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


CONCLUSIONS
VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.
Levine
Alexandra M
AM
Department of Medicine, University of Southern California (USC), Keck School of Medicine, Los Angeles, CA 90033, USA. alevine@usc.edu
Tulpule
Anil
A
Quinn
David I
DI
Gorospe
Gerardo
G
Smith
D Lynne
DL
Hornor
Laurie
L
Boswell
William D
WD
Espina
Byron M
BM
Groshen
Susan G
SG
Masood
Rizwan
R
Gill
Parkash S
PS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood; D042582:Vascular Endothelial Growth Factor C / Q000097:blood
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C