The PACOVAR-trial: A multicenter phase I trial of pazopanib (GW786034) and metronomic cyclophosphamide in patients with recurrent platinum-resistant ovarian cancer

Background: A combined therapy consisting of the investigational anti-VEGFR tyrosine kinase inhibitor pazopanib (GW786034, paz) and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent platinum-resistant epithelial ovarian cancer (EOC).

Methods: This study was designed as a multicenter phase I trial evaluating the optimal dose for paz as well as activity and tolerability of a combination regimen consisting of paz and metronomic cyclophosphamide 50 mg daily p.o. in monthly cycles. Patients with histologically proven recurrent platinum-resistant EOC were included. Toxicity and survival data were obtained.

Results: 16 patients were treated within this trial, mean age was 66 years. Median number of administered cycles was 6, with three patients being treated for at least 13 months. Median progression-free survival (PFS) and overall survival (OS) were 6.7 months and 15.2 months, respectively. A total of 254 adverse events (AE) occurred. The most often documented AE were leukopenia in 14.6% of the cases, followed by elevation of ALT (10.2%) and elevation of AST (9.5%). Moreover, 27 AE were probably or very likely related to cyclophosphamide (10.6%) and 55 AE were probably or very likely related to paz (21.7%). A total of five serious adverse events (SAE) occurred in four patients. The events were hypertension as well as sepsis, vomiting, ileus and fatigue. Besides sepsis, which had a fatal outcome, all other SAE were recovered.

Conclusion: Paz 600 mg daily p.o. and metronomic cyclophosphamide 50 mg daily p.o. is a feasible regimen for patients with platinum-resistant recurrent, pre-treated EOC.