A Phase I/II Trial of BMS-247550 for Treatment of Patients With Recurrent High-Grade Gliomas

Study Overview
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Brief Summary
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Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. This phase I/II trial is studying the side effects and best dose of ixabepilone and how well it works in treating patients with recurrent glioma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of BMS-247550 when administered to adults with recurrent malignant gliomas, receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex. II. To describe the pharmacokinetics of this route of administration, measuring BMS-247550, and determine the effects of hepatic enzyme inducing drugs, such as anticonvulsants, on the pharmacokinetics. III. To determine the response rate of adult patients with recurrent glioma to BMS-247550 administered at the MTD. IV. To describe the toxicity associated with this regimen in adult patients with recurrent malignant gliomas. SECONDARY OBJECTIVES: I. To determine the percent of patients with 6 month progression free survival, duration of progression free survival and survival associated with this therapy in adult patients with recurrent malignant gliomas. OUTLINE: This is a phase I, dose-escalation, multicenter study followed by a phase II, safety and efficacy, multicenter study. For phase I only, patients are stratified according to cytochrome P450-inducing anticonvulsant use (yes vs no). Phase I: Patients receive ixabepilone IV over 1 hour on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3 patients receive escalating doses of ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 patients experience dose-limiting toxicity. Phase II: Once the MTD is determined, additional patients receive ixabepilone as above at the MTD. Patients are followed every 2 months. PROJECTED ACCRUAL: A minimum of 10-15 patients will be accrued for the phase I portion of this study. A total of 22-33 patients will be accrued for the phase II portion of this study within 4-6 months.

Official Title
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A Phase I/II Trial of BMS-247550 for Treatment of Patients With Recurrent High-grade Gliomas

Conditions
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Adult Anaplastic Astrocytoma, Adult Giant Cell Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: ixabepilone
* Other: pharmacological study
* Drug: Anticonvulsant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically proven malignant glioma (anaplastic astrocytoma or glioblastoma multiforme) which is progressive or recurrent following radiation therapy +/- chemotherapy; patients with previous low grade glioma who progressed after radiotherapy +/- chemotherapy and are biopsied and found to have a high grade glioma are eligible Patients must have measurable progressive or recurrent malignant glioma by MRI or CT imaging Patients must have recovered from severe toxicity of prior therapy; an interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy while at least 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others) Absolute neutrophil count >= 1500/mm^3 Platelets >= 100,000/mm^3 HgB > 9 g/dl Creatinine =< 1.5mg/dl Total Bilirubin =< 1.5mg/dl Transaminases =< 2.5 times above the upper limits of the institutional norm) Patients must be able to provide written informed consent Patients must have =< 2 prior chemotherapy regimens Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception; the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant; female patients of child-bearing potential must have a negative pregnancy test Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast; patients with prior malignancies must be disease-free for >= five years Patients must be maintained on a stable corticosteroid regimen from the time of their baseline scan until the start of treatment Patients must have a Mini Mental State Exam score of >= 15 Exclusion Criteria: Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety Patients who are pregnant or breast-feeding Patients with more than 2 prior chemotherapy regimens Patients receiving concurrent investigational agents Patients receiving any of the following medications which are known to be moderate to significant inhibitors of CYP3A4 are not eligible: Antibiotics: clarithromycin, erythromycin, troleandomycin Anti-HIV agents: delavirdine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, lopinavir Antifungals: itraconazole, ketoconazole, fluconazole (doses > 200mg/day), voriconazole Antidepressants: nefazodone, fluvoxamine Calcium channel blockers: verapamil, diltiazem Miscellaneous: amiodarone NOTE: The above list of agents was provided by the National Cancer Institute as moderate to significant inhibitors of CYP3A4 that should not be administered with BMS; there may be other agents that have similar activities on CYP3A4, however these are currently unspecified; if investigators are concerned about a particular medication's inhibitory effect on CYP3A4, they are encouraged to consult local pharmacy services for more information and to contact the principal investigator to discuss the situation further

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A [Anticonvulsants]<br>Phase I: Dose Escalation - Patients receive ixabepilone IV over 1 hour on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3 patients receive escalating doses of ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 patients experience dose-limiting toxicity. Pharmacological Study Phase 1 | Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Drug: Anticonvulsant<br>* Drugs that induce hepatic Metabolic enzymes<br>* Other names: P450;|
| Experimental: Group B [No Anticonvulsants]<br>Phase I: Dose Escalation - Patients receive ixabepilone IV over 1 hour on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3 patients receive escalating doses of ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 patients experience dose-limiting toxicity. Pharmacological Study Phase 1 | Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Group C [MTD-Phase 2)<br>Maximum tolerated Dose (MTD-Phase 2) - subjects treated at dose determined by Group B Drug: ixabepilone Other Names: BMS-247550 epothilone B lactam Ixempra Given IV | Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicity to Determine Maximum Tolerated Dose (MTD) of BMS-247550 in Patients With Recurrent or Progressive Malignant Glioma | Starting dose for both Group A and Group B was 5mg/m2/day. A continuing reassessment method (CRM) was employed independently for each group to estimate the maximum tolerated dose. Only toxicity observed during 1st cycle of treatment (21 days) was used for dose finding. Dose limiting toxicity (DLT) defined as: ANC<500/ul, platelets<25,000, febrile neutropenia or treatment-related grade 3 or 4 non-hematologic toxicity with the exception of nausea and vomiting. | 21 days (1 cycle) | 
| Group A (P450) Estimated MTD and Group B (nonP450) Estimated MTD of BMS-247550 in Patients With Recurrent or Progressive Malignant Glioma | Starting dose for both Group A and Group B was 5mg/m2/day. A continuing reassessment method (CRM) was employed independently for each group to estimate the maximum tolerated dose. Only toxicity observed during 1st cycle of treatment (21 days) was used for dose finding. Dose limiting toxicity (DLT) defined as: ANC<500/ul, platelets<25,000, febrile neutropenia or treatment-related grade 3 or 4 non-hematologic toxicity with the exception of nausea and vomiting. | 21 days (1 cycle) | 
| Measure Pharmacokinetic Parameters Using Estimation of Half-lives Related to BMS-247550 and Anticonvulsants | T1/2,z = terminal half-life (T1/2) --- for a 2 or 3 compartment drug, idea of how long drugs stick around | Course 1, Day 1 (pre-infusion, midpoint of infusion, 5min prior to end of infusion, 15min, 30min, 1hr, 2hr, 3hr, 4hr and 6hr post infusion | 
| Measure Pharmacokinetic Parameters Using Clearance as Related to BMS-247550 and Anticonvulsant Measurements | CL = clearance (how much volume of blood is cleared of the drug per unIT of time | Course 1, Day 1 (pre-infusion, midpoint of infusion, 5min prior to end of infusion, 15min, 30min, 1hr, 2hr, 3hr, 4hr and 6hr post infusion | 
| Measure Pharmacokinetic Parameters Using Volume of Distribution at Steady State as Related to BMS-247550 and Anticonvulsants | Vss = volume of distribution at steady-state (how widely distributed in the body the drug gets) | Course 1, Day 1 (pre-infusion, midpoint of infusion, 5min prior to end of infusion, 15min, 30min, 1hr, 2hr, 3hr, 4hr and 6hr post infusion | 
| Response Rate of Patients at the MTD | Complete Response: Complete disappearance of all tumor on MRI scan, off all glucocorticoids with stable/improving neurologic exam for min4 wks. Partial Response: Greater than or equal to 50% reduction in tumor size on volumetric MRI scan, on a stable/decreasing dose of glucocorticoids, with stable/improving neurologic examination for min 4 wks. Progressive Disease: Progressive neurologic abnormalities not explained by causes unrelated to tumor progression (e.g. anticonvulsant or corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, etc.) or a greater than 25% increase in the volume of the tumor by MRI scan. If neurologic status deteriorates, on stable/increasing dose of steroids, or if new lesions appear on serial MRI, further study treatment will be discontinued. Stable Disease: A patient whose clinical status and MRI volumetrics do not meet the criteria for Complete Response, Partial Response or Progressive Disease. | 3 years | 
| Grade 3 and 4 Toxicity (NCI Common Terminology Criteria for Adverse Events Associated With BMS-247550 Treatment in at Least 5% of Patients | Proportion of patients with serious or life threatening toxicities in at least 5% of patients | Up to 30 days post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Survival |  | 1.5 years | 
| The Duration of Progression Free Survival (Phase 2) | only patients treated on the nonP450 MTD | 1.5 years | 
| Percent of Subjects With 6M Progression Free Survival at the Phase 2 Arm of Study | subjects who are progression free at 6 month scan | 6 months |