Eribulin Mesylate in Treating Patients With Locally Advanced or Metastatic Cancer of the Urothelium and Kidney Dysfunction

• MTD and RP2D of eribulin mesylate graded according to CTCAE v4.0 (phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  
• Overall response rate calculated as the ratio of the number of eligible patients who experienced a confirmed CR or PR by RECIST v1.1 (phase II) [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  A response rate of 20% or greater would be of interest.
  
  

• Progression-free survival (phase II) [ Time Frame: From the start of treatment on Day 1, until progression, death, or the start of another treatment, assessed up to 12 months ] [ Designated as safety issue: No ]
  Will be summarized with Kaplan-Meier plots and confidence intervals.
  
  
• Overall survival (phase II) [ Time Frame: From the start of treatment on Day 1, until progression, death, or the start of another treatment, assessed up to 12 months ] [ Designated as safety issue: No ]
  Will be summarized with Kaplan-Meier plots and confidence intervals.
  
  

PRIMARY OBJECTIVES:

I. To establish whether E7389 can be given safely to patients with moderate and severe renal dysfunction at 1.4 mg/m2/week (the MTD previously defined for patients with normal renal function) on days 1 and 8 of a 21-day cycle. (Phase I) II. To characterize the pharmacokinetic (PK) profile of E7389 in patients with moderate and severe renal dysfunction. (Phase I) III. To determine the response rate of patients with advanced urothelial carcinomas to E7389 in the first-line setting. (Phase II) IV. To determine the 6-month, progression-free survival and overall survival of patients with advanced urothelial carcinomas treated with E7389. (Phase II) V. To document the toxicity associated with the administration of E7389 to patients with advanced urothelial carcinoma patients and varying degrees of renal dysfunction. (Phase II) VI. To determine the response rate of patients with advanced urothelial carcinomas to E7389 in the setting of progression after prior platinum-based chemotherapy for advanced or recurrent disease, in two cohorts: tubulin-inhibitor treated or tubulin-inhibitor naïve. (Tubulin inhibitors in common use for urothelial cancer include paclitaxel, docetaxel and vinblastine). (Phase II) VII. To determine the 6-month progression-free survival and overall survival of patients with advanced urothelial carcinomas treated with E7389 after platinum-based therapy for recurrent or advanced disease. (Phase II) VIII. To document the toxicity associated with the administration of E7389 to patients with advanced urothelial carcinoma patients in the second line and later setting. (Phase II)

OUTLINE: This is a multicenter, dose-escalation, phase I study followed by an open-label phase II study. Patients in the phase I portion of the study are stratified by renal dysfunction (moderate vs severe).

PHASE I: Patients receive eribulin mesylate intravenously (IV) over 1-2 minutes on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive eribulin mesylate IV over 1-2 minutes on days 1 and 8 at the MTD. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for at least 6 months.