Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioblastoma

Glioma

Brain Neoplasms

Astrocytoma

Gliosarcoma

Disease Attributes

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Tumor, Adult

Anaplastic Astrocytoma

Neuroepithelioma

Anti-Infective Agents

All Drugs and Chemicals

Anticonvulsants

Antineoplastic Agents

Lactams

Epothilones

Epothilone B

Tubulin Modulators

Antimitotic Agents

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

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

ixabepilone

pharmacological study

Drugs that induce hepatic Metabolic enzymes

Anticonvulsant

David Peereboom, MD

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.

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.

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

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

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.

T1/2,z = terminal half-life (T1/2) --- for a 2 or 3 compartment drug, idea of how long drugs stick around

CL = clearance (how much volume of blood is cleared of the drug per unIT of time

Vss = volume of distribution at steady-state (how widely distributed in the body the drug gets)

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.

Proportion of patients with serious or life threatening toxicities in at least 5% of patients

subjects who are progression free at 6 month scan

National Cancer Institute (NCI)

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.

Phase II: Once the MTD is determined, additional patients receive ixabepilone as above at the MTD.

Pharmacological Study

ixabepilone: Given IV pharmacological study: Correlative studies

Group A [Anticonvulsants] - Phase 1

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.

Phase II: Once the MTD is determined, additional patients receive ixabepilone as above at the MTD.

Pharmacological Study

ixabepilone: Given IV

pharmacological study: Correlative studies

Group B [No Anticonvulsants] - Phase 1

Phase II: Once the MTD is determined, additional patients receive ixabepilone at the MTD.

Phase 2

Total

Age, Continuous

Sex: Female, Male

100%

Performance status is a range where the higher score is the better score:

100 - Normal; no complaints; no evidence of disease; 90 - Able to carry on normal activity; minor signs or symptoms of disease, 80 - Normal activity with effort; some signs or symptoms of disease; 70 - Cares for self; unable to carry on normal activity or to do active work; 60 - Requires occasional assistance, but is able to care for most of his personal needs

Karnofsky Performance Status (KPS)

Glioblastoma multiforme

Malignant glioma

Anaplastic astrocytoma

Histology

+EIAED

-EIAED

None

subjects were either on an anticonvulsant (EIAED) enzyme inducing antiepileptic drug or on an anticonvulsant that was not enzyme inducing (-EIAED) or on NO anticonvulsant

Anticonvulsant Use

Phase 2 was completed using only nonP450 MTD (6.8mg/m21) as the MTD for P450 was not determined until the Phase 2 accrual had completed.

Director Adult Brain Tumor Consortium

Dose level 5.0mg/m2/day

Dose level 6.0mg/m2/day

Dose level 6.6mg/m2/day

Dose level 6.8mg/m2/day

Dose level 7.0mg/m2/day

Dose level 7.5mg/m2/day

Dose level 7.7mg/m2/day

Dose level 8.7mg/m2/day

Dose Level 9.5mg/m2/day

Dose level 9.6mg/m2/day

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

ixabepilone: Given IV

pharmacological study: Correlative studies

Group A [Anticonvulsants]

Group B [No Anticonvulsants]

Phase II: Once the MTD is determined, additional patients receive ixabepilone as above at the MTD.

ixabepilone: Given IV

MTD for no anticonvulsant arm = 6.8mg/m2/day MTD for anticonvulsant arm = 9.6mg/m2/day

Only no anticonvulsant subjects at 6.8mg/m2/day treated in Phase 2

Group 3 - MTD (6.8mg/m2/Day) Phase 2

4 subjects from Group B (Phase 1) were included in Group 3 (Phase 2). Only those on non-anticonvulsants at the dose of 6.8mg/m2/day were treated in Phase 2. No subjects treated at the MTD for P450, as the accrual goal for phase 2 reached before MTD for p450 was determined. P450 MTD determined as 9.6mg/m2 per CRM after all enrollment of phase 2

Number of Dose Limiting Toxicity to Determine Maximum Tolerated Dose (MTD) of BMS-247550 in Patients With Recurrent or Progressive Malignant Glioma

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

ixabepilone: Given IV

pharmacological study: Correlative studies

Group A (P450) Estimated MTD and Group B (nonP450) Estimated MTD of BMS-247550 in Patients With Recurrent or Progressive Malignant Glioma

13 of the 21 samples for P450 collected day 1 sample set and 16 of the 17 samples for the nonP40 collected day 1 sample set

Measure Pharmacokinetic Parameters Using Estimation of Half-lives Related to BMS-247550 and Anticonvulsants

Measure Pharmacokinetic Parameters Using Clearance as Related to BMS-247550 and Anticonvulsant Measurements

Measure Pharmacokinetic Parameters Using Volume of Distribution at Steady State as Related to BMS-247550 and Anticonvulsants

no objective responses observed. 19 patients treated at the MTD from during Phase 2 and 4 patients treated at the MTD during the Phase 1 nonP450 arm 2 were included in the response analysis.

Response Rate of Patients at the MTD

Neutropenia (ANC)

WBC (leukopenia)

Hypophosphatemia (PO4)

Transfusion:pRBCs

Anemia (HGB)

Hyponatremia

Grade 3 and 4 Toxicity (NCI Common Terminology Criteria for Adverse Events Associated With BMS-247550 Treatment in at Least 5% of Patients

Group A [Anticonvulsants] Phase 1

Group B [No Anticonvulsants] Phase 1

Duration of Overall Survival

Phase II: Once the MTD is determined, additional patients receive ixabepilone at the MTD (6.8mg/m2).

19 patients treated at the MTD from during Phase 2 and 4 patients treated at the MTD during the Phase 1 nonP450 arm 2 were included in the response analysis.

The Duration of Progression Free Survival (Phase 2)

Percent of Subjects With 6M Progression Free Survival at the Phase 2 Arm of Study

Phase II: Once the MTD is determined, additional patients receive ixabepilone as above at the MTD.

Spots Global Cancer Trial Database for anticonvulsant