Safety and Activity of Sorafenib in Addition to Vinflunine in Post‐Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial

LESSONS LEARNED. First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post‐platinum metastatic urothelial cancer (mUC) patients. A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia. An overall response rate of 41% to second‐line vinflunine plus sorafenib treatment in patients with platinum‐resistant mUC was confirmed. BACKGROUND. Platinum‐progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC. METHODS. In addition to standard dose of vinflunine (320 or 280 mg/m(2)), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose‐escalation phase I design. RESULTS. Twenty‐two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m(2) and 17 received 280 mg/m(2). The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m(2) was 600 mg, and with vinflunine 320 mg/m(2) it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy‐evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8–41.7). CONCLUSION. The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m(2) plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m(2). The ORR of 41% to this second‐line combination treatment of mUC is noteworthy and supports further trials.