Pharmacokinetics in Patients With Newly Diagnosed High-Grade Glioma Receiving Temozolomide and Radiation Therapy

Study Overview
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Brief Summary
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RATIONALE: Studying samples of blood in the laboratory from patients receiving temozolomide may help doctors learn how temozolomide works in the body. It may also help doctors learn more about how a patient's genes may affect the risk of developing thrombocytopenia. PURPOSE: This clinical trial is studying the pharmacokinetics in patients with newly diagnosed high-grade glioma receiving temozolomide and radiation therapy.

Detailed Description
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OBJECTIVES: Compare the pharmacokinetic (PK) profiles of temozolomide (TMZ) in patients who develop severe thrombocytopenia vs PK profiles in patients who do not develop severe thrombocytopenia while receiving standard first-line therapy for management of newly diagnosed high-grade gliomas. Determine if patients who develop thrombocytopenia have any single nucleotide polymorphisms in the O6-methylguanine-DNA methyltransferase gene. OUTLINE: This is a pilot, prospective, multicenter study. Patients receive oral temozolomide once daily on days 1-42. Patients also undergo cranial radiotherapy 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for pharmacokinetic and pharmacogenomic analysis, genotype analysis, plasma temozolomide levels, and MGMT repair gene polymorphism analysis. After completion of study treatment, patients are followed for 1 month. PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

Official Title
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A Pharmacokinetic and Pharmacogenomic Study of Patients With High-Grade Gliomas Receiving Daily Radiation Therapy and Temozolomide

Conditions
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Brain and Central Nervous System Tumors, Thrombocytopenia

Intervention / Treatment
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* Drug: temozolomide
* Genetic: comparative genomic hybridization
* Genetic: polymorphism analysis
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed high-grade glioma (WHO grade III or IV) Must be scheduled to receive standard first-line therapy (cranial radiotherapy and temozolomide) PATIENT CHARACTERISTICS: ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 1.7 mg/dL Bilirubin ≤ 1.5 mg/dL Transaminases ≤ 4 times upper limit of normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy within the past 5 years except curatively treated carcinoma in situ or basal cell carcinoma of the skin PRIOR CONCURRENT THERAPY: No prior hormonal therapy for brain tumor No prior biological agents (including immunotoxins, immunoconjugates, antisense agents, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cells, or gene therapy) No prior immunotherapy No prior chemotherapy No prior radiotherapy, including cranial radiotherapy Concurrent glucocorticoid therapy allowed No concurrent carbamazepine No other concurrent experimental therapy No other concurrent cytotoxic therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: temozolomide|nan|
|Genetic: comparative genomic hybridization|nan|
|Genetic: polymorphism analysis|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of temozolomide (TMZ) in patients with severe thrombocytopenia after standard first-line therapy as measured by Area Under the Curve (AUC) | AUC (mg*h/L)in patients who develop severe thrombocytopenia after receiving standard first-line therapy of temozolomide (TMZ) for management of newly diagnosed high-grade gliomas. | Day 1, Day 22, Day 43 | 
| Pharmacokinetics (PK) of temozolomide (TMZ) in patients with severe thrombocytopenia after standard first-line therapy as measured by maximum drug concentration (Cmax) | Cmax in patients who develop severe thrombocytopenia after receiving standard first-line therapy of temozolomide (TMZ) for management of newly diagnosed high-grade gliomas. | Day 1, Day 22, Day 43 | 
| Pharmacokinetic (PK) profile of temozolomide (TMZ) in patients without severe thrombocytopenia after standard first-line therapy as measured by AUC | AUC in patients in patients who do not develop severe thrombocytopenia after receiving standard first-line therapy of TMZ for management of newly diagnosed high-grade gliomas. | Day 1, Day 22, Day 43 | 
| Pharmacokinetic (PK) profile of temozolomide (TMZ) in patients without severe thrombocytopenia after standard first-line therapy as measured by Cmax | Cmax in patients in patients who do not develop severe thrombocytopenia after receiving standard first-line therapy of TMZ for management of newly diagnosed high-grade gliomas. | Day 1, Day 22, Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of single nucleotide polymorphisms in the O6-methylguanine-DNA methyltransferase gene. | Presence of single nucleotide polymorphisms in the O6-methylguanine-DNA methyltransferase gene of patients who develop thrombocytopenia after receiving standard first-line therapy for management of newly diagnosed high-grade gliomas. | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thrombocytopenia, adult anaplastic oligodendroglioma, adult brain stem glioma, adult mixed glioma, adult giant cell glioblastoma, adult gliosarcoma, adult glioblastoma, adult anaplastic astrocytoma, adult anaplastic ependymoma, adult pineal gland astrocytoma