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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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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
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* Drug: bafetinib
* Procedure: microdialysis
* Other: pharmacological study
* Other: liquid chromatography
* Other: mass spectrometry
* Other: laboratory biomarker analysis
* Genetic: protein expression analysis
* Genetic: western blotting
* Other: immunohistochemistry staining method
* Procedure: therapeutic conventional surgery


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: bafetinib<br>* Given orally<br>* Other names: NS-187;Procedure: microdialysis<br>* Catheter placed intracerebrally during debulking craniotomy or stereotactic biopsy<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: liquid chromatography<br>* Correlative studies<br>* Other names: LC;Other: mass spectrometry<br>* Correlative studies<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: protein expression analysis<br>* Correlative studies<br>Genetic: western blotting<br>* Correlative studies<br>* Other names: Western Blot;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Procedure: therapeutic conventional surgery<br>* debulking craniotomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Los Angeles