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

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

The purpose of this study is to determine whether Patients with Locally Advanced or Metastatic Bladder Cancer who receive Eribulin Mesylate Administered in Combination with Gemcitabine Plus Cisplatin Versus Gemcitabine Plus Cisplatin Alone as First-Line Therapy is safety and tolerable when administered to patients with locally advanced or metastatic bladder cancer and to gain preliminary data on whether patients may benefit from this combination.

This open-label, multicenter, randomized study will consist of 2 phases:

• Phase Ib: a safety run-in period with 3 ascending doses of eribulin;
• Phase II: a randomized 2-arm design. Phase Ib Patients will be recruited into cohorts, with a minimum of 3 and a maximum of 6 patients per cohort. All patients will receive the same dose of gemcitabine (1000 mg/m2 on Days 1 and 8 of a 21-day cycle) and cisplatin (70 mg/m2 on Day 1) in combination with eribulin (administered on Days 1 and 8 of the cycle). All patients in a cohort will receive the same dose level of eribulin.

The dose level of eribulin will be escalated for additional cohorts unless greater than 2 dose limiting toxicities (DLTs) are reported at the lower dose level(s) prior to enrollment of the next dose level. If one DLT occurs at any dose level, the cohort will be expanded to include up to a maximum of 6 patients.

A Dose Escalation Committee will determine when no further dose escalation is appropriate and whether the MTD will be defined as a preceding dose or an intermediate dose.

Phase II Patients will be randomized in a 1:1 ratio to receive either eribulin in combination with gemcitabine plus cisplatin (Arm 1) or gemcitabine plus cisplatin alone (Arm 2). The eribulin dose will be 1.0 mg/m2 administered on Days 1 and 8 of each 21-day treatment cycle, the recommended Phase II dose for eribulin when administered in combination gemcitabine plus cisplatin, as determined in the Phase Ib portion of the study.

Allocation of patients will be stratified based on metastatic disease status (patients with visceral metastases versus patients with non-visceral metastases). This stratified randomization will be centrally allocated across all centers via an Interactive Voice Activated Response System (IVRS).

For both the Phase Ib and Phase II portions, 1 cycle of therapy will last 21 days, with a maximum number of 6 gemcitabine plus cisplatin cycles. Radiologic examinations including a computed tomography (CT) scan of the chest, abdomen, and pelvis as appropriate (and CT or magnetic resonance imaging [MRI] scan as appropriate), will be performed during Screening and after every 6 weeks while on therapy. In the case of dose delays, scans should be performed according to the original Cycle 1 Day 1 schedule (ie, scans should not be delayed). Radiographic assessments should be repeated at withdrawal if the last assessment was obtained greater than 3 weeks from withdrawal of therapy. Patients will be followed until death following completion of therapy. Scans will be required every 2 months until documentation of PD or the start of a next line of therapy, whichever occurs first. In patients experiencing PD, follow-up will be for survival only and radiographic scans are not required.

Inclusion Criteria

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

1. Male or female patient greater than 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 greater than or equal to 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 greater than or equal to 55 mL/min per the Cockcroft and Gault formula;
9. Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L, hemoglobin greater than or equal to 10.0 g/dL (a hemoglobin less than 10.0 g/dL at Screening is acceptable if it is corrected to greater than or equal to 10.0 g/dL by growth factor or transfusion prior to first dose), and platelet count greater than or equal to 100 x 10^9/L;
10. Patients must have adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limit of the normal range (ULN), and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases, less than or equal to 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 greater than or equal to 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 less than or equal to 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 greater than 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 greater than or equal to 2 constipation;
15. CTCAE v.4.0 Grade greater than or equal to 2 peripheral neuropathy;
16. Have any medical condition that would interfere with the conduct of the study.