Gemcitabine Hydrochloride and Eribulin Mesylate in Treating Patients With Bladder Cancer That is Advanced or Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase II trial studies how well gemcitabine hydrochloride and eribulin mesylate work in treating patients with bladder cancer that has spread to other places in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and eribulin mesylate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the objective response rate of gemcitabine (gemcitabine hydrochloride)-eribulin (eribulin mesylate) (GE) when given to cisplatin ineligible patients with advanced or unresectable urothelial carcinoma who have not received any prior chemotherapy for the advanced disease. SECONDARY OBJECTIVES: I. To estimate the median progression-free survival (PFS). II. To summarize the toxicity profile (using Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4 criteria) of the GE regimen in these patients. OUTLINE: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 36 months.

Official Title
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Phase II Trial of Gemcitabine-Eribulin (GE) in Cisplatin Ineligible Patients With Advanced or Unresectable Urothelial Carcinoma of the Bladder

Conditions
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Metastatic Ureter Carcinoma, Metastatic Urethral Carcinoma, Stage III Bladder Urothelial Carcinoma AJCC v6 and v7, Stage III Ureter Cancer AJCC v7, Stage III Urethral Cancer AJCC v7, Stage IV Bladder Urothelial Carcinoma AJCC v7, Stage IV Ureter Cancer AJCC v7, Stage IV Urethral Cancer AJCC v7, Ureter Urothelial Carcinoma, Urethral Urothelial Carcinoma

Intervention / Treatment
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* Drug: Eribulin Mesylate
* Drug: Gemcitabine Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have locally advanced or metastatic predominantly urothelial carcinoma of the bladder, ureter, or urethra that is not amenable to curative surgical treatment Patients must have histologically confirmed predominantly urothelial carcinoma of the bladder, ureter, or urethra Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam Patients must be ineligible for treatment with cisplatin, based on one of: Calculated creatinine clearance (CrCl) >= 30 and < 60 mL/min (Cockcroft-Gault) CTCAE grade (Gr) >= 2 hearing loss CTCAE Gr >= 2 neuropathy Patients must not have received prior systemic therapy for their advanced cancer; prior intravesical therapy completed 4 weeks prior to enrollment and adjuvant/neoadjuvant chemotherapy completed more than 6 months prior to diagnosis of advanced disease are permitted Zubrod performance status =< 2 (Karnofsky >= 60%) Life expectancy of greater than 3 months Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin < 1.5 times the upper limit of normal (x ULN) for the institution Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal Creatinine clearance; calculated creatinine clearance (CrCl) >= 30 mL/min and < 60 mL/min (Cockroft-Gault) unless the patient qualified based on hearing loss or neuropathy Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of gemcitabine and eribulin administration Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with a small cell component in their histology are excluded Patients who have had chemotherapy for the treatment of the advanced or unresectable urothelial cancer of the bladder are not eligible; patients who were previously treated for local disease must not have received radiotherapy or chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and must have recovered from adverse events due to agents administered more than 4 weeks earlier; patients who have received neoadjuvant or adjuvant chemotherapy must have completed treatment at least 6 months prior to diagnosis of metastatic disease Patients who are receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine and eribulin Uncontrolled intercurrent illness including, but not limited to, a second cancer diagnosis within the past 5 years, or a cancer undergoing any treatment, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with eribulin and gemcitabine Human immunodeficiency virus (HIV)-positive patients with inadequate cluster of differentiation (CD)4 counts or those who are on combination antiretroviral therapy with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) effects are ineligible for this trial Patients with baseline corrected QT (QTc) prolongation greater than grade 1 are excluded from this study; patients with grade 1 QTc elevation are eligible but must be monitored with electrocardiogram (ECG) (EKG) exams, for the first 3 cycles of treatment; eribulin time to maximum concentration (Cmax) after infusion is about 10 minutes, and half life is 40 minutes; ECG (EKG) should be performed between 10 to 40 minutes after eribulin administration (on day 1 and day 8 of treatment); continued ECG (EKG) monitoring beyond cycle 3 can be done at the discretion of the treating physician Patients with congenital long QT syndrome are excluded from this study Other medications known to prolong QT interval should be discontinued and if not possible, patient is excluded from this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (eribulin mesylate and gemcitabine hydrochloride)<br>Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Eribulin Mesylate<br>* Given IV<br>* Other names: Halichondrin B Analog;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Overall Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Observed Overall Response Rate = Number of patients who experienced a confirmed CR or PR divided by the number of eligible patients who began treatment. | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | From the start until progression, death, or the start of another treatment, assessed up to 12 months | 
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | From start of treatment until death from any cause ,up to 36 months | 
| Incidence of Adverse Events. | Toxicities that Occurred in 10% or More of Patients or At Least Once as a Grade 3+ Adverse Event (excluding those toxicities classified as unrelated or unlikely related to study drugs). Toxicities graded using CTCAEv4 criteria. | Up to 36 months |