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

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ClinicalTrials.gov Identifier: NCT00365157
Recruitment Status : Active, not recruiting
First Posted : August 17, 2006
Last Update Posted : April 15, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE August 16, 2006
First Posted Date  ICMJE August 17, 2006
Last Update Posted Date April 15, 2021
Actual Study Start Date  ICMJE October 23, 2006
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 12, 2021)
  • 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) [ Time Frame: 21 days ]
    MTD and RP2D will be graded according to Common Terminology Criteria for Adverse (CTCAE) version 5.0.
  • MTD and RP2D of eribulin mesylate for patients who have not received a tubulin-inhibitor for the recurrent/advanced disease (Phase I) [ Time Frame: 21 days ]
    MTD and RP2D will be graded according to CTCAE version 5.0.
  • Overall response rate [ Time Frame: Up to 6 months ]
    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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2021)
  • 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 ]
    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.
  • 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 ]
    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 ]
    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 [ Time Frame: Up to 24 months ]
    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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: March 2, 2018)
  • 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 ]
    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 ]
    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 (complete response [CR] + partial response [PR] + stable disease [SD]) [ Time Frame: 12 weeks ]
    Logistic regression will be used to compare males and females, adjusting for the PK variables as well as age, renal status, and prior therapy.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Eribulin Mesylate in Treating Patients With Locally Advanced or Metastatic Cancer of the Urothelium and Kidney Dysfunction
Official Title  ICMJE A Phase I/II Study of E7389 Halichondrin B Analog (NSC # 707389) in Metastatic Urothelial Tract Cancer and Renal Insufficiency
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Urothelial Carcinoma
  • Locally Advanced Urothelial Carcinoma
  • Metastatic Urothelial Carcinoma
  • Recurrent Urothelial Carcinoma
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage IV Bladder Urothelial Carcinoma AJCC v7
  • Unresectable Urothelial Carcinoma
Intervention  ICMJE
  • Drug: Eribulin Mesylate
    Given IV
    Other Names:
    • B1939 Mesylate
    • E7389
    • ER-086526
    • Halaven
    • Halichondrin B Analog
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
Study Arms  ICMJE 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.
Interventions:
  • Drug: Eribulin Mesylate
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: December 7, 2015)
132
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00365157
Other Study ID Numbers  ICMJE NCI-2009-00170
NCI-2009-00170 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000492014
PHII-75
7435 ( Other Identifier: City of Hope Comprehensive Cancer Center )
7435 ( Other Identifier: CTEP )
N01CM00038 ( U.S. NIH Grant/Contract )
N01CM00071 ( U.S. NIH Grant/Contract )
N01CM62201 ( U.S. NIH Grant/Contract )
N01CM62209 ( U.S. NIH Grant/Contract )
P30CA033572 ( U.S. NIH Grant/Contract )
U01CA062505 ( U.S. NIH Grant/Contract )
UM1CA186705 ( U.S. NIH Grant/Contract )
UM1CA186717 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: David I Quinn City of Hope Comprehensive Cancer Center
PRS Account National Cancer Institute (NCI)
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP