Tipifarnib and Radiation Therapy in Treating Young Patients With Brainstem Glioma

Study Overview
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Brief Summary
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Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Tipifarnib may make tumor cells more sensitive to radiation therapy. Combining tipifarnib with radiation therapy may kill more tumor cells. This phase I/II trial is studying the side effects and best dose of tipifarnib to see how well it works when given together with radiation therapy in treating young patients with newly diagnosed brain stem glioma. (Phase I closed to accrual as of 1/19/06)

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of R115777 administered concurrently with radiation therapy to pediatric patients with non-disseminated, diffuse, intrinsic brainstem gliomas who are not receiving enzyme-inducing anti-convulsant drugs (EIACD). II. To assess the efficacy of R115777 treatment in combination with radiation therapy for patients with non-disseminated, diffuse, intrinsic pontine gliomas as measured by progression-free survival and survival distributions. SECONDARY OBJECTIVES: I. To characterize toxicities associated with R115777 treatment in combination with and post radiation therapy. II. To characterize radiographic changes in brainstem gliomas treated with radiation and R115777 using MRI, perfusion and diffusion imaging and PET scans. OUTLINE: This is a phase I (closed to accrual as of 1/19/06), multicenter, dose-escalation study of tipifarnib followed by a phase II safety and efficacy study. PHASE I: Patients undergo radiotherapy 5 days a week for 6 weeks. Beginning 0-2 days before radiotherapy, patients receive oral tipifarnib twice daily until the completion of radiotherapy. Beginning 2 weeks after the completion of radiotherapy, patients receive oral tipifarnib twice daily in weeks 1-3. Treatment repeats every 4 weeks for up to 24 additional courses (total of 26 courses) in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib during radiotherapy until the maximum tolerated dose is determined. The MTD is defined as the dose level preceding that at which 2 of 6 patients experience dose-limiting toxicity. PHASE II: Patients undergo radiotherapy and receive tipifarnib at the MTD as in phase I (closed to accrual as of 1/19/06). Treatment continues for up to 24 months (26 courses) in the absence of disease progression or unacceptable toxicity. FOLLOW-UP: Phase I: Participants contributing only to the phase I part are followed for 90 days after completion of therapy. Adverse events that have not resolved within 90 days after stopping treatment will be followed until resolution. Phase II: Participants in the phase I part treated at the MTD or participants in the phase II part are followed until the earliest of death or three years after starting treatment. PROJECTED ACCRUAL: A total of 3-55 patients (3-18 patients for phase I [closed to accrual as of 1/19/06] and a total of 40 patients for phase II [including 6 patients treated in the dose-finding portion of phase I (closed to accrual as of 1/19/06)]) will be accrued for this study within 2.3 years.

Official Title
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Phase I/II Trial of R115777 and XRT in Pediatric Patients With Newly Diagnosed Non-Disseminated Intrinsic Diffuse Brainstem Gliomas

Conditions
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Untreated Childhood Brain Stem Glioma

Intervention / Treatment
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* Radiation: radiation therapy
* Drug: tipifarnib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed non-disseminated intrinsic diffuse brainstem glioma Karnofsky performance scale (KPS) (for > 16 yrs of age) or Lansky performance score (LPS) (for =< 16 years of age) => 50 assessed within two weeks prior to registration Prior/concurrent therapy: Chemo: No prior therapy allowed Radiation therapy (XRT): No prior therapy allowed Bone Marrow Transplant: None prior Anti-convulsants: Patients receiving EIACDs will not be eligible; however, patients may switch from EIACDs to non-EIACDs and must then be on non-EIACDs for a minimum of 7 days prior to registration Growth factors: Off all colony forming growth factor(s) > 2 weeks prior to registration (G-CSF, GM-CSF, erythropoietin) Absolute neutrophil count >= 1,000/mm^3 Platelets >= 100,000/mm^3 (transfusion independent) Hemoglobin >= 8 gm/dL (transfusion independent) Serum creatinine that is less than the upper limit of institutional normal for age or GFR > 70 ml/min/1.73m2 Bilirubin =< 1.5 time upper limit of normal for age SGPT (ALT) and SGOT (AST) < 2.5 times institutional upper limit of normal Female patients of childbearing potential must have negative serum or urine pregnancy test; patient must not be pregnant or breast-feeding Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study Signed informed consent according to institutional guidelines must be obtained Exclusion Criteria: Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism Patients with disseminated intrinsic diffuse brainstem glioma Patients taking enzyme-inducing anticonvulsant drugs Patients with known allergy to topical or systemic imidazoles (e.g., clotrimazole, ketoconazole, miconazole, econazole) Patients receiving any other anticancer or experimental drug therapy Patients with uncontrolled infection

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 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: Treatment (radiation therapy and tipifarnib)<br>PHASE I: Patients undergo radiotherapy 5 days a week for 6 weeks. Beginning 0-2 days before radiotherapy, patients receive oral tipifarnib twice daily until the completion of radiotherapy. Beginning 2 weeks after the completion of radiotherapy, patients receive oral tipifarnib twice daily in weeks 1-3. Treatment repeats every 4 weeks for up to 24 additional courses (total of 26 courses) in the absence of disease progression or unacceptable toxicity. PHASE II: Patients undergo radiotherapy and receive tipifarnib at the MTD as in phase I (closed to accrual as of 1/19/06). Treatment continues for up to 24 months (26 courses) in the absence of disease progression or unacceptable toxicity. | Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Drug: tipifarnib<br>* Given orally<br>* Other names: Zarnestra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in the Phase I Component With Dose-limiting Toxicities (DLTs) Observed During the First 8 Weeks (Courses 1 and 2) of Tipifarnib Therapy | The dose limiting toxicity (DLT) analysis population consists of phase I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (courses 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD. | Day 1 of tipifarnib therapy to week 8 | 
| Progression-free Survival (PFS) | PFS was defined as the interval from initiation of treatment to the earliest of disease progression (tumor increase of 25% over baseline tumor measurement; appearance of new lesion(s); or progressive/worsening neurological status) or death for patients who failed, or to the last date of follow up for patients without failure. | Assessed before the first dose of tipifarnib, every 8 weeks for the first 48 weeks, and then every 12 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of treatment on changes in neuroimaging meaurements. Neuroimaging changes may have some association with outcome (response, survival, etc.). Perfusion values are obtained from magnetic resonance perfusion imaging and were measured at baseline, every 8 weeks for the first 48 weeks, and then every 12 weeks until treatment is discontinued. | Baseline and two weeks post completion of radiation | 
| Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation. | This study attempted to investigate in an exploratory manner the effect of treatment on changes in neuroimaging meaurements. Neuroimaging changes may have some association with outcome (response, survival, etc.). Diffusion values are obtained from magnetic resonance diffusion imaging and were measured at baseline, every 8 weeks for the first 48 weeks, and then every 12 weeks until treatment is discontinued. | Baseline and two weeks post completion of radiation | 
| Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response, survival, etc.). Volume FLAIR is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain. Volume FLAIR was obtained at baseline and within two weeks after completion of radiation. | Baseline and two weeks post completion of radiation | 
| Mean Tumor to Gray Matter Ratio Measured at Baseline | This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal gray matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to gray matter ratio value and the median of these values across patients is reported. | Baseline | 
| Mean Tumor to White Matter Ratio Measured at Baseline | This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal white matter to provide ratios of tumor/white matter. Each patient has a mean tumor to white matter ratio value and the median of these values across patients is reported. | Baseline |