Eribulin Mesylate in Treating Patients With Locally Advanced or Metastatic Cancer of the Urothelium and Kidney Dysfunction

A Phase I/II Study of E7389 Halichondrin B Analog (NSC # 707389) in Metastatic Urothelial Tract Cancer and Renal Insufficiency

This phase I/II trial studies the effect of eribulin mesylate and to see how well it works in treating patients with cancer of the urothelium that has spread to nearby tissue (locally advanced) or to other places in the body (metastatic)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, by stopping them from dividing, or by stopping them from spreading. Chemotherapy drugs may have different effects in patients who have changes in their kidney function.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Urothelial Carcinoma; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7; Stage IV Bladder Urothelial Carcinoma AJCC v7; Locally Advanced Urothelial Carcinoma; Recurrent Urothelial Carcinoma; Unresectable Urothelial Carcinoma; Advanced Urothelial Carcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Eribulin Mesylate

Detailed Description

PRIMARY OBJECTIVES:

I. To establish whether eribulin mesylate (E7389) can be given safely to patients with moderate and severe renal dysfunction at 1.4 mg/m^2/week (the maximum tolerated dose [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 naive. (tubulin inhibitors in common use for urothelial cancer include paclitaxel, docetaxel and vinblastine). (Phase II) (per Amendment 6) 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) (per Amendment 6) 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) (per Amendment 6) IX. To compare men and women with advanced bladder cancer treated with E7389 with respect to toxicity of E7389 as classified by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 for (i) all hematologic toxicities, (ii) all non- hematologic toxicities, and (iii) the most frequently observed toxicities (neutropenia, anemia, leucopenia, infection). (Enrollment to additional females) (per Amendment 11) X. To compare men and women with advanced bladder cancer treated with E7389 with respect to response to E7389 as evidenced by (i) disease control rate (DCR) defined as stable disease (SD)+partial response (PR)+complete response (CR) at 12 weeks, (ii) progression-free survival (PFS), and (iii) overall survival (OS). (Enrollment to additional females) (per Amendment 11) XI. To compare men and women with advanced bladder cancer treated with E7389 with respect to pharmacokinetics of E7389. (Enrollment to additional females) (per Amendment 11) XII. To compare men and women with advanced bladder cancer treated with E7389 with respect to tumoral expression of genes involved in the mechanism of action of E7389, including tubulin isotypes, microtubule-associated protein 4 (MAP4), and stathmin. (Enrollment to additional females) (per Amendment 11)

OUTLINE:

Patients receive eribulin mesylate intravenously (IV) over 1-2 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 12 months and then every 3 months for up to 24 months.

• Study Type: Interventional
• Enrollment (Estimated): 132
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Tower Cancer Research Foundation
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Lancaster, California, United States, 93534
      • City of Hope Antelope Valley
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Martinez, California, United States, 94553-3156
      • Contra Costa Regional Medical Center
    • Martinez, California, United States, 94553
      • Veterans Administration Hospital - Martinez
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem-Evanston Hospital
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
    • Joliet, Illinois, United States, 60435
      • Duly Health and Care Joliet
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
    • Springfield, Illinois, United States, 62702
      • Central Illinois Hematology Oncology Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc-Parkview
    • Kokomo, Indiana, United States, 46904
      • Community Howard Regional Health
    • South Bend, Indiana, United States, 46628
      • Northern Indiana Cancer Research Consortium
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • Saint Joseph, Michigan, United States, 49085
      • Oncology Care Associates PLLC
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have locally advanced or metastatic urothelial cancer that is not amenable to surgical treatment
• Patients must have histologically or cytologically confirmed urothelial tract carcinoma
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
• All patients may have received up to two prior lines of chemotherapy for recurrent/advanced disease
• Patients must have received at least one platinum-based chemotherapy for recurrent/advanced disease; recurrent disease is defined as having recurred after definitive therapy and advanced disease is defined as T4 and/or N2 and/or M1; in addition, for completion of Cohort #2, patients must also have received a tubulin inhibitor as part of their therapy for urothelial cancer; for purposes of this evaluation, treatment with chemotherapy regimens where carboplatin or similar is substituted for cisplatin or where a taxane is added or removed will be considered the same regimen; tubulin inhibitors in common use include paclitaxel, docetaxel, and vinblastine; the exception to this requirement applies to women
• Women with and without prior therapy are also eligible; priority will be given to those who consent to participating in the pharmacokinetic studies
• Life expectancy of greater than 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and Karnofsky >= 60%
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 institutional upper limit of normal (IULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X IULN
• Patients must have either (a) normal kidney function (i.e. creatinine =< 1.5 X upper limit of normal [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
• Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of E7389 Halichondrin analog will be determined following review of their case by the principal investigator
• The effects of E7389 Halichondrin analog on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because tubulin inhibitors are known to be teratogenic, women and men of child-bearing potential 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 participating in this study, she should inform her treating physician immediately
• Patients must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients may not be receiving any other investigational agents
• Patients with brain metastasis that are unstable (i.e. presenting with neurologic symptoms that progress or require increasing doses of steroids within a 4-week period) or are untreated (i.e. not radiated) should be excluded
• Uncontrolled intercurrent illness including, but not limited to, 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 because E7389 Halichondrin analog is tubulin inhibitor agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with E7389 Halichondrin analog, breastfeeding should be discontinued if the mother is treated with E7389
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with E7389 Halichondrin analog; HIV-positive patients with CD4+ =< 500/mm3 are ineligible because they are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in this group of patients when indicated
• Prior therapy with E7389 Halichondrin analog (eribulin)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (eribulin mesylate); Patients receive eribulin mesylate IV over 1-2 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Eribulin Mesylate; Given IV; Other Names: Halaven; E7389; B1939 Mesylate; Halichondrin B Analog; ER-086526 Mesylate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of eribulin mesylate for patients who have received a tubulin-inhibitor for the recurrent/advanced disease (Phase I)	MTD and RP2D will be graded according to Common Terminology Criteria for Adverse (CTCAE) version 5.0.	21 days
MTD and RP2D of eribulin mesylate for patients who have not received a tubulin-inhibitor for the recurrent/advanced disease (Phase I)	MTD and RP2D will be graded according to CTCAE version 5.0.	21 days
Overall response rate	Calculated as the ratio of the number of eligible patients who experienced a confirmed complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II). 95% confidence intervals will be constructed.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (Phase II)	Summarized with Kaplan-Meier plots and confidence intervals. The Cox proportional hazards model will be used to compare males and females, adjusting for the pharmacokinetic (PK) variables as well as age, renal status, and prior therapy.	From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed at 6 months
Progression-free survival (Phase II)	Summarized with Kaplan-Meier plots and confidence intervals. The Cox proportional hazards model will be used to compare males and females, adjusting for the PK variables as well as age, renal status, and prior therapy.	From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed up to 12 months
Overall survival (Phase II)	Summarized with Kaplan-Meier plots and confidence intervals. The Cox proportional hazards model will be used to compare males and females, adjusting for the PK variables as well as age, renal status, and prior therapy.	From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed up to 12 months
Incidence of adverse events	Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All observed toxicities will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by the CTCAE version 5.0), and time of onset (i.e. course of treatment). Tables will be created to summarize these toxicities and side effects, overall, by course, by renal insufficiency status, and by prior exposure to tubulin-inhibitors.	Up to 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters for eribulin mesylate	Analyzed using compartmental and non-compartmental models. max concentration, systemic clearance, renal clearance, volume of distribution, half life, and area under the curve tabulated overall, and by prior exposure to tubulin-inhibitors, with summary statistics (means and standard deviations, or medians and ranges) and displayed with box-plots; the relationship between the PK parameters and indices of renal function (e.g. serum creatinine and creatinine clearance) will be examined using scatterplots and correlations.	At baseline; at 5, 10, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 12, and 24 hours on day 1 of course 1 and at end of days 2-4 and 8 of course 1
Expression levels of the tubulin isotypes	For each of the tubulin isotypes, the distribution of the expression levels will be summarized with plots and standard statistical summary numbers; prior to analysis, the expression levels may be transformed to render the distributions more compatible with the assumptions of normal distribution. The association between the expression levels and response will be summarized with means and standard deviations and confidence intervals (or medians and ranges) and displayed with box-plots.	Baseline
Disease control rate (complete response [CR] + partial response [PR] + stable disease [SD])	Logistic regression will be used to compare males and females, adjusting for the PK variables as well as age, renal status, and prior therapy.	12 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: David I Quinn, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2006
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: August 16, 2006
• First Submitted That Met QC Criteria: August 16, 2006
• First Posted (Estimated): August 17, 2006

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Halichondrin B
• Other Study ID Numbers: NCI-2009-00170 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CM62201 (U.S. NIH Grant/Contract); P30CA033572 (U.S. NIH Grant/Contract); N01CM62209 (U.S. NIH Grant/Contract); U01CA062505 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); UM1CA186717 (U.S. NIH Grant/Contract); N01CM00038 (U.S. NIH Grant/Contract); UM1CA186705 (U.S. NIH Grant/Contract); CDR0000492014; PHII-75; 7435 (CTEP)