An Open-Label, Multicenter, Randomized Phase Ib/II Study of Eribulin Mesylate Administered in Combination With Gemcitabine Plus Cisplatin Versus Gemcitabine Plus Cisplatin Alone as First-Line Therapy for Locally Advanced or Metastatic Bladder Cancer

Inclusion Criteria

Inclusion Criteria

Patients may be entered in the study only if they meet all of the following criteria:

1. Male or female patient >18 years of age;

2. Histologically or cytologically confirmed, locally advanced Stage 4 (eg, T4b) or
metastatic transitional cell cancer of the bladder; including other transitional cell
cancers of the urothelium (prostate, urethra, ureter, and renal pelvis)

3. Not previously treated with systemic chemotherapy for metastatic bladder cancer (one
regimen of adjuvant or neoadjuvant chemotherapy is permitted). Patients must have a
disease-free interval of 6 months after adjuvant therapy;

4. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid
Tumors version 1.1 (RECIST version 1.1) guidelines;

5. Life expectancy of ≥3 months;

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1; 7. Patients
must have active bowel function defined as at least 3 bowel movements per week
according to subject history and must be willing to maintain a diary of bowel
function prior to dosing and continuing through completion of study treatment.
Laxatives may be used to maintain adequate bowel function;

8. Patients must have adequate renal function as evidenced by calculated creatinine
clearance ≥55 mL/min per the Cockcroft and Gault formula; 9. Patients must have adequate
bone marrow function as evidenced by absolute neutrophil count (ANC) ≥1.5 X 109/L,
hemoglobin ≥10.0 g/dL (a hemoglobin <10.0 g/dL at Screening is acceptable if it is
corrected to ≥10.0 g/dL by growth factor or transfusion prior to first dose), and platelet
count ≥100 X 109/L; 10. Patients must have adequate liver function as evidenced by
bilirubin ≤1.5 times the upper limit of the normal range (ULN), and alkaline phosphatase,
alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 X ULN (in the case
of liver metastases, ≤5 X ULN). If there are bone metastases, liver-specific alkaline
phosphatase may be separated from the total and used to assess liver function instead of
total alkaline phosphatase; 11. Male or female patients of child-producing potential must
agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy
measures during the study and for 90 days after the last day of treatment; 12. Females of
childbearing potential must have a negative serum pregnancy test at screening; 13. Females
may not be breastfeeding; 14. Ability to understand and willingness to sign a written
informed consent.

Exclusion Criteria

Patients will not be entered in the study for any of the following reasons:

1. Prior treatment with epothilone, ixabepilone, patupilone, vinflunine, halichondrin B,
and/or halichondrin B chemical derivatives;

2. History of other malignancies except: (1) adequately treated basal or squamous cell
carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine
cervix, or b) prostate cancer, or c) superficial bladder cancer; or (3) other
curatively treated solid tumor with no evidence of disease for ≥3 years;

3. Presence of brain metastases, unless the patient has received adequate treatment at
least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids
for at least 4 weeks prior to randomization;

4. Received an investigational agent, chemotherapy, biological therapy, hormonal
therapy, targeted therapy, or radiotherapy within 30 days prior to commencing study
treatment, or have not recovered from all treatment-related toxicities to Common
Toxicity Criteria (CTC) Grade ≤1, except for alopecia;

5. Are currently receiving an investigational agent or any other systemic anticancer
treatment, including palliative radiotherapy;

6. Significant cardiovascular impairment (history of congestive heart failure New York
Heart Association [NYHA] Grade >2, unstable angina or myocardial infarction within
the past 6 months, or serious cardiac arrhythmia);

7. Subjects with a high probability of Long QT Syndrome;

8. Patients with organ allografts requiring immunosuppression;

9. Known active infection with human immunodeficiency virus (HIV), hepatitis B, virus
(HBV) or hepatitis C; virus (HCV);

10. Hypersensitivity to halichondrin B and/or halichondrin B chemical derivative

11. Prior pelvic radiation;

12. History of known or suspected peritoneal carcinomatosis with risk of bleeding or
perforation, or intraluminal or serosal metastatic lesions with risk of bleeding or
perforation of any lesions;

13. History of abdominal adhesions, fistula, diverticulitis, gastrointestinal
perforation, intra-abdominal abscess, documented peptic ulcer disease (active
gastroesophageal reflux disease/dyspepsia are allowed), or other gastrointestinal
conditions with increased risk of perforation;

14. Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v.4.0) Grade ≥2
constipation;

15. CTCAE v.4.0 Grade ≥2 peripheral neuropathy;

16. Have any medical condition that would interfere with the conduct of the study.