Bafetinib in Treating Patients With Recurrent High-Grade Glioma or Brain Metastases

BAFETINIB-P1-GBM-01: A Pilot Study Using Intracerebral Microdialysis to Determine the Neuropharmacokinetics of Bafetinib in Patients With Recurrent Brain Tumors

RATIONALE: Bafetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This clinical trial studies bafetinib in treating patients with recurrent high-grade glioma or brain metastases.

Study Overview

• Status: Completed
• Conditions: Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Tumors Metastatic to Brain; Adult Anaplastic Oligoastrocytoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Other: immunohistochemistry staining method; Other: liquid chromatography; Other: mass spectrometry; Genetic: western blotting; Genetic: protein expression analysis; Drug: bafetinib; Procedure: microdialysis; Procedure: therapeutic conventional surgery

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the neuropharmacokinetics (nPK) and systemic levels of bafetinib in patients with recurrent malignant brain tumors.

SECONDARY OBJECTIVES:

I. To investigate the intrapatient variability of nPK parameters as assessed by intracerebral microdialysis.

II. To document the toxicity of bafetinib in this cohort of patients. III. To describe the response rate, progression-free survival, and overall survival in patients with malignant brain tumors treated with bafetinib.

IV. To assess for the expression of Lyn and Fyn kinases and phosphorylation status in pre-treatment tumor samples.

OUTLINE:Patients undergo intracerebral microdialysis during debulking craniotomy or stereotactic biopsy. Beginning 24 hours later, patients receive oral bafetinib twice daily for 1 day. Beginning at least 2 weeks after craniotomy or 1 week after biopsy, patients continue to receive oral bafetinib twice daily in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 8 weeks thereafter.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • South Pasadena, California, United States, 91030
      • South Pasadena Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have radiographic findings consistent with either:

  • Recurrent high-grade glioma, or
  • Metastatic disease to the brain that has progressed after treatment with whole brain radiation therapy or stereotactic radiosurgery; patients who have a resectable brain metastasis as the only site of disease (i.e., no evidence of systemic disease), are not eligible to participate
• Patients who are in need of a surgical debulking or a stereotactic biopsy for the purpose of diagnosis or differentiating between tumor progression versus treatment-induced effects following radiation therapy +/- chemotherapy will be eligible to participate in the microdialysis part of the study prior to beginning cycle 1 of bafetinib if the study neurosurgeon thinks there is a likelihood of being able to place the microdialysis catheter into residual tumor (enhancing brain tissue)
• Patients who choose not to participate in the microdialysis part of the study may enroll in the study and start treatment at cycle 1 of bafetinib
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for 3 months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
• Patients must have a Karnofsky Performance Status (KPS) >= 60%
• If corticosteroids are required for controlling cerebral edema, patients must be on a stable dose for at least 1 week prior to enrollment
• Patients must not be taking any hepatic enzyme-inducing anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) for at least 2 weeks prior to enrollment
• Absolute neutrophil count >= 1500 cells/mm^3
• Platelet count >= 100,000 cells/mm^3
• Total bilirubin =< 2.0 mg/dl
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 3 times the institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 3 times the institutional upper limit of normal
• Serum creatinine =< 1.5 x the institutional upper limit of normal
• QTc interval < 480 msec on electrocardiogram (ECG)
• All subjects must have the ability to understand and the willingness to sign a written informed consent
• Patients must have recovered from any toxicity of prior therapies (including brain radiation); an interval of at least 6 weeks must have elapsed since the completion of a nitrosourea-containing chemotherapy regimen; patients who have undergone a recent craniotomy cannot begin bafetinib until at least 2 weeks after the surgery

Exclusion Criteria:

• Patients who are currently receiving chemotherapy or are enrolled in another treatment clinical trial
• Patients with a coagulopathy or bleeding disorder
• Patients on anticoagulant drug therapy or medications that inhibit platelet function, such as ibuprofen or other non-steroidal anti-inflammatory drugs
• Clinically evident congestive heart failure > class II of the New York Heart Association (NYHA) guidelines
• Clinically significant cardiac arrhythmias
• Patients taking a drug that can prolong the QT interval; if a potential study patient is taking one of the prohibited drugs but s/he can safely stop it, then a washout period of >= 7 days is required prior to starting bafetinib
• History or signs of active coronary artery disease with or without angina pectoris
• Patients who have a serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol or may not be able to comply with the safety monitoring requirements of the study
• Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from the study due to the possibility of pharmacokinetic (PK) interactions with bafetinib; however, patients will not be routinely screened for HIV
• Female patients who are pregnant or breast-feeding
• Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or anti-fungals
• Patients who have not recovered from the toxicities of prior chemotherapy or radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm I; Patients undergo intracerebral microdialysis during debulking craniotomy or stereotactic biopsy. Beginning 24 hours later, patients receive oral bafetinib twice daily for 1 day. Beginning at least 2 weeks after surgery, patients continue to receive oral bafetinib twice daily in the absence of disease progression or unacceptable toxicity.

Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Other: liquid chromatography; Correlative studies; Other Names: LC; Other: mass spectrometry; Correlative studies; Genetic: western blotting; Correlative studies; Other Names: Blotting, Western; Western Blot; Genetic: protein expression analysis; Correlative studies; Drug: bafetinib; Given orally; Other Names: INNO-406; dual Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406; NS-187; Procedure: microdialysis; Catheter placed intracerebrally during debulking craniotomy or stereotactic biopsy; Procedure: therapeutic conventional surgery; debulking craniotomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area-under-the-concentration-time-curve (AUC) of bafetinib in dialysate	every hour for 24 hours after first dose of bafetinib
Peak concentration (Cmax) of bafetinib in dialysate	every hour for 24 hours after first dose of bafetinib
AUC of bafetinib in plasma	1, 2, 3, 4, 6, 8, and 12 hours after the first dose of bafetinib and then 1, 2, 3, 4, 6, 8, and 12 hours after the second dose of bafetinib
Cmax of bafetinib in plasma	1, 2, 3, 4, 6, 8, and 12 hours after the first dose of bafetinib and then 1, 2, 3, 4, 6, 8, and 12 hours after the second dose of bafetinib

Secondary Outcome Measures

Outcome Measure	Time Frame
Determination of adverse events associated with bafetinib in patient with recurrent malignant brain tumors	30 days after last dose of bafetinib
Response rate in patients with malignant brain tumors treated with bafetinib	30 days after last dose of bafetinib
Progression-free survival in patients with malignant brain tumors treated with bafetinib	1 year after last dose of bafetinib
Overall survival in patients with malignant brain tumors treated with bafetinib	2 years after last dose of bafetinib
Assessment for expression of Lyn and Fyn kinases and phosphorylation status in pre-treatment tumor samples.	Pre-treatment tumor samples

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Portnow J, Badie B, Markel S, Liu A, D'Apuzzo M, Frankel P, Jandial R, Synold TW. A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas. Eur J Cancer. 2013 May;49(7):1634-40. doi: 10.1016/j.ejca.2013.01.001. Epub 2013 Feb 4.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: September 28, 2010
• First Submitted That Met QC Criteria: November 3, 2010
• First Posted (Estimate): November 4, 2010

Study Record Updates

• Last Update Posted (Actual): April 17, 2018
• Last Update Submitted That Met QC Criteria: April 12, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Los Angeles
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Glioblastoma; Recurrence; Glioma; Brain Neoplasms; Ependymoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Bafetinib
• Other Study ID Numbers: 10134 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2010-01963