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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00365157
First received: August 16, 2006
Last updated: November 15, 2014
Last verified: August 2014
  Purpose

This phase I/II trial studies the side effects and best dose of eribulin mesylate and to see how well it works in treating patients with cancer of the urothelium that has spread to nearby tissue or to other places in the body 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.


Condition Intervention Phase
Distal Urethral Cancer
Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter
Proximal Urethral Cancer
Recurrent Bladder Cancer
Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter
Recurrent Urethral Cancer
Regional Transitional Cell Cancer of the Renal Pelvis and Ureter
Stage III Bladder Cancer
Stage III Urethral Cancer
Stage IV Bladder Cancer
Stage IV Urethral Cancer
Ureter Cancer
Urethral Cancer Associated With Invasive Bladder Cancer
Drug: eribulin mesylate
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of E7389 Halichondrin B Analog (NSC # 707389) in Metastatic Urothelial Tract Cancer and Renal Insufficiency

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD and recommended phase II dose (RP2D) of eribulin mesylate for patients who have received a tubulin-inhibitor for the recurrent/advanced disease, graded according to CTCAE v4.0 (Phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • MTD and RP2D of eribulin mesylate for patients who have not received a tubulin-inhibitor for the recurrent/advanced disease, graded according to CTCAE v4.0 (Phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Overall response rate calculated as the ratio of the number of eligible patients who experienced a confirmed CR or PR by Response Evaluation Criteria in Solid Tumors v1.1 (Phase II) [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
    95% confidence intervals will be constructed.


Secondary Outcome Measures:
  • Progression-free survival (Phase II) [ Time Frame: From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed at 6 months ] [ Designated as safety issue: No ]
    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.

  • Progression-free survival (Phase II) [ Time Frame: From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed up to 12 months ] [ Designated as safety issue: No ]
    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.

  • Overall survival (Phase II) [ Time Frame: From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed up to 12 months ] [ Designated as safety issue: No ]
    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.

  • Incidence of adverse events, graded according to the CTCAE v4.0 [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]
    All observed toxicities will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by the CTCAE v4.0), 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.


Other Outcome Measures:
  • Pharmacokinetic parameters for eribulin mesylate [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Expression levels of the tubulin isotypes [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Disease control rate (CR+PR+SD) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Logistic regression will be used to compare males and females, adjusting for the PK variables as well as age, renal status, and prior therapy.


Estimated Enrollment: 132
Study Start Date: October 2006
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (eribulin mesylate)
Patients receive eribulin mesylate IV over 1-2 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: eribulin mesylate
Given IV
Other Names:
  • B1939
  • E7389
  • ER-086526
  • Halaven
  • halichrondrin B analog
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To establish whether E7389 (eribulin mesylate) 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 naïve. (Tubulin inhibitors in common use for urothelial cancer include paclitaxel, docetaxel and vinblastine). (Phase II) 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) 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) 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) 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) XI. To compare men and women with advanced bladder cancer treated with E7389 with respect to pharmacokinetics of E7389. (Enrollment to additional females) 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)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive eribulin mesylate intravenously (IV) over 1-2 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 monthly for 12 months and then every 3 months for up to 24 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • 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; breastfeeding should be discontinued if the mother is treated with E7389
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; HIV-positive patients with cluster of differentiation (CD)4+ =< 500/mm^3 are ineligible; appropriate studies will be undertaken in this group of patients when indicated
  • Prior therapy with E7389 Halichondrin analog (eribulin)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00365157

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Przemyslaw W. Twardowski    626-256-4673    ptwardowski@coh.org   
Principal Investigator: Przemyslaw W. Twardowski         
City of Hope Antelope Valley Recruiting
Lancaster, California, United States, 93534
Contact: Nimit Sudan    661-902-5633    nsudan@coh.org   
Principal Investigator: Nimit Sudan         
University of Southern California/Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: David I. Quinn    323-865-3360    diquinn@usc.edu   
Principal Investigator: David I. Quinn         
Contra Costa Regional Medical Center Recruiting
Martinez, California, United States, 94553-3156
Contact: Sharon L. Hiner    925-370-5114    shiner@hsd.co.contra-costa.ca.us   
Principal Investigator: Sharon L. Hiner         
Veterans Administration Hospital - Martinez Recruiting
Martinez, California, United States, 94553
Contact: Theodore (Ted) Wun    925-372-2062    Theodore.Wun@ucdmc.ucdavis.edu   
Principal Investigator: Theodore (Ted) Wun         
City of Hope Medical Group Inc Recruiting
Pasadena, California, United States, 91105
Contact: Stephen C. Koehler    626-396-2900    Skoehler@cohmg.com   
Principal Investigator: Stephen C. Koehler         
University of California at Davis Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: David R. Gandara    916-734-3772    david.gandara@ucdmc.ucdavis.edu   
Principal Investigator: David R. Gandara         
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Walter M. Stadler    773-702-4400    wstadler@medicine.bsd.uchicago.edu   
Principal Investigator: Walter M. Stadler         
Decatur Memorial Hospital Recruiting
Decatur, Illinois, United States, 62526
Contact: James L. Wade    217-876-6600    JLWADE3@aol.com   
Principal Investigator: James L. Wade         
Kellogg Cancer Center - Evanston Hospital Recruiting
Evanston, Illinois, United States, 60201
Contact: Bruce E. Brockstein    847-570-2515    b-brockstein@northwestern.edu   
Principal Investigator: Bruce E. Brockstein         
Ingalls Memorial Hospital Recruiting
Harvey, Illinois, United States, 60426
Contact: Mark F. Kozloff    708-339-4800    mfkozloff@aol.com   
Principal Investigator: Mark F. Kozloff         
Joliet Oncology-Hematology Associates Limited Recruiting
Joliet, Illinois, United States, 60435
Contact: Sanjiv S. Modi    815-725-1335    smodi@jolietoncology.com   
Principal Investigator: Sanjiv S. Modi         
Illinois CancerCare-Peoria Recruiting
Peoria, Illinois, United States, 61615
Contact: Sachdev P. Thomas    309-243-3605    sthomas@ohaci.com   
Principal Investigator: Sachdev P. Thomas         
Central Illinois Hematology Oncology Center Recruiting
Springfield, Illinois, United States, 62702
Contact: Edem S. Agamah    217-525-2500    ihdn@aol.com   
Principal Investigator: Edem S. Agamah         
Southern Illinois University School of Medicine - Department of Surgery Recruiting
Springfield, Illinois, United States, 62702
Contact: John E. Godwin    217-545-5817    jgodwin@siumed.edu   
Principal Investigator: John E. Godwin         
United States, Indiana
Fort Wayne Medical Oncology and Hematology Inc-Parkview Recruiting
Fort Wayne, Indiana, United States, 46845
Contact: Sreenivasa R. Nattam    260-484-8830      
Principal Investigator: Sreenivasa R. Nattam         
Community Howard Regional Health Recruiting
Kokomo, Indiana, United States, 46904
Contact: Naftali Bechar    765-453-8571    nbechar@gmail.com   
Principal Investigator: Naftali Bechar         
Northern Indiana Cancer Research Consortium Recruiting
South Bend, Indiana, United States, 46628
Contact: David A. Taber    574-647-7370    lwiseman@memorialsb.org   
Principal Investigator: David A. Taber         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: David C. Smith    734-936-6884    dcsmith@umich.edu   
Principal Investigator: David C. Smith         
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Elisabeth I. Heath    313-576-8715    heathe@karmanos.org   
Principal Investigator: Elisabeth I. Heath         
Oncology Care Associates PLLC Recruiting
Saint Joseph, Michigan, United States, 49085
Contact: Eric P. Lester    269-985-0029    oncology@parrett.net   
Principal Investigator: Eric P. Lester         
United States, Missouri
Saint John's Mercy Medical Center Recruiting
Saint Louis, Missouri, United States, 63141
Contact: Bethany G. Sleckman    314-251-7057    slecbg@stlo.mercy.net   
Principal Investigator: Bethany G. Sleckman         
United States, Pennsylvania
University of Pittsburgh Cancer Institute Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Athanassios (Ethan) Argiris    412-623-4083    argirisae@upmc.edu   
Principal Investigator: Athanassios (Ethan) Argiris         
Sponsors and Collaborators
Investigators
Principal Investigator: David Quinn Beckman Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00365157     History of Changes
Other Study ID Numbers: NCI-2009-00170, NCI-2009-00170, CDR0000492014, PHII-75, 7435, N01CM62201, N01CM00071, U01CA062505, N01CM00038, N01CM62209, P30CA033572
Study First Received: August 16, 2006
Last Updated: November 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Kidney Neoplasms
Ureteral Neoplasms
Urethral Neoplasms
Carcinoma
Kidney Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Ureteral Diseases
Urethral Diseases
Urinary Bladder Diseases
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms

ClinicalTrials.gov processed this record on November 20, 2014