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.

This phase I/II trial is studying the side effects and best dose of eribulin mesylate and to see how well it works in treating patients with locally advanced or metastatic cancer of the urothelium and kidney dysfunction. Drugs used in chemotherapy, such as eribulin mesylate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemotherapy drugs may have different effects in patients who have changes in their kidney function.

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.

• Distal Urethral Cancer
• Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter
• Proximal Urethral Cancer
• Recurrent Bladder Cancer
• Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter
• Recurrent Urethral Cancer
• Regional Transitional Cell Cancer of the Renal Pelvis and Ureter
• Stage III Bladder Cancer
• Stage IV Bladder Cancer
• Transitional Cell Cancer of the Renal Pelvis and Ureter
• Urethral Cancer
• Urethral Cancer Associated With Invasive Bladder Cancer

• Drug: eribulin mesylate
  Given IV
  Other Names:

  • B1939
  • E7389
  • ER-086526
  • halichrondrin B analog
• Other: laboratory biomarker analysis
  correlative study
• Other: pharmacological study
  correlative study
  Other Name: pharmacological studies

Inclusion Criteria:

• Locally advanced or metastatic disease that is not amenable to surgical treatment
• No brain metastasis that is unstable (i.e., presenting with neurologic symptoms that progress or require increasing doses of steroids within a 4-week period) or is untreated (i.e., not radiated)
• Life expectancy > 6 months
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled intercurrent illness including, but not limited to, any of the following: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness or social situations that would limit study compliance
• No more than 2 prior lines of therapy (for patients enrolled in phase I); more than 6 months since prior chemotherapy in the adjuvant setting* [Note: *for patients enrolled at dose level 3 of phase I and all of phase II]
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies
• No concurrent prophylactic granulocyte or platelet colony-stimulating factors
• Measurable disease, defined as >= 1 lesion that can be accurately measured in >= 1 dimension as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan (for patients enrolled in phase II or dose level 3 of phase I)
• Absolute neutrophil count >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• AST and ALT =< 2.5 times ULN

• Patients must have either (a) normal kidney function (i.e. creatinine =< 1.5 X ULN OR calculated creatinine clearance >= 60 mL/min by the modified Cockcroft and Gault Formula - OR a creatinine clearance >= 60 mL/min obtained from a 24-hour urine collection) or (b) moderate or severe renal dysfunction (i.e. creatinine clearance < 60 mL/min and >= 20 mL/min)

  • Patients with symptomatic uremia, uncontrolled edema or unstable serum electrolytes should not enter the trial until such time as they have been stabilized - such patients should be discussed with the Principal Investigator
• Histologically or cytologically confirmed urothelial tract carcinoma
• ECOG performance status (PS) 0-2 or Karnofsky PS 70-100%
• No HIV-positive patients on combination antiretroviral therapy or with CD4+ count ≤ 500/mm³
• No concurrent dialysis