A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer

Abstract

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.

Conclusion: 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.

Figure 1

(A) Systolic and diastolic blood pressure (mean±s.d.) before and every hour for 6 h after combretastatin A4 phosphate (CA4P) infusion in all 46 patients during the first cycle. ^*P<0.05 vs pretreatment measurement. n=46 patients. (B) Relationship between CA4P dose (mg m⁻²) and systolic blood pressure changes (in percent) 1 h after CA4P infusion during the first cycle with fitted regression line. n=46 patients. (C) Blood pressure changes in a patient with hypertension after CA4P, responding to 0.3 mg sublingual glyceryl trinitrate.