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The combination of the investigational agent MGCD0103 and azacitidine was clinically active in one-third of adults with advanced myelodysplastic syndrome or acute myelogenous leukemia in a phase I/II trial.
Four of 37 patients (11%) achieved complete remission, 5 achieved complete remission without platelet or neutrophil recovery (14%), and 2 achieved partial remission (5%), according to data presented in a poster.
All four with complete remissions had acute myelogenous leukemia, suggesting MGCD0103 may represent a new therapy for them, said investigator Dr. Guillermo García-Manero in an interview.
The rationale for the study was preclinical work demonstrating antitumor synergy between agents that inhibit histone deacetylation and agents that reduce DNA methylation. Aberrant DNA methylation and histone acetylation are common in leukemia.
MGCD0103 is a nonhydroxamate, orally available selective inhibitor of human histone deacetylase (HDAC) isoforms 1, 2, 3, and 11. Azacitidine (Vidaza) is a DNA hypomethylation inhibitor approved for myelodysplastic syndrome and chronic myelomonocytic leukemia. It is clinically active in patients with acute myelogenous leukemia.
Patients received azacitidine 75 mg/m² subcutaneously daily for 7 days of each 28-day treatment cycle and oral MGCD0103 three times weekly starting on day 5 of every cycle at an initial dose of 35 mg. MGCD0103 also was evaluated at 60, 90, 110, and 135 mg.
Clinical activity at doses of 60, 90, and 110 mg was reported in 11 patients (30%) in the study, supported by MethylGene Inc. and Pharmion Corp., which have a licensing and collaborative agreement for MGCD0103.
HDAC activity was inhibited after treatment in most patients, said Dr. García-Manero of the M.D. Anderson Cancer Center in Houston. HDAC activity was elevated at baseline in peripheral blood buffy coat cells and bone marrow of 26 patients, when compared with healthy volunteers. Induction of IL-6 also appeared to increase with dose.
Dose-limiting toxicities included nausea, vomiting, diarrhea, dehydration, and anorexia, and occurred in seven patients.
The maximum tolerated dose of MGCD0103 was initially determined to be 110 mg, but the incidence of dose-limiting toxicities was considered too high. Enrollment in Phase II is continuing at a dose of 90 mg.
No pharmacokinetic characteristics of either drug were altered by coadministration, the investigators reported.
García-Manero G. et al. 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.