Originally published as JCO Early Release 10.1200/JCO.2008.17.2064 on September 29 2008

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Phase I and Pharmacokinetic Study of YM155, a Small-Molecule Inhibitor of Survivin

Anthony W. Tolcher, Alain Mita, Lionel D. Lewis, Christopher R. Garrett, Elizabeth Till, Adil I. Daud, Amita Patnaik, Kyri Papadopoulos, Chris Takimoto, Pamela Bartels, Anne Keating, Scott Antonia

From the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; Norton Cotton Cancer Center at the Dartmouth Hitchcock Medical Center, Lebanon, NH; H. Lee Moffitt Cancer Center, Tampa, FL; and Astellas Pharma US Inc, Deerfield IL

Corresponding author: Anthony W. Tolcher, MD, FRCPC, South Texas Accelerated Research Therapeutics, San Antonio, TX 78229; e-mail: atolcher{at}start.stoh.com

Purpose To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin.

Patients and Methods Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion.

Results Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m²/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m². The MTD was 4.8 mg/m². At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non–small-cell lung cancer had a minor response.

Conclusion YM155 can be administered safely at 4.8 mg/m²/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

published online ahead of print at www.jco.org on September 29, 2008.

Supported by Astellas Pharma US.

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

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