A phase I dose-escalation trial of 2-deoxy- d -glucose alone or combined with docetaxel in patients with advanced solid
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CLINICAL TRIAL REPORT
A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors Luis E. Raez • Kyriakos Papadopoulos • Alejandro D. Ricart • E. Gabriella Chiorean Robert S. DiPaola • Mark N. Stein • Caio M. Rocha Lima • James J. Schlesselman • Khaled Tolba • Virginia K. Langmuir • Stewart Kroll • Donald T. Jung • Metin Kurtoglu • Joseph Rosenblatt • Theodore J. Lampidis
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Received: 19 June 2012 / Accepted: 25 November 2012 / Published online: 11 December 2012 Ó Springer-Verlag Berlin Heidelberg 2012
Abstract Purpose This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors. Methods A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and Presented in part at the 2005 and 2007 ASCO Annual Meetings, 2006 AACR Annual Meeting and the 2006 Fourth International Chicago Symposium on Malignancies of the Chest and Head and Neck. Trial registry number: NCT00096707. L. E. Raez C. M. Rocha Lima J. J. Schlesselman K. Tolba J. Rosenblatt Department of Medicine, Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101, USA K. Papadopoulos A. D. Ricart Institute for Drug Development, San Antonio, TX, USA E. G. Chiorean Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA R. S. DiPaola M. N. Stein UMDNJ-Cancer Institute of New Jersey, New Brunswick, NJ, USA V. K. Langmuir S. Kroll D. T. Jung Threshold Pharmaceuticals, Redwood City, CA, USA M. Kurtoglu T. J. Lampidis (&) Department of Cell Biology (R-124), Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, P.O. Box 016960, Miami, FL 33101, USA e-mail: [email protected]
docetaxel was administered intravenously at 30 mg/m2 for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles. Results Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63–88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no
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