BMS 247550 to Treat Kidney Cancer

Study Overview
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Brief Summary
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This study will examine whether the experimental drug BMS 247550 (Ixabepilone) is an effective treatment for kidney cancer. BMS 247550 belongs to a class of drugs called epothilones that interfere with the ability of cancer cells to divide. In the way they kill cells, they are very similar to a class of compounds known as the taxanes, which include the drug Taxol. Other characteristics of the epothilones, however, enable them to work in cells that are resistant to Taxol. Patients 18 years of age or older with kidney cancer that has not spread to the central nervous system (unless the brain tumor has remained stable for at least six months after surgical or radiation treatment) may be eligible for this study. Pregnant or nursing women may not participate. Candidates are screened with various tests that may include blood and urine tests, electrocardiogram (EKG), and chest x-ray. Computerized tomography (CT) scans or X-rays, and possibly nuclear medicine studies may be done to determine the extent of disease. Participants receive BMS 247550 by a 1-hour infusion into a vein for 5 consecutive days (days 1, 2, 3, 4 and 5) of each 21-day treatment cycle. Patients must stay in the National Institutes of Health (NIH) area near Bethesda, Maryland, for 7 to 8 days during the first treatment cycle and for the 5 days of treatment in subsequent cycles. The total number of cycles will vary among patients, depending on their individual clinical situation. The drug dose may be increased gradually in subsequent cycles in patients who can tolerate such increases. In addition, participants undergo the following tests and procedures: Periodic physical examinations and frequent blood tests X-ray and other imaging studies to determine if the tumor is responding to the treatment. Tumor biopsies to confirm the diagnosis or spread of tumor and to examine the reaction of certain proteins in cancer cells to BMS 247550. Two biopsies will be done. For this procedure, a small piece of tumor tissue is withdrawn through a needle under local anesthetic. Treatment will be stopped in patients whose tumor grows while receiving BMS 247550. Patients whose tumor disappears completely will be followed at NIH periodically for examinations and tests. Patients whose disease does not completely resolve or whose disease recurs may be advised of other appropriate research protocols at NIH or, if none are available, will be returned to the care of their local doctor.

Detailed Description
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Background: BMS-247550 (NSC 710428), (ixabepilone) is a semi-synthetic analog of the natural product epothilone B. The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum. BMS-247550 is active against cancer models that are naturally insensitive to paclitaxel or have developed resistance to paclitaxel, both in-vitro and in-vivo. Objectives Establish the efficacy of the investigational agent BMS-247550 in patients with renal cell carcinoma when administered as a one hour infusion on day 1 to 5 every 21 days. Evaluate the plasma pharmacokinetics of BMS-247550. Explore the pharmacodynamics of BMS-247550 using an assay that measures the amount of endogenous tubulin in peripheral blood mononuclear cells (PBMC) that exists in the polymerized versus the unpolymerized state. Determine the extent to which pharmacodynamic changes are observed over a range of doses of BMS-247550. Determine if cross-resistance to BMS-247550 exists in patients who have previously received sorafenib or sunitinib. Eligibility: Age greater than 18. Pathological confirmation of renal cell carcinoma. Prior chemotherapy including sorafenib and sunitinib is allowed. Design: Phase II study. BMS-247550 will be administered on days 1 through 5, every 21 days. Restaging will be done every two cycles.

Official Title
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A Phase II Clinical Trial of BMS-247550 (NSC 710428), an Epothilone B Analog, in Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: BMS-247550
* Drug: Ranitidine
* Drug: Diphenhydramine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must fulfill all of the following criteria to be eligible for study admission: Age greater than or equal to 18 years. Histologic or cytologic confirmation of renal cell carcinoma (clear cell, type I and type II papillary, chromophobe, collecting duct and medullary). Patients should either: have received interleukin-2 (IL-2); have been evaluated for therapy with IL-2 and deemed to be ineligible; or (c) have been evaluated for therapy with IL-2 and refused treatment. Measurable extent of disease. Performance Status Eastern Cooperative Oncology Group (ECOG) 0-2. Life expectancy of 3 months or greater. Suitable candidate for receiving planned therapy as evidenced by screening laboratory assessments of hematologic, renal, hepatic, and metabolic functions: platelet count greater than or equal to 100,000/mL, absolute granulocyte count (AGC) greater than or equal to 1,500/mL, serum creatinine less than or equal to 1.6 or a measured creatinine clearance greater than or equal to 40 ml/min, serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) less than or equal to 2.5 x normal limit (NL), and total bilirubin less than or equal to 1.5 x NL (in patients with clinical evidence of Gilberts' disease, less than or equal to 3 x NL). Greater than or equal to 4 weeks from prior cytotoxic chemotherapy, radiation or immunotherapy; greater than or equal to 2 weeks from prior targeted-therapy (cytostatic agents); such patients should have recovered from toxicity from the prior therapy. No serious intercurrent medical illness. The ability to understand and willingness to sign a written informed consent form, and to comply with the protocol. Patients should either: (a) have received sorafenib and or sunitinib and had progressive disease while receiving the drug(s) or (b) been intolerant to the drugs(s), or (c) been evaluated for therapy with sorafenib and or sunitinib and deemed to be ineligible; or (d) have been evaluated for therapy with sorafenib and or sunitinib and refused treatment. EXCLUSION CRITERIA: Patients with any of the following will be excluded from study entry: Pregnant or nursing women are not eligible; neither are women or men of childbearing potential unless using effective contraception as determined by the patient's physician. Patients with a history of central nervous system (CNS) metastases, because symptoms/signs of progressive disease may be confused with drug-related toxicities, unless control has been achieved with either radiation or surgical resection at least six months prior to enrollment on study. Patients who are poor medical risk because of other non-malignant systemic disease or active, uncontrolled infection. Human immunodeficiency virus (HIV) seropositive patients. Patients infected with the HIV virus will be excluded from this trial because the effect of BMS-247550 on HIV replication and/or the immune system is unknown and may be potentially harmful. Prior craniospinal radiation, or total body irradiation (TBI). Patients receiving other investigational drugs, or St. John's Wort (St. John's Wort can induce P450 and alter drug metabolism). Common Toxicity Criteria (CTC) Grade 2 or greater motor or sensory neuropathy. Known prior severe hypersensitivity reactions to agents containing Cremophor EL.

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: BMS-247550<br>One hour infusion on five successive days (daily x 5) every three weeks. Starting dose of 6 mg/m^2/day for a total per cycle dose of 30 mg/m^2 | Drug: BMS-247550<br>* One hour infusion on five successive days (daily x 5) every three weeks. Starting dose of 6 mg/m^2/day for a total per cycle dose of 30 mg/m^2<br>Drug: Ranitidine<br>* 50 mg 30-60 minutes prior to Ixabepilone (BMS-247550)<br>* Other names: Zantac;Drug: Diphenhydramine<br>* 50 mg intravenously 30-60 minutes prior to Ixabepilone (BMS-247550)<br>* Other names: Diphedryl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response rate is the percentage of participants with a response assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions, Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions,progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesions, stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module. | 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epothilone B, Ixabepilone, Renal Cell Carcinoma, Kidney Cancer