Originally published as JCO Early Release 10.1200/JCO.2005.03.4801 on March 6 2006

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Phase I Study of Antisense Oligonucleotide Against Vascular Endothelial Growth Factor: Decrease in Plasma Vascular Endothelial Growth Factor With Potential Clinical Efficacy

Alexandra M. Levine, Anil Tulpule, David I. Quinn, Gerardo Gorospe, III, D. Lynne Smith, Laurie Hornor, William D. Boswell, Byron M. Espina, Susan G. Groshen, Rizwan Masood, Parkash S. Gill

From the Departments of Medicine, Pathology, and Preventive Medicine, University of Southern California (USC), Keck School of Medicine, Los Angeles, CA

Address reprint requests to Alexandra M. Levine, MD, USC/Norris Comprehensive Cancer Center and Hospital, 1441 Eastlake Ave, Suite 3468, Los Angeles, CA 90033; e-mail: alevine{at}usc.edu

PURPOSE: Vascular endothelial growth factor antisense (VEGF-AS) is an antisense oligonucleotide that targets VEGF, inhibiting angiogenesis and tumor cell proliferation. This study established the safety, biologic effects, and pharmacokinetics of VEGF-AS in 51 patients with advanced malignancies.

METHODS: VEGF-AS was administered as a 2-hour infusion daily for 5 consecutive days for only one cycle on the first four dose levels, and then administered daily for 5 days every other week for up to 4 months on subsequent levels. Pharmacokinetics, tumor response, and the effect on plasma VEGF levels were determined.

RESULTS: The maximum-tolerated dose was 200 mg/m². Dose-limiting toxicities included grade 4 fever, and pulmonary embolism in one patient each at 250 mg/m². Mild anemia, fever, fatigue, and gastrointestinal complaints were the most common adverse events. VEGF-AS t_1/2ß (beta-phase terminal half-life of drug concentration) was 2.25 hours (range, 1.97 to 2.95 hours). Mean plasma VEGF-A (P = .002) and VEGF-C (P = .01) levels decreased 24 hours postinfusion, with a trend towards greater decreases at higher dose levels. At the maximum-tolerated dose, five of six patients demonstrated reductions in plasma VEGF. Clinical responses included complete remission in one patient with AIDS-Kaposi's sarcoma, a mixed but dramatic response in one patient with cutaneous T-cell lymphoma, and prolongation of progression-free survival compared with that obtained on the immediate prior regimen in six patients (12%) with renal cell, bronchoalveolar, small cell lung, thyroid, and ovarian carcinomas, and chondrosarcoma, respectively.

CONCLUSION: VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.

Supported by in part by VasGene Therapeutics Inc, an L.K. Whittier Foundation grant to the USC/Norris Comprehensive Cancer Center and Hospital, Concern Foundation for Cancer Research, The Ezralow Family Foundation, and research Grant No. 1R01 CA 79218 from National Institutes of Health and the National Cancer Institute (Bethesda, MD).

Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 5-9, 2003; the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the 29th Congress of the European Society of Medical Oncology, Vienna, Austria, October 29-November 2, 2004.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

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