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
Conditions
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.
Interventions
DRUGEribulin Mesylate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Eribulin Mesylate for Patients Who Have Received a Tubulin-inhibitor for the Recurrent/Advanced Disease (Phase I) | 21 days | MTD will be graded according to Common Terminology Criteria for Adverse (CTCAE) version 5.0. |
| MTD of Eribulin Mesylate for Patients Who Have Not Received a Tubulin-inhibitor for the Recurrent/Advanced Disease (Phase I) | 21 days | MTD will be graded according to CTCAE version 5.0. |
| Number of Subjects With Overall Response | Up to 6 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all target lesions and disappearance of all non-target lesions and normalization of tumor marker level; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter (LD) of target lesions; Overall Response (OR) = CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (Phase II) | From the start of treatment on day 1 until progression, death, or the start of another treatment, assessed at 6 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, and appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
| Overall Survival (Phase II) | From the start of treatment on day 1 until death, assessed up to 12 months | Overall survival will be summarized as time from the start of treatment until death from any cause. |
| Number of Participants With Adverse Events (AE) | Up to 24 months, or until the patient dies or refuses further follow up. | Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All observed toxicities (excluding unrelated or unlikely related AEs) will be summarized from the start of treatment until the end of treatment visit up to 24 months, or until the patient dies or refuses further follow up. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid I Quinn
City of Hope Medical Center
Participant flow
Recruitment details
Between October 2006 and August 2015, 171 patients were enrolled. Three patients who did not receive treatment or were deemed ineligible were excluded from analysis.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 68 years |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 123 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 6 / 6 | 38 / 42 | 54 / 58 | 44 / 45 |
| other Total, other adverse events | 2 / 2 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 5 / 6 | 42 / 42 | 58 / 58 | 44 / 45 |
| serious Total, serious adverse events | 1 / 2 | 2 / 3 | 2 / 6 | 1 / 3 | 3 / 3 | 5 / 6 | 19 / 42 | 44 / 58 | 24 / 45 |
Outcome results
None listed