Doubling Up on MDS/CMML: Left Hook + Right Hook = T.K.O., Or Just "More Weight"?

A Randomized Phase II Study of Azacitidine in Combination With Lenalidomide versus Azacitidine in Combination With Vorinostat versus Azacitidine Alone for Higher-Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

National Cancer Institute (NCI); a Southwest Oncology Group (SWOG)-led Intergroup Study with participation from The Alliance (including the former Cancer and Acute Leukemia Group B and North Central Cancer Treatment Group), the Eastern Cooperative Oncology Group (ECOG), and NCI-Canada

NCT01522976

More than 50 trial sites across the United States and Canada are participating in the study.

240 patients (80 patients randomized per treatment arm). This trial is not yet open for participant recruitment.

Eligible patients are ≥ 18 years of age, have a Zubrod performance status of 0-2, have been diagnosed with higher-risk MDS or with CMML, and have not previously received azacitidine, decitabine, lenalidomide, or vorinostat. For this study, higher-risk MDS is defined as 5 to 19 percent marrow blasts or an International Prognostic Scoring System risk stratification of either intermediate-2 or high risk. Patients are randomized in a 1:1:1 manner to receive either azacitidine 75 mg/m2 daily for seven days subcutaneously or intravenously every 28 days (azacitidine monotherapy); parenteral azacitidine plus oral lenalidomide, 10 mg daily for 21 out of every 28 days; or parenteral azacitidine plus concomitant oral vorinostat 600 mg per day. The primary objective is to compare overall response rate (ORR) between the three study arms using the 2006 International Working Group (IWG 2006) standardized response criteria for MDS (Cheson BD et al. Blood. 2006). The study is powered to have an 81 percent probability of detecting a 20 percent difference in ORR with alpha 0.05 in the comparison of either combination arm versus azacitidine monotherapy. Secondary study objectives include the following: comparison of rates of disease progression and overall survival between the treatment arms, correlation of outcomes with pre-treatment cytogenetic results, and evaluation of the comparative safety and tolerability of each regimen.

Based on a prospective, randomized study that showed a statistically significant enhancement of median survival from 15 months in the conventional therapy control arm to 24 months in the experimental treatment arm (Fenaux P et al. Lancet Oncology. 2009), azacitidine has become the standard of care for patients with higher-risk MDS. However, complete responses (CRs) with azacitidine monotherapy are uncommon (observed in less than 25 percent of treated patients) and relatively short-lived (median response duration of less than two years). In an effort to augment response rates and response duration, combination approaches that build on the backbone of azacitidine’s success are being investigated. A phase I/II trial conducted by Mikkael Sekeres (the principal investigator of this trial) and his colleagues in the Bone Marrow Failure Consortium that combined azacitidine with lenalidomide showed an overall response rate of 72 percent, including a 42 percent CR rate, in 36 evaluable patients (Sekeres M et al. Blood. 2011 ASH Annual Meeting abstract #607; Sekeres M et al. J Clin Oncol. 2010). The biologic basis for the improved efficacy of this combination is unclear. Based on effects on gene expression, in vitro synergism between hypomethylating agents (HMAs), such as azacitidine, and deacetylase inhibitors (DACIs), such as vorinostat, has been observed, leading to a number of trials using HMA/DACI combinations. Two early-phase studies have evaluated azacitidine in combination with vorinostat. One such study (Silverman LR et al. Blood. 2008 ASH Annual Meeting abstract #3656) demonstrated an impressive 86 percent response rate in patients with higher-risk MDS, while another study, which enrolled 30 patients with MDS or acute myeloid leukemia who were ineligible for other clinical trials due to comorbid conditions, found a 30 percent ORR (Garcia-Manero G et al. Blood. 2011 ASH Annual Meeting abstract #608).

MDS drug development is moving forward again after a relatively torpid period following FDA approval between 2004 and 2006 of the three currently available MDS disease-modifying therapies. Hopefully, this study, with “two chances to win” over azacitidine monotherapy, will fare better than E1905, which was a randomized, 150-patient, phase II cooperative group trial that compared azacitidine monotherapy with the combination of azacitidine and the DACI entinostat/ MS-275 (Prebet T et al. Blood. 2010 ASH Annual Meeting abstract #601). Combination therapy did not improve response rate in the E1905 study. While it is perhaps unfortunate that the current trial is not powered to detect a survival difference as the primary endpoint, such a design would have required a prohibitively large number of patients.