Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies.
SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).
Stopeck
Alison
A
Arizona Cancer Center, Tucson, Arizona 85724-5024, USA.
Sheldon
Marrae
M
Vahedian
Mahmood
M
Cropp
Gillian
G
Gosalia
Rishi
R
Hannah
Alison
A
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D016228:Endothelial Growth Factors / Q000652:urine; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000652:urine; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000652:urine; D008222:Lymphokines / Q000652:urine; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016879:Salvage Therapy; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014839:Vomiting / Q000139:chemically induced
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C116890:Semaxinib