BMS-247550 Plus Carboplatin in Treating Patients With Recurrent or Refractory Solid Tumors

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of BMS-247550 when given together with carboplatin in treating patients with recurrent or refractory solid tumors. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of BMS-247550 when given in combination with carboplatin in patients with recurrent or refractory solid tumors. II. Determine the dose-limiting toxicity and safety of this regimen in these patients. III. Determine the plasma pharmacokinetics of this regimen in these patients. IV. Determine, preliminarily, any antitumor activity of this regimen in these patients. V. Correlate the protein expression of survivin with the expression of other apoptotic regulators, the apoptotic index, and response in patients treated with this regimen. OUTLINE: This is a dose-escalation study of BMS-247550. Patients receive BMS-247550 IV over 1 hour on days 1, 8, and 15 followed by carboplatin IV over 1 hour on day 1. Treatment repeats every 28 days for at least 2 courses in the absence of disease progression or unacceptable toxicity. Patients with a complete response (CR) receive 2 additional courses after achieving CR or up to a total of 6 courses. The first two cohorts of 3-6 patients each receive escalating doses of BMS-247550 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT).The third and fourth cohorts of 10 patients each receive escalating doses of BMS-247550 until the MTD is determined. The MTD is defined as the dose preceding that at which at least 3 of 10 patients experience DLT. Once the MTD is determined for the third and fourth cohorts, 15 additional patients are treated at the MTD. Patients are followed for 30 days.

Official Title
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A Phase I Study of Epothilone B Analog BMS 247550 in Combination With Carboplatin in Recurrent and/or Refractory Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: ixabepilone
* Drug: carboplatin
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective Measurable or evaluable disease Lesion accessible for core or excisional biopsy if being treated at the maximum tolerated dose (MTD) No biliary tract dilation if radiologically guided biopsy of the liver is planned No requirement for core biopsy of lung lesion that is not pleural based No requirement for laparotomy or thoracotomy solely for biopsy No medical condition that would preclude biopsy No known brain metastases Performance status - ECOG 0-2 Performance status - ECOG 0-1 if being treated at the MTD More than 3 months Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 No prior bleeding disorder or unexplained bleeding if being treated at the MTD Bilirubin no greater than 1.5 mg/dL AST/ALT no greater than 2 times upper limit of normal (ULN) (5 times ULN if liver metastases present) PT/PTT normal Creatinine no greater than 1.5 times ULN Creatinine clearance at least 60 mL/min No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other concurrent uncontrolled illness that would preclude study participation No ongoing or active infection No grade 2 or greater neuropathy (sensory or motor) No prior severe allergic reaction attributable to compounds containing Cremophor EL or platinum agents No psychiatric illness or social situation that would preclude study compliance No medical condition that would preclude study if being treated at the MTD At least 4 week since prior immunotherapy At least 24 hours since prior growth factors At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) No more than 3 prior chemotherapy regimens No prior epothilone agents At least 1 week since prior hormonal therapy directed at malignancy Concurrent hormone replacement therapy allowed At least 4 weeks since prior wide-field radiotherapy involving 30% or more of bone marrow See Disease Characteristics At least 4 weeks since prior investigational agents No prior or concurrent St. John's Wort No concurrent combination anti-retroviral therapy for HIV-positive patients No other concurrent investigational agents No concurrent heparin or other anticoagulants if being treated at the MTD No concurrent inhibitors of cytochrome P450 3AP (CYP3A4)

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: Treatment (ixabepilone, carboplatin)<br>Patients receive BMS-247550 IV over 1 hour on days 1, 8, and 15 followed by carboplatin IV over 1 hour on day 1. Treatment repeats every 28 days for at least 2 courses in the absence of disease progression or unacceptable toxicity. Patients with a CR receive 2 additional courses after achieving CR or up to a total of 6 courses | Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of ixabepilone defined as the first dosage tier below the MAD in which =< 1/6 patients experiences a DLT |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of ixabepilone and carboplatin |  | Week 1 |