A randomized phase 2 trial of combretatstatin A4 phosphate (CA4P) in combination with paclitaxel and carboplatin to evaluate safety and efficacy in subjects with advanced imageable malignancies

Abstract

14060 Background: CA4P is the lead compound in a class of agents termed Vascular Disrupting Agents. Phase I studies of CA4P demonstrated toxicities that do not overlap those of chemotherapy. In vitro studies show synergistic cytotoxicity for CA4P and chemotherapy. This study was designed to assess safety, toxicity and tumor perfusion of CA4P at 2 doses when combined with paclitaxel and carboplatin at fixed doses. Methods: A one stage, randomized trial for subjects with imageable tumors by DCE-MRI for perfusion. Subjects received either 45 or 63 mg/m2 CA4P IV on Days 1, 8, and 15, then 200 mg/m2 paclitaxel and AUC 6 carboplatin on Day 2 of each 21 day cycle. After completion of 6 cycles, subjects could continue with CA4P alone. DCE-MRI was measured prior and 24 hours after the first dose of CA4P. Results: 13 subjects were accrued from 3/05–11/05. 78 cycles were administered and 1 subject continues active therapy on cycle 19. The median number of cycles administered was 6. Both 45 and 63 CA4P with paclitaxel/carboplatin were well tolerated. The most frequent adverse events are listed in Table 1 . Grade 3–4 AEs were similar between the two dose groups. Table 1 : Most Frequent AEs by CA4P Dose DCE-MRI data showed a mean reduction in blood flow for both dose groups (46% vs. 19% respectively) confirming CA4P’s tumor vascular disrupting capabilities. Tumor responses were observed and were similar between both dose groups. Best overall response through cycle 6 was 3 PR, and 6 SD. Two subjects with thyroid cancer were randomized to the low dose group and completed cycle 6. The 1st had SD and progressed after cycle 6. The 2nd achieved PR and progressed after 8 cycles. These subjects also had the greatest reduction in tumor blood flow. Ktrans was reduced by 73 and 79% 24 hours post CA4P. Conclusion: These doses of CA4P in combination with paclitaxel and carboplatin were well tolerated, demonstrated anti-tumor activity and reduction of tumor blood flow. [Table: see text] No significant financial relationships to disclose.