Phase I study of antisense oligonucleotide against vascular endothelial growth factor: decrease in plasma vascular endothelial growth factor with potential clinical efficacy.

J Clin Oncol 2006 Apr 6;24(11):1712-9. Epub 2006 Mar 6.

Department of Medicine, University of Southern California (USC), Keck School of Medicine, Los Angeles, CA 90033, USA.

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(1/2beta) (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.

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2005.03.4801DOI Listing
April 2006
5 Reads

Publication Analysis

Top Keywords

growth factor
12
endothelial growth
12
vascular endothelial
12
plasma vegf
8
clinical efficacy
8
dose levels
8
maximum-tolerated dose
8
antisense oligonucleotide
8
biologic effects
8
vegf-as
5
levels
5
fatigue gastrointestinal
4
fever fatigue
4
patients 12%
4
anemia fever
4
renal cell
4
mild anemia
4
mg/m2 mild
4
12% renal
4
common adverse
4

Altmetric Statistics

Similar Publications