be achieved), toxicity and response rates compared to standard Ida and Ara-C (IA) combination at MD Anderson. Planned interim analyses are performed every 6 months by an independent statistician to monitor the above endpoints. To test the safety of the combination, this study included a “reversed” phase 1 run-in phase starting at the maximal dose of vorinostat planned (500 mg po qd tid x 3 days). Three patients were treated at this dose with no excess toxicity and 3 of 3 pts achieved a response. After this, the phase II portion of the study started. A maximum of 75 pts are to be treated if no stopping rule is met. Currently 52 pts have been enrolled and 45, all with AML, are evaluable for response (median age 53 yeas (range 19-65), 21 (46%) female, 9 (20%) with Flt-3 mutations, 30 (66%) with abnormal cytogenetics, 24 (53%) with t-AML or antecendent MDS, median WBC was 5.5 (range 0.9-110.6). In total 43 (95%) pts had poor risk AML as defined by poor CG or Flt-3 or t-AML/MDS. Induction mortality was 2 (4%), Complete remission (CR) after was one course of therapy was achieved in 35 pts and 1 pt achieved a CRP (incomplete platelet recovery) for an overall response rate of 80%. Seven (15%) pts did not respond to therapy. CR by molecular characteristics are: diploid 13 of 15 (86%), Flt-3 9 of 9 (100%), abnormal CG (20 of 30, 66%). No excess toxicity with the addition of vorinostat has been observed compared to standard IA. Common complications were related to myelosuppresion typical of IA. No excess nausea or vomiting or diarrhea was observed. With a median follow up of 4.2 months (range 0.7 – 13 months), median OS has not been reached and median DFS was 9.5 months. The study continues to be open after two interim analysis, as the PFS is higher than 7 months (expected from standard IA). The median number of courses of consolidation therapy is 2+ (range 0-5) and 4 pts are receiving maintenance therapy without excess toxicity. Markers of induction of autophagy (LC3-II), ROS activiation and NF-Kb signaling are upregulated in pts receiving this therapy. This study indicates that the combination of vorinostat, Ida and ara-C is safe and active in AML. The role of vorinostat in Flt-3 postive leukemias needs to be further studied. A randomized study of Ida and ara-C with or without vorinostat needs to be performed to establish the role of vorinostat in front-line AML therapy. At the current accrual rate, this study will be completed by the ASH meeting. Disclosures: Garcia-Manero:Merck: Research Funding. Off Label Use: Vorinostat is not approved for use in AML or MDS.