A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer.
BACKGROUND
The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy.


METHODS
Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin.


RESULTS
Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma.


CONCLUSIONS
The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.
Rustin
G J
GJ
Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK. grustin@nhs.net
Shreeves
G
G
Nathan
P D
PD
Gaya
A
A
Ganesan
T S
TS
Wang
D
D
Boxall
J
J
Poupard
L
L
Chaplin
D J
DJ
Stratford
M R L
MR
Balkissoon
J
J
Zweifel
M
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001259:Ataxia / Q000139:chemically induced; D016190:Carboplatin / Q000627:therapeutic use* / Q000633:toxicity; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008017:Life Expectancy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use* / Q000633:toxicity; D018579:Patient Selection; D013267:Stilbenes / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity
D013267:Stilbenes; D016190:Carboplatin; C058728:fosbretabulin; D017239:Paclitaxel
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