Toucan: A Randomised Phase Ii Trial Of Carboplatin And Gemcitabine Plus /- Vandetanib In First Line Treatment Of Advanced Urothelial Cell Cancer In Patients Who Are Not Suitable To Receive Cisplatin.

Background: Whilst cisplatin combination therapy remains the standard of care for patients with advanced urothelial cancers, many patients are unsuitable for cisplatin and go on to receive carboplatin combination therapy. Although responses are frequent, overall outcomes remain poor, and there is a high unmet need for more effective first line treatment. Vandetanib is a well-tolerated, oral inhibitor of vascular and epidermal growth factor receptor tyrosine kinases, both of which are implicated in the pathogenesis of urothelial cancers. Methods: Patients with metastatic or inoperable urothelial cancer who had no prior chemotherapy and were unsuitable for cisplatin were randomly allocated to receive carboplatin (AUC 4.5, day 1) plus gemcitabine (1000mg/m2, days 1 and 8) plus either vandetanib (100mg od, days 1-21) (GCV) or matching placebo (GCP) in 21-day cycles up to a total of 6 cycles. Treatment allocation was double-blind. There was a planned safety review after the first 40 patients had received at least one cycle. The primary endpoint was progression free survival (PFS). Sample size (n=82) was calculated using a one-sided alpha of 0.2 and power 80% to detect a HR of 0.65 for PFS. We present the final efficacy results. The trial was coordinated by the Wales Cancer Trials Unit at Cardiff University and funded by Cancer Research UK (CRUK/09/024) and AstraZeneca. Results: Of 82 patients, 40 received GCV. 62 (76%) had a bladder primary, and 56 (68%) had poor renal function. The arms were well balanced except for age u003e 75 (13 (16%) GCV, 23 (28%) GCP). Median PFS was 8.5 months (m) (95% CI 6.0, 9.7) and 8.8 m (5.8, 9.0) for GCV and GCP respectively (adjusted hazard ratio (HR) 0.93 (0.50, 1.71), P=0.89). Overall survival was 10.8 m (8.0, 13.0) and 13.8 m (11.1, 16.6) for GCV and GCP respectively (adjusted HR 1.38 (0.77, 2.46), P=0.24). Response rates were 50% (n=20) and 55% (n=23) for GCV and GCP. All-grade adverse events were similar but there were significantly more grade 3+ events in the GCV arm. Conclusion: Vandetanib did not improve efficacy of chemotherapy but increased toxicity in advanced urothelial cancer not suitable for cisplatin. Clinical trial information: 68146831.