A phase Ib and randomised phase II trial of pazopanib with or without fosbretabulin in advanced recurrent ovarian cancer

Abstract

Background: Prospective trials have validated angiogenesis as a treatment target in ovarian cancer although improvements in PFS have been modest. One potential strategy to improve efficacy is to combine anti‐vascular agents. Fosbretabulin (F) is an intravenous vascular disrupting agent and pazopanib (P) is an oral VEGFR tyrosine kinase inhibitor. Methods: A multi‐centre Phase 1b(P1b)/randomised phase 2 (RP2) trial that recruited women with recurrent epithelial ovarian cancer and a platinum‐free interval of 3‐12 months. Any Bevacizumab had been received ≥6 months prior to recruitment. Phase 1b dose levels ranged from F=54mg/m2 d1,8,15q28d + P=600mg/day (F54+P600) up to F=60mg/m2 d1,8,15q28d+ P=800mg/day. In RP2 participants received either RP2D or P=800mg/day (P800). Primary outcome in P1b was safety plus RP2D and in RP2 was RECIST PFS. Results: 12 and 21 patients were recruited to P1b & RP2 respectively. The RP2D was F54+P600. In the RP2 median PFS was 7.6 months (95%CI 4.1‐not estimated) in F54+P600 group vs. 3.7 months (95%CI 1.0‐8.1) in P800 group (HR 0.30, 95%CI 0.08‐ 1.03, P=0.06). Four patients who received F+P (2 in P1b and 2 in RP2) developed acute hypertension plus reversible secondary cardiac toxicity. The occurrence of cardiac toxicity resulted in premature discontinuation of the trial. Data on circulating biomarkers of angiogenesis collected in in P1b & RP2 will also be presented. Conclusions: F54+P600 appeared effective but was associated with reversible secondary cardiac toxicity that with better hypertension control might have been avoided.