BMS 247550 to Treat Kidney Cancer

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.

• 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.