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Phase I Study of MGCD0103 Given As a Three-Times-Per-Week Oral Dose in Patients With Advanced Solid Tumors

Lillian L. Siu, Roberto Pili, Ignacio Duran, Wells A. Messersmith, Eric X. Chen, Rana Sullivan, Martha MacLean, Serina King, Shirley Brown, Gregory K. Reid, Zuomei Li, Ann M. Kalita, Eric J. Laille, Jeffrey M. Besterman, Robert E. Martell, Michael A. Carducci

From the Princess Margaret Hospital, Toronto; MethylGene Inc, Montreal, Canada; Kimmel Cancer Center at Johns Hopkins, Baltimore, MD; and Pharmion Inc, Boulder, CO

Corresponding author: Lillian L. Siu, MD, FRCPC, Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Ste 5-718, Toronto, Ontario, M5G 2M9, Canada; e-mail: lillian.siu{at}uhn.on.ca

Purpose: MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies.

Patients and Methods: A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs.

Results: Six dose levels ranging from 12.5 to 56 mg/m²/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m²/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m²/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103.

Conclusion: At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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