pazopanib and vinflunine

We comprehensively reviewed current efforts and advances in the field of chemotherapeutic and biologically targeted treatment options after the failure of cisplatin based, first line regimens for urothelial carcinoma.. We searched MEDLINE®, Central®, and meeting abstracts of ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) to identify original articles, reviews and retrospective analyses on second line treatment of urothelial carcinoma. Articles were included in analysis if they described prospective phase II/III studies or larger high quality retrospective studies of second line treatment of urothelial carcinoma.. Although considered a chemosensitive disease, most patients with advanced or metastatic urothelial carcinoma relapse after cisplatin based first line treatment. Today none of the commonly used drugs, ie paclitaxel, carboplatin and/or gemcitabine, are approved by the FDA (Food and Drug Administration) for second line systemic treatment. In Europe vinflunine plus best supportive care is the only option approved by the EMA (European Medicines Agency) with moderate clinical efficacy. Responses to combined chemotherapy approaches are often better but associated with remarkable toxicity. In patients who respond well to first line treatment and, thus, are considered cisplatin sensitive readministration of a platinum based combination regimen may be an option. To date targeted therapies do not have a role in second line treatment of urothelial cancer. Immunotherapeutic strategies to target the PD-1/PD-L1 axis are emerging. In a recent phase I trial evaluating the PD-L1 targeted monoclonal antibody MPDL3280A a promising 43% response rate with good tolerability was achieved, which led to an immediate breakthrough therapy designation by the FDA. Combining chemotherapy with targeted agents, eg weekly paclitaxel and pazopanib, also shows promising activity in this prognostically poor treatment situation.. Response rates and survival are poor after second line chemotherapy for advanced or metastatic urothelial carcinoma. To improve outcomes of salvage treatment novel biologically targeted drugs as monotherapy or as part of a combination with conventional cytostatics are urgently needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Factors; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Gemcitabine; Humans; Indazoles; Neoplasm Recurrence, Local; Paclitaxel; Pemetrexed; Pyrimidines; Salvage Therapy; Sulfonamides; Urinary Bladder Neoplasms; Vinblastine

The role of pazopanib in the second-line setting of refractory metastatic transitional cell carcinoma of the urothelium has not been defined clearly. The aim of this phase I/II trial was to assess the safety, tolerability, and efficacy of combining pazopanib and vinflunine in patients with metastatic transitional cell carcinoma of the urothelium after failure of first-line platinum-containing therapy. From May 2011 to December 2011, five patients were enrolled in this trial. Pazopanib was the investigated compound; four levels were planned (200, 400, 600, and 800 mg/day). Vinflunine was dosed at 280 mg/m for the first dose and 320 mg/m every 3 weeks thereafter. After the definition of a tolerated dose for the combined therapy, a subsequent phase II study was planned. At the starting level, pazopanib 200 mg/day, dose-limiting toxicities were observed in two of five patients. One patient experienced grade 4 febrile neutropenia, which led to treatment discontinuation. A second patient showed grade 3 hepatobiliary disorder with an increase in γ-glutamyltransferase. The study was interrupted at dose level 1 for safety reasons. The initially planned phase II study was therefore not carried out. This phase I study showed that combined therapy of daily pazopanib (200 mg) and vinflunine (280/320 mg/m) every 3 weeks is poorly tolerated in patients with refractory advanced urothelial cancer.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Early Termination of Clinical Trials; Humans; Indazoles; Male; Neutropenia; Organoplatinum Compounds; Palliative Care; Prospective Studies; Pyrimidines; Salvage Therapy; Sulfonamides; Thrombocytopenia; Urologic Neoplasms; Vinblastine