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A Phase I Pharmacokinetic Study of HMN-214, a Novel Oral Stilbene Derivative with Polo-Like Kinase-1–Interacting Properties, in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Arizona Cancer Center, University of Arizona, Tucson, Arizona; ² Cancer Care Associates, Tulsa, Oakland; and ³ TGen, Phoenix, Arizona

Requests for reprints: Linda Garland, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Suite 1969E, Tucson, AZ 85724. Phone: 520-626-3434; Fax: 520-626-2225; E-mail: lgarland{at}azcc.arizona.edu.

Purpose: HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose.

Experimental Design: Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m²/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1.

Results: A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m²/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m²/d. The maximum tolerated dose was defined as 8 mg/m²/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not C_max. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted.

Conclusions: The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m²/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).