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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Bladder Cancer

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Trial Information

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

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

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 >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

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

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

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety parameters

Outcome Description:

Safety parameters: adverse events (AEs); vital signs; ECOG PS; clinical laboratory evaluations; physical examinations; and 12 lead electrocardiograms (ECGs).

Outcome Time Frame:

[Time Frame: AEs and conmeds - until study termination; lab tests Day 1 and every 21 days until study termination; ECGs - Day 1 and 21 days after therapy ended

Safety Issue:



United States: Food and Drug Administration

Study ID:




Start Date:

April 2010

Completion Date:

September 2014

Related Keywords:

  • Bladder Cancer
  • Locally Advanced or Metastatic Bladder Cancer, including other transitional cell cancers of the urothelium (prostate, urethra, ureter, and renal pelvis)
  • Urinary Bladder Neoplasms



Mayo Clinic Rochester, Minnesota  55905
University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan  48109-0752
Virginia Oncology Associates Newport News, Virginia  23606
Comprehensive Cancer Centers of Nevada Las Vegas, Nevada  89109
Florida Cancer Specialists Fort Myers, Florida  33901
UAB Comprehensive Cancer Center Birmingham, Alabama  35294
Texas Oncology P.A. Dallas, Texas  75230-2503
Tower Cancer Research Foundation Beverly Hills, California  90211
Arizona Clinical Research Center, Inc. Tucson, Arizona  85712
East Orange VA Medical Center East Orange, New Jersey  07018
Chattanooga Oncology and Hematology Associates, PC Chattanooga, Tennessee  37404
Florida Cancer Specialists-Broadway Ft. Myers, Florida  33916
Tennessee Cancer Specialist Knoxville, Tennessee  37909
TX Oncology- Deke Slaton Ca Ctr Webster, Texas  77598
Texas Oncology Memorial City Houston, Texas  77024