Cleveland, Ohio 44106

  • Recurrent Adult Brain Tumor

Purpose:

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.


Study summary:

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.


Criteria:

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


Study is Available At:


Original ID:

NCI-2012-03016


NCT ID:

NCT00045708


Secondary ID:

NABTT 2111


Study Acronym:


Brief Title:

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


Official Title:

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


Overall Status:

Completed


Study Phase:

Phase 1/Phase 2


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Cancer Institute (NCI)


Oversight Authority:

United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

3


Number of Groups:

0


Total Enrollment:

57


Enrollment Type:

Actual


Overall Contact Information

Official Name:David Peereboom, MD
Principal Investigator
National Cancer Institute (NCI)

Study Dates

Start Date:October 2002
Completion Date:May 2010
Completion Type:Actual
Primary Completion Date:May 2010
Primary Completion Type:Actual
Verification Date:September 2017
Last Changed Date:September 15, 2017
First Received Date:September 6, 2002
First Results Date:October 14, 2016

Study Outcomes

Outcome Type:Primary Outcome
Measure:Number of Dose Limiting Toxicity to Determine Maximum Tolerated Dose (MTD) of BMS-247550 in Patients With Recurrent or Progressive Malignant Glioma
Time Frame:21 days (1 cycle)
Safety Issues:False
Description: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
Outcome Type:Primary Outcome
Measure:Group A (P450) Estimated MTD and Group B (nonP450) Estimated MTD of BMS-247550 in Patients With Recurrent or Progressive Malignant Glioma
Time Frame:21 days (1 cycle)
Safety Issues:False
Description: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
Outcome Type:Primary Outcome
Measure:Measure Pharmacokinetic Parameters Using Estimation of Half-lives Related to BMS-247550 and Anticonvulsants
Time Frame:Course 1, Day 1 (pre-infusion, midpoint of infusion, 5min prior to end of infusion, 15min, 30min, 1h
Safety Issues:False
Description:T1/2,z = terminal half-life (T1/2) --- for a 2 or 3 compartment drug, idea of how long drugs stick around
Outcome Type:Primary Outcome
Measure:Measure Pharmacokinetic Parameters Using Clearance as Related to BMS-247550 and Anticonvulsant Measurements
Time Frame:Course 1, Day 1 (pre-infusion, midpoint of infusion, 5min prior to end of infusion, 15min, 30min, 1h
Safety Issues:False
Description:CL = clearance (how much volume of blood is cleared of the drug per unIT of time
Outcome Type:Primary Outcome
Measure:Measure Pharmacokinetic Parameters Using Volume of Distribution at Steady State as Related to BMS-247550 and Anticonvulsants
Time Frame:Course 1, Day 1 (pre-infusion, midpoint of infusion, 5min prior to end of infusion, 15min, 30min, 1h
Safety Issues:False
Description:Vss = volume of distribution at steady-state (how widely distributed in the body the drug gets)
Outcome Type:Primary Outcome
Measure:Response Rate of Patients at the MTD
Time Frame:3 years
Safety Issues:False
Description: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/dec
Outcome Type:Primary Outcome
Measure:Grade 3 and 4 Toxicity (NCI Common Terminology Criteria for Adverse Events Associated With BMS-247550 Treatment in at Least 5% of Patients
Time Frame:Up to 30 days post treatment
Safety Issues:False
Description:Proportion of patients with serious or life threatening toxicities in at least 5% of patients
Outcome Type:Secondary Outcome
Measure:Duration of Overall Survival
Time Frame:1.5 years
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:The Duration of Progression Free Survival (Phase 2)
Time Frame:1.5 years
Safety Issues:False
Description:only patients treated on the nonP450 MTD
Outcome Type:Secondary Outcome
Measure:Percent of Subjects With 6M Progression Free Survival at the Phase 2 Arm of Study
Time Frame:6 months
Safety Issues:False
Description:subjects who are progression free at 6 month scan

Study Interventions

Intervention Type:Drug
Name:ixabepilone
Description:Given IV
Arm Name:Group A [Anticonvulsants]
Other Name:BMS-247550
Intervention Type:Other
Name:pharmacological study
Description:Correlative studies
Arm Name:Group A [Anticonvulsants]
Other Name:pharmacological studies
Intervention Type:Drug
Name:Anticonvulsant
Description:Drugs that induce hepatic Metabolic enzymes
Arm Name:Group A [Anticonvulsants]
Other Name:P450

Study Arms

Study Arm Type:Experimental
Arm Name:Group A [Anticonvulsants]
Description: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
Study Arm Type:Experimental
Arm Name:Group B [No Anticonvulsants]
Description: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
Study Arm Type:Experimental
Arm Name:Group C [MTD-Phase 2)
Description: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

Study Agencies

Agency Class:NIH
Agency Type:Lead Sponsor
Agency Name:National Cancer Institute (NCI)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Results Reference
Citation:Peerebom D, Batchelor T, Lesser G, et al.: NABTT 2111: a phase I trial of BMS-247550 for patients with recurrent high-grade gliomas. [Abstract] J Clin Oncol 23 (Suppl 16): A-1563, 129s, 2005.

Data Source: ClinicalTrials.gov

Date Processed: April 03, 2020

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