Tipifarnib in Treating Patients With Recurrent or Progressive Malignant Glioma

Study Overview
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Brief Summary
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RATIONALE: Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. PURPOSE: Phase II trial to study the effectiveness of tipifarnib in treating patients who have recurrent or progressive malignant glioma.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of tipifarnib in patients with recurrent or progressive malignant glioma receiving enzyme-inducing antiepileptic drugs. (Stratum II in the phase I portion of this study closed to accrual effective 07/16/2001.) (Phase I completed effective 10/2/2001.) (Phase II open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003].) Define the safety and pharmacokinetic profile of this drug in this patient population. Assess for evidence of antitumor activity of this drug in these patients. Assess for evidence of inhibition of farnesyl protein transferase (FTase) on peripheral blood monocytes as a surrogate endpoint of effective biologic activity of this drug in these patients. Determine the efficacy of this drug as measured by 6-month progression-free survival and objective tumor response in these patients. Evaluate further the safety profile of this drug in these patients. Correlate treatment response with inhibition of FTase in peripheral blood monocytes in patients treated with this drug. OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to their pretreatment medications (not receiving enzyme-inducing antiepileptic drugs [EIAEDs] vs receiving EIAEDs with or without steroids). Patients receive oral tipifarnib twice daily on days 1-21. Courses repeat every 4 weeks in the absence of unacceptable toxicity or disease progression. Phase I (completed 10/2/2001): Cohorts of 3-6 patients from stratum II receive escalating doses of tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. (Stratum II in the phase I portion of this study closed to accrual effective 07/16/2001.) Phase II (open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003]): Once the MTD is determined, additional patients with glioblastoma multiforme from stratum II are accrued to receive treatment with tipifarnib at the recommended phase II dose. Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, and then every 6 months until progression. Patients are then followed every 4 months thereafter. PROJECTED ACCRUAL: Approximately 30 patients (15 per stratum) will be accrued for the phase I portion of this study within 10 months. (Stratum II in the phase I portion of this study closed to accrual effective 07/16/2001.) (Phase I completed effective 10/2/2001.) A total of 24 patients with glioblastoma multiforme from stratum II will be accrued for the phase II portion of this study. (Phase II open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003].)

Official Title
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Phase I/II Trial of R115777 in Patients With Recurrent Malignant Glioma

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: tipifarnib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed intracranial primary malignant glioma Glioblastoma multiforme Anaplastic astrocytoma* Anaplastic oligodendroglioma* Anaplastic mixed oligodendroglioma* Malignant astrocytoma (not otherwise specified)* NOTE: *Closed to accrual effective 5/28/2002 Progressive or recurrent disease confirmed by MRI or CT scan within the past 14 days Stable steroid dose for at least 5-7 days Confirmation of true progressive disease by PET scan, thallium scan, MR spectroscopy, or surgery if prior therapy included interstitial brachytherapy or stereotactic radiosurgery Failed prior radiotherapy Phase I (phase I completed effective 10/2/2001): No more than 2 prior chemotherapy or cytotoxic regimens, including 1 prior adjuvant therapy and 1 prior regimen for progressive or recurrent disease, or 2 prior regimens for progressive disease Phase II (phase II open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003]): No more than 2 prior chemotherapy or cytotoxic regimens for relapsed disease following initial therapy (radiotherapy with or without chemotherapy) Prior surgical resection for relapsed disease with no anticancer therapy for up to 12 weeks followed by another surgical resection is considered 1 relapse Patients who received prior therapy for a low-grade glioma with a surgical diagnosis of a high-grade glioma are considered to be in first relapse PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Karnofsky 60-100% Life expectancy: More than 8 weeks Hematopoietic: WBC at least 3,000/mm^3 Absolute neutrophil count at least 2,000/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 10 g/dL (transfusion allowed) Hepatic: Bilirubin no greater than 2.5 times upper limit of normal (ULN) SGOT no greater than 2.5 times ULN Renal: Creatinine less than 1.5 mg/dL Cardiovascular: No uncontrolled high blood pressure No unstable angina No symptomatic congestive heart failure No myocardial infarction within the past 6 months No serious uncontrolled cardiac arrhythmia Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No severe nonmalignant systemic diseases or active infections No other severe concurrent disease that would preclude study therapy No allergy to azoles (e.g., ketoconazole, itraconazole, or voriconazole) HIV negative PRIOR CONCURRENT THERAPY: Biologic therapy: At least 1 week since prior interferon No concurrent anticancer immunotherapy No concurrent routine prophylactic filgrastim (G-CSF) during first course of study No concurrent sargramostim (GM-CSF) Chemotherapy: See Disease Characteristics At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, suramin, or mitomycin) At least 3 weeks since prior procarbazine At least 2 weeks since prior vincristine No other concurrent anticancer chemotherapy Endocrine therapy: See Disease Characteristics At least 1 week since prior tamoxifen Concurrent corticosteroids allowed No concurrent anticancer hormonal therapy Radiotherapy: See Disease Characteristics At least 4 weeks since prior radiotherapy and recovered No concurrent anticancer radiotherapy Surgery: See Disease Characteristics At least 3 weeks since prior resection and recovered Prior recent resection of recurrent or progressive tumor allowed Other: Recovered from all prior therapy (excluding neurotoxicity or alopecia) Prior radiosensitizers allowed Concurrent H2 blockers and antacids allowed provided taken at least 2 hours before and after tipifarnib No concurrent proton pump inhibitors (e.g., omeprazole or lansoprazole) No other concurrent medication that would preclude study therapy (e.g., immunosuppressive agents) No other concurrent anticancer therapy No other concurrent investigational drugs No concurrent participation in any other clinical study No other concurrent medications except analgesics, chronic treatments for concurrent medical conditions, or agents for life-threatening medical problems

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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: tipifarnib|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult brain tumor, adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma