Phase I Trial of Combretastatin A4 Phosphate (CA4P) in Combination with Bevacizumab in Patients with Advanced Cancer
Clinical Cancer Research, 06/04/2012
Nathan P et al. - Combretastatin A4 phosphate (CA4P) in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.Methods
- Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m2 on day 1, day 8, and then every 14 days.
- Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P.
- Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab.
- A total of 63 mg/m2 CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose.
- A total of 15 patients were enrolled.
- Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage.
- Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia.
- Asymptomatic electrocardiographic changes were seen in five patients.
- Nine of 14 patients experienced disease stabilization.
- A patient with ovarian cancer had a CA125 response lasting for more than a year.
- 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 granulocyte colony-stimulating factor levels.