Lonafarnib and Temozolomide in Treating Patients With Recurrent Primary Supratentorial Gliomas

Study Overview
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Brief Summary
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RATIONALE: Lonafarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving lonafarnib together with temozolomide may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of lonafarnib when given together with temozolomide in treating patients with recurrent primary supratentorial glioma.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and dose-limiting toxicity of lonafarnib when administered with temozolomide in patients with recurrent primary supratentorial gliomas. Determine the safety and tolerability of this regimen in these patients. Secondary Determine the mechanism of action of lonafarnib in these patients. Determine the pharmacodynamics and pharmacokinetics of this regimen in these patients. Determine the activity of this regimen in these patients. Determine the response to this regimen in patients who have measurable disease. OUTLINE: This is a nonrandomized, multicenter, open-label, dose-escalation study of lonafarnib. Patients receive oral temozolomide once daily on days 2-6 of course 1 and on days 1-5 of all subsequent courses. Patients also receive oral lonafarnib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of lonafarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 1 of 6 patients experience dose-limiting toxicity. An additional 3 patients may be treated at the highest dose level achieved. Patients are followed every 8 weeks for 6 months and then every 3 months thereafter. PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study.

Official Title
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Phase I Study Of SCH66336 (Lonafarnib), A Farnesyl Protein Transferase Inhibitor In Combination With Temozolomide In Gliomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: lonafarnib
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary supratentorial glioma Multifocal disease allowed Recurrent disease after prior surgery and/or radiotherapy Radiological evidence of increased and/or enhanced target lesion Amenable to temozolomide therapy PATIENT CHARACTERISTICS: Age Over 18 Performance status ECOG 0-2 OR WHO 0-2 Life expectancy Not specified Hematopoietic Neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10.0 g/dL Hepatic Alkaline phosphatase < 2.5 times upper limit of normal (ULN) Transaminases < 2.5 times ULN Bilirubin < 1.5 times ULN Renal Creatinine < 1.7 mg/dL Cardiovascular Cardiac function clinically normal Normal 12-lead ECG QTc ≤ 440 msec on ECG No ischemic heart disease within the past 6 months Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation No unstable systemic disease No active uncontrolled infection No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up No other active or recurrent malignancy within the past 5 years except cone biopsied carcinoma of the cervix or adequately treated basal cell or squamous cell skin cancer PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent anticancer biologic agents Chemotherapy At least 4 weeks since prior chemotherapy (6 weeks for temozolomide) Prior adjuvant chemotherapy allowed No more than 1 prior chemotherapy regimen for recurrent disease No other concurrent chemotherapy Endocrine therapy Concurrent corticosteroids allowed provided treatment remains at a stable or decreasing dose for at least 2 weeks Radiotherapy See Disease Characteristics No concurrent radiotherapy Surgery See Disease Characteristics At least 3 months since prior surgery for primary brain tumor Other Concurrent anticonvulsants allowed No other concurrent anticancer agents No other concurrent investigational therapy

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: lonafarnib|nan|
|Drug: temozolomide|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity and maximum tolerated dose of lonafarnib determined by CTCAE v3.0 |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (complete [CR] or partial response [PR]) measured by McDonald's criteria at least 4 weeks after first documented response and every 8 weeks until disease progression or until start of another treatment |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult brain tumor, adult mixed glioma, adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult glioblastoma, adult pilocytic astrocytoma, adult anaplastic ependymoma, adult subependymoma, adult myxopapillary ependymoma, adult oligodendroglioma, adult giant cell glioblastoma, adult gliosarcoma, adult diffuse astrocytoma, adult subependymal giant cell astrocytoma, adult pineal gland astrocytoma