Tipifarnib and Radiation Therapy in Treating Young Patients With Brainstem Glioma

• 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 [ Time Frame: Day 1 of tipifarnib therapy to week 8 ] [ Designated as safety issue: Yes ]
  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.
  
  
• Progression-free Survival (PFS) [ Time Frame: Assessed before the first dose of tipifarnib, every 8 weeks for the first 48 weeks, and then every 12 weeks. ] [ Designated as safety issue: No ]
  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.
  
  

• Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post completion of radiation ] [ Designated as safety issue: No ]
  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.
  
  
• Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation. [ Time Frame: Baseline and two weeks post completion of radiation ] [ Designated as safety issue: No ]
  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.
  
  
• Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post completion of radiation ] [ Designated as safety issue: No ]
  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.
  
  
• Mean Tumor to Gray Matter Ratio Measured at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  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.
  
  
• Mean Tumor to White Matter Ratio Measured at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  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.
  
  

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of tipifarnib when administered with radiotherapy in patients with non-disseminated, diffuse, intrinsic brainstem gliomas.
• Determine the efficacy of this regimen in these patients.

Secondary

• Determine the toxic effects of this regimen in these patients.
• Determine the radiographic changes of brainstem gliomas using magnetic resonance imaging (MRI), perfusion and diffusion imaging, and positron-emission tomography scans in patients treated with this regimen.

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 (closed to accrual as of 1/19/06): 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.