A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: A New York Cancer Consortium

7000 Background: Epigenetic silencing plays a role in MDS and AML. The hypomethylating agent azacitidine (azaC) alters the natural history of MDS and improves survival (Silverman JCO 2002, Fenaux Blood 2007). In AML, azaC produces responses and appears to affect survival (Silverman JCO 2006). Time to response is slow, median 4 cycles and CR+PR ranges from 7 to 27%. Vorinostat has demonstrated single agent activity in MDS and AML (Garcia-Manero Blood 2006). In sequenced combination vorinostat synergizes with azaC to reactivate epigenetically silenced genes. Methods: For the phase I component eligible patients (pts) were entered into one of 8 cohorts with the combination of vorinostat and azaC in a 3+3 dose escalating de-escalating design (see table). Results: As of the data cut for this submission 16 pts are evaluable for toxicity and the first 6 cohorts have been completed, full data will be available for the meeting. Among the 20 pts entered: 14 have MDS, 6 AML, median age 68. Responses among evaluable pts have occurred in 9 of 11 (82%); 5 CR, 1 CRi, (CR+CRi=55%), 3 HI, 2 SD. Median time to response is 2 cycles. Among pts with poor risk cytogenetics 4/5 responded (CR, CRi, 2 HI). A total of 90 cycles have been administered, range 1 to 11 with a mean 4.7 cycles. Only 3 pts have come off study for progression, co-morbidities, or consent withdrawal. No grade 3 or 4 non-hematologic toxicities were observed. Grade 2 anorexia and fatigue occurred in cycle 1 in 31.6% and 57.9% of pts, respectively. Grade 2 fatigue occurred in 89% in cohorts 2, 3 and 4. Correlative studies of effects on gene expression and methylation are underway. Conclusion: The combination is safe, tolerated in repetitive cycles and appears superior for time to response, overall response and CR rate compared to azaC alone. The phase II study will utilize the optimal epigenetic and clinical dose to determine this. Cohort Dosing in Relation to Adverse Events and Response Cohort No of Pts AzaC dose mg/m2/d 1–7 SQ Vorinostat Dose mg/d Total Dose AzaC/Vorinostat Adverse Events anorexia/Fatigue grade Response 1 3 55 200 bid x 14d 385/5600 1;0;0/2;1;2 CR;CR;CR 2 3 55 200 tid x 14d 385/8400 2;2;2/2;2;2 CR;SD;CRi 3 3 75 200 tid x 14d 525/8400 1;0;1/2;0;2 SD;CR;HI 4 3 75 200 bid x 14d 525/5600 2;1;2/2;2;2 IE;HI;HI 5 4 75 300 bid x 7d 525/4200 1;2;0/2;1;0 TE;TE;TE 6 3 55 300 bid x 7d 385/4200 TE;TE;TE TE;TE;TE 7 1 55 200 bid x 7d 385/2800 TE TE 8 0 55 300 bid x 3d 385/1800 NA NA Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion