Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer

Abstract

Purpose Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. Patients and Methods The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. Results In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. Conclusion In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.

The combination of paclitaxel and carboplatin as second-line chemotherapy can be a preferred regimen for patients with urothelial carcinoma after the failure of gemcitabine and cisplatin chemotherapy

“…Several studies have examined the various prognostic factors of patients. Buti et al identified nine studies (29)(30)(31)(32)(33)(34)(35)(36)(37)) that aimed at evaluate the prognostic factors of 1,273 patients in a second-line treatment setting. In most studies, PS, Hb, and visceral metastasis were identified as the main independent prognostic factors for OS (38).…”

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

“…Most responses to chemotherapy are partial and of short duration with median overall survival for metastatic disease between 12 and 15 months. 3 While recent advances in systemic therapy have demonstrated a slight improvement in overall survival, prognosis remains poor with a substantial need for clinical improvement.…”

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

“…Others have shown that dasatinib, nilotinib, and imatinib are competitive inhibitors of P-glycoprotein and BCRP, meaning that they are substrates at low concentrations, while they inhibit transport function at high concentrations [24]. Although these data indicate the potential for kinase inhibitors to be used as tools to overcome chemoresistance through ABC efflux transporter inhibition in vitro, several clinical trials employing kinase inhibitors for mitigation of chemoresistance have been unable to definitively demonstrate improvements in progression free survival and/or overall survival of patients [25][26][27][28].…”