Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas

¹ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
² Cedar Sinai Medical Center, Los Angeles, CA, USA
³ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
⁴ Cleveland Clinic Foundation, Cleveland, OH, USA
⁵ University of Alabama at Birmingham, Birmingham, AL, USA
⁶ Wake Forest University School of Medicine, Hematology and Oncology Medical Center, Winston-Salem, NC, USA
⁷ BioNumerik Pharmaceuticals, Inc., San Antonio, TX, USA

^* To whom correspondence should be addressed. E-mail: grossman{at}jhmi.edu or jfisher@jhmi.edu.

	Abstract

Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m²/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m2 in +EIASD patients and 1.5 mg/m² in -EIASD patients. The mean (±SD) total body clearance of karenitecin was 15.9 ± 9.6 liters/h/m² in +1EIASD patients and 10.2 ± 3.5 liters/h/m² in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.

Key Words: brain cancer, cancer therapy, drug interactions, glioblastoma multiforme, karenitecin

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