A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.
OBJECTIVE
This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.


METHODS
Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib.


RESULTS
Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months.


CONCLUSIONS
The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.
Mita
Monica M
MM
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.
Rowinsky
Eric K
EK
Forero
Leonardo
L
Eckhart
S Gail
SG
Izbicka
Elzbieta
E
Weiss
Geoffrey R
GR
Beeram
Muralidhar
M
Mita
Alain C
AC
de Bono
Johann S
JS
Tolcher
Anthony W
AW
Hammond
Lisa A
LA
Simmons
Paul
P
Berg
Kristin
K
Takimoto
Chris
C
Patnaik
Amita
A
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001247:Asthenia / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013792:Thalidomide / Q000009:adverse effects / Q000493:pharmacokinetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000652:urine; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000652:urine; D020246:Venous Thrombosis / Q000139:chemically induced
D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; C116890:Semaxinib