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

NCT00045708 | Completed Phase 1 Results DMC

• 4 other identifiers: NCI-2012-03016NABTT 2111CDR257118U01CA062475
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Adult Anaplastic Astrocytoma; Adult Giant Cell Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (3)

• Duration of Overall Survival

  1.5 years

• The Duration of Progression Free Survival (Phase 2)

  1.5 years

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

  6 months

Study Arms (3)

Group A [Anticonvulsants]

EXPERIMENTAL

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; Other: pharmacological study; Drug: Anticonvulsant

Group B [No Anticonvulsants]

EXPERIMENTAL

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; Other: pharmacological study

Group C [MTD-Phase 2)

EXPERIMENTAL

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

Interventions

ixabepilone DRUG

Given IV

Also known as: BMS-247550, epothilone B lactam, Ixempra

Group A [Anticonvulsants]; Group B [No Anticonvulsants]; Group C [MTD-Phase 2)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Group A [Anticonvulsants]; Group B [No Anticonvulsants]

Anticonvulsant DRUG

Drugs that induce hepatic Metabolic enzymes

Also known as: P450

Group A [Anticonvulsants]

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

Emory University

Atlanta, Georgia, 30322, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Wake Forest University

Winston-Salem, North Carolina, 27157, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44106, United States

Location

MeSH Terms

Conditions

Astrocytoma; Glioblastoma; Gliosarcoma; Brain Neoplasms

Interventions

ixabepilone; Anticonvulsants; Cytochrome P-450 CYP3A

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Central Nervous System Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Cytochrome P450 Family 3; Cytochrome P-450 Enzyme System; Cytochromes; Enzymes and Coenzymes; Oxidoreductases, N-Demethylating; Oxidoreductases Acting on CH-NH Group Donors; Oxidoreductases; Enzymes; Mixed Function Oxygenases; Oxygenases; Hemeproteins; Proteins; Amino Acids, Peptides, and Proteins

Limitations and Caveats

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.

Results Point of Contact

• Title: Director Adult Brain Tumor Consortium
• Organization: Johns Hopkins - Adult Brain Tumor Consortium (ABTC)

jfisher@jhmi.edu

410-955-8837

Study Officials

• David Peereboom, MD

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2002
• First Posted: January 27, 2003
• Study Start: October 1, 2002
• Primary Completion: May 1, 2010
• Study Completion: May 1, 2010
• Last Updated: October 18, 2017
• Results First Posted: May 9, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)