A phase I study of combretastatin A4 phosphate (CA4P) and bevacizumab in subjects with advanced solid tumors

Abstract

3550 Background: The vascular disruptive agent (VDA) CA4P induces significant tumor necrosis as a single agent. Vascular shut down is reversible and tumors can re-grow due to vascularisation of the surviving tumor rim. Pre-clinical models have demonstrated that the addition of an anti-VEGF antibody to a VDA significantly increases anti-tumor activity. Methods: Patients with advanced solid malignancies received CA4P at 45mg/m2 (cohort 1), 54mg/m2 (cohort 2) or 63mg/m2 (cohort 3) every 14 days followed by bevacizumab 10mg/kg 4 hours later. Functional imaging with DCE-MRI was performed at baseline, after CA4P alone and after cycle 1 CA4P + bevacizumab. Results: 63mg/m2 CA4P + 10mg/kg bevacizumab q14 is the recommended phase II dose. Two grade 3/4 dose limiting toxicities possibly related to study medication were seen. One patient developed transient self-limiting asymptomatc atrial fibrillation after 54mg/m2 CA4P and was withdrawn from study. A patient with metastatic angiosarcoma and a history of haemorrhage experienced grade 3 haemorrhage 2 weeks post treatment. Most common grade 1/2 toxicities were headache, hypertension, pruritis, and pyrexia. Asymptomatic transient self-limiting ECG changes were seen in 3 patients with no evidence of myocardial damage. No partial responses were seen. 9/14 patients experienced disease stabilization for > 12 weeks. 3 patients experienced disease stabilization for > 24 weeks with 2 of these on- going at 47 and 29 weeks respectively at time of data cutoff. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34+ and CD133+ bone marrow progenitors increased following CA4P as did VEGF and GCSF levels. Conclusion: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule with early evidence of clinical activity. CA4P induced profound vascular changes which were maintained by the presence of bevacizumab. CA4P induced an acute rise in circulating bone marrow progenitors which may in part be mediated by GCSF and VEGF release. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oxigene Inc Oxigene Inc Oxigene Inc Oxigene Inc Oxigene Inc