The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation

![Graphic][1] Background The hypomethylating agent (HMA) azaC reverses epigenetic silencing and is the first agent demonstrated to improve survival in patients with higher-risk MDS (Silverman et al JCO 2002, Fenaux et al Lancet Oncology 2009). Time to initial response with single agent azaC, is 3 to 4 cycles, the CR rate ranges from 7 to 17% and overall response is 45-50%. Vorinostat, a histone deacetylase inhibitor (HDACI) which inhibits class I and II HDAC, has demonstrated single agent activity in patients with MDS with responses of 20% (Garcia-Manero Blood 2006). In vitro the 2 agents are synergistic in reactivating epigenetically silenced genes. The effect is sequence-dependent requiring exposure to the HMA first followed by the HDAC. We conducted a phase I pilot study of escalating and de-escalating doses of the 2 drugs in combination in 8 cohorts and demonstrated broad activity with responses ranging up to 80% across all of the cohorts tested (Blood 2008). Purpose To determine the response rate of patients treated with the combination of vorinostat and azacitidine at the doses established as safe and effective in Phase I in an expanded cohort of patients with MDS. Methods In the phase II component 3 schedules of the combination were chosen based on response and adverse event profile for further evaluation. Eligible patients were entered into one of 3 cohorts with the combination (see [table 1][2]): cohort 1: azaC 55 mg/m2/d 1-7 SC, vorinostat 200mg po Bid d3-16; cohort 2: azaC 75 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3-9; cohort 3: azaC 55 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3- 9. Patients with IPSS int-1, -2 and high-risk disease were eligible. Patients with secondary MDS were eligible, those with AML were excluded. Using a simon 2 stage design 13 patients were entered in each cohort and assessed for response, scored according to IWG 2006 criteria and toxicity. View this table: Table 1 Results 40 patients have been entered and 39 (21 male, 18 female) are evaluable for toxicity and 33 for response, 1 pt was registered but never treated. IPSS classification among the 39 patients: int-1 8; int-2 12; high-risk 12; unclassified 7, with median age 67 (23-79). Responses among evaluable patients have occurred in 23 of 33 (70%); 10 CR, 4 CRi, (CR+CRi=42%) 9 HI, 5 SD, 5 NR. Median time to response is 2 cycles (8 weeks). Responses by cohort ([table 1][2]) are 70%, 73% and 67% for cohort 1, 2 and 3, respectively. Analysis for the MDS clone at the time of best response demonstrated the persistence of the clone in 45% of patients as marked by cytogenetic or FISH abnormalities, suggesting a modulating rather than cytotoxic effect of the combination on the clone. Cycles administered, range from 1 to 26+ with a median of 6 cycles. Median duration of response is 16 months overall and 9.5, 23 and 27 months, respectively for cohorts 1, 2 and 3. Eighteen patients have come off study for: death or due to disease complications (6); co-morbidities (2); consent withdrawal (5); and withdrawal for stem cell transplant (3). Median OS is 21.1 months and is 10.1, 37.4 and 19 months for cohorts 1, 2, and 3 respectively (NS). Grade 3 fatigue occurred during cycle 1, 2 or 3 in cohort 1 (8%), cohort 2 (16%) and cohort 3 (8%). GI toxicity grade 3 (vomiting, diarrhea, dehydration) occurred in 8% of patients in each of the cohorts. There was no suggestion of cumulative toxicity for either fatigue or GI adverse events. Correlative biologic study analysis is underway. Conclusion The combination of azaC and vorinostat can be safely administered, and is well tolerated in repetitive cycles. The dose of azaC in cohort 2 adheres to the FDA approved dose and schedule. OR and CR rates and time to initial response are comparable among the cohorts and these data suggest that the combination is superior to published results of azaC alone. Cohorts 2 and 3, with vorinostat administered for 7 days, appears to be associated with longer response duration and OS. An intergroup study (SWOG-S1117) comparing azaC and vorinostat to either azaC alone or combined with lenalidomide is underway utilizing the doses and schedule in cohort 2 from this study. Correlative studies that may shed light on mechanism of action or guide patient selection are being conducted. Supported in part by NYCC- N01 CM-62204 and the Henry and Mickey Taub Foundation. Disclosures: Silverman: Merck: Research Funding. Off Label Use: vorinostat for treatment of patients with a myelodysplastic syndrome investigational use. [1]: /embed/inline-graphic-2.gif [2]: #T1