Originally published as JCO Early Release 10.1200/JCO.2008.17.9788 on October 27 2008

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Phase I Study of ON 01910.Na, a Novel Modulator of the Polo-Like Kinase 1 Pathway, in Adult Patients With Solid Tumors

Antonio Jimeno, Jing Li, Wells A. Messersmith, Daniel Laheru, Michelle A. Rudek, Manoj Maniar, Manuel Hidalgo, Sharyn D. Baker, Ross C. Donehower

From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; and Onconova Therapeutics Inc, Newtown, PA

Corresponding author: Antonio Jimeno, MD, PhD, University of Colorado Cancer Center, PO Box 6511, Mail Stop 8117, Aurora, CO 80045; e-mail: antonio.jimeno{at}uchsc.edu

Purpose We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G₂/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).

Patients and Methods Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1.

Results Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months.

Conclusion ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.

published online ahead of print at www.jco.org on October 27, 2008

Supported by Onconova Therapeutics, Inc.

Presented in part at the 98th Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA.

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

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