Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)

Abstract

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.