Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data.
OBJECTIVE
Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens.


METHODS
Twelve adult patients were enrolled four on each combination. rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with (1) doxorubicin 50 mg/m(2) every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m(2) every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m(2) with leucovorin 20 mg/m(2) weekly, weeks 1 to 6 every 8 weeks.


RESULTS
The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea (one 5-FU patient), thrombocytopenia (two patients on carboplatin plus paclitaxel), and leukopenia (one patient on carboplatin plus paclitaxel). These toxicities were likely attributable to the chemotherapy component of the regimen. The mean (+/- SD) peak serum level of rhuMAbVEGF was 167 +/- 46 microg/mL, and the mean terminal half-life was 13 days. Total (free plus bound) serum VEGF levels increased from 51 +/- 39 pg/mL (day 0) to 211 +/- 112 (day 49) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy, receiving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumulative or late toxicities.


CONCLUSIONS
rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials.
Margolin
K
K
Department of Medical Oncology and Therapeutics Research, City of Hope National Cancer Center, Duarte, CA 91010, USA. kmargolin@coh.org
Gordon
M S
MS
Holmgren
E
E
Gaudreault
J
J
Novotny
W
W
Fyfe
G
G
Adelman
D
D
Stalter
S
S
Breed
J
J
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel; D002955:Leucovorin; D005472:Fluorouracil