Pazopanib and Vinflunine in Urothelial Cancer of the Bladder
Urothelial carcinoma of the bladder mostly is chemically induced and represents the second prevalent urooncological disease. About 20% of newly diagnosed urothelial carcinoma cases of the bladder are already advanced or metastasized. Before 2008 2009 no second line therapy after failure of primary systemic therapy of advanced / metastatic disease was established outside of clinical trials. The actual standard for this situation was a supportive, symptomatic therapy. Vinflunine has demonstrated improved survival from 4.3 to 6.9 months (p=0.04), with an adequate disease control, good symptom control and with acceptable toxicity. Based on these results, this compound became standard se¬cond line treatment for refractory metastatic bladder cancer disease after failure of platinum-containing therapy. As the prognosis still remains poor, new treatment opportunities have to be explored.
The target-specific therapy with Pazopanib suggests a positive influence of both inductive and perioperative treatment of solid tumors. Pazopanib has been approved by the FDA and the EMA for the treatment of advance renal cell carcinoma. Results for advanced urothelial carcinoma are missing so far as well as data on tolerability of the combination of both vinflunine and pazopanib. As the pharmacodynamic properties as well as the safety profile of both drugs are different, assumption is justified that there might occur additive efficacy effects without addition of adverse outcomes. Aim of the study thus is
- To define the maximum tolerated dose (MTD) of Pazopanib in combination with Vinflunine in a phase-I-setting and
- To further assess efficacy and safety of the combination at the MTD level in phase II.
During the pase-I-part of the study different doses of pazopanib will be added to the standard vinflunine scheme in groups of 6 patients maximum. Dose escalation will only be performed in the next patient group if not more than one out of six patients shows dose-limiting toxicity. Each patient will be treated with the drug combination for a duration of two vinflunine cycles, that is six weeks.
During the phase-II study new patients will be treated with the drug combination at maximum-tolerated dose until disease progression (assessed by RECIST 1.1 procedures).
Advanced Urothelial Cancer of Bladder After Failure of Platinum-containing Therapy.
Drug: Pazopanib as add-on to vinflunine
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Target-specific Therapy With Pazopanib as Add-on to Vinflunine in Patients With Advanced or Metastatic Urothelial Carcinoma of the Bladder After Failure of Platinum-based Treatment|
- Phase I: Definition of the Maximum Tolerated Dose (MTD) of Pazopanib in combination with Vinflunine. [ Time Frame: 6 weeks (two cycles of vinflunine) ] [ Designated as safety issue: Yes ]MTD ist defined as the dose level with dose-limiting toxicity occurring in maximum one out of six patients.
- Phase II: Progression-free survival rate [ Time Frame: 3 months ] [ Designated as safety issue: No ]Progression-free survival will be assessed by means of RECIST 1.1. methodology
- Phase I: Progression-free survival rate, Phase II: Safety profile, overall survival [ Time Frame: Six weeks after first administration of study drug. ] [ Designated as safety issue: Yes ]Progression-free survival will be assessed by means of RECIST 1.1. methodology
|Study Start Date:||March 2011|
|Study Completion Date:||August 2012|
|Primary Completion Date:||January 2012 (Final data collection date for primary outcome measure)|
|Experimental: Pazopanib + Vinflunine||
Drug: Pazopanib as add-on to vinflunine
Patients will receive vinflunine standard regimen (intravenous infusion every three weeks) as specified per drug label plus additional pazopanib as daily oral medication. Doses of pazopanib will be escalated in 200 mg/d steps during phase I up to a maximum of 800 mg/d.
In Phase II the patients will be given pazopanib + vinflunine at maximum tolerated dose.