Tipifarnib and Radiation Therapy in Treating Young Patients With Brainstem Glioma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00079339
• Collaborator: (none)
• Enrollment: 51
• Location: 1
• Arm: 1
• Duration (Months): 70
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

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)

Condition or Disease	Intervention/Treatment	Phase
Untreated Childhood Brain Stem Glioma	Radiation: radiation therapy; Drug: tipifarnib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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).

2. 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:

1. To characterize toxicities associated with R115777 treatment in combination with and post radiation therapy.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of R115777 and XRT in Pediatric Patients With Newly Diagnosed Non-Disseminated Intrinsic Diffuse Brainstem Gliomas
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (radiation therapy and tipifarnib) 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; Undergo radiotherapy; Other Names: irradiation radiotherapy therapy, radiation ; Drug: tipifarnib; Given orally; Other Names: R115777 Zarnestra

Outcome Measures

Primary Outcome Measures

1. 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 [Day 1 of tipifarnib therapy to week 8]

   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.

2. Progression-free Survival (PFS) [Assessed before the first dose of tipifarnib, every 8 weeks for the first 48 weeks, and then every 12 weeks.]

   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.

Secondary Outcome Measures

1. Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation [Baseline and two weeks post 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.

2. Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation. [Baseline and two weeks post 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.

3. Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation [Baseline and two weeks post 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.

4. Mean Tumor to Gray Matter Ratio Measured at Baseline [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.

5. Mean Tumor to White Matter Ratio Measured at Baseline [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pediatric Brain Tumor Consortium	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Daphne Haas-Kogan, Pediatric Brain Tumor Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00079339
• Other Study ID Numbers: NCI-2012-03021; NCI-2012-03021; PBTC-014; PBTC-014; U01CA081457
• First Posted: Mar 10, 2004
• Last Update Posted: May 15, 2014
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Glioma; Tipifarnib

Study Results

Participant Flow

Recruitment Details	Participants from PBTC member institutions were enrolled on the phase I component between 01/30/2004 and 01/19/2006. The phase II component of the study opened on 06/02/2006 and completed accrual on 12/26/2007.

Arm/Group Title	Tipifarnib 100-mg/m2	Tipifarnib 125-mg/m2	Tipifarnib 150-mg/m2
Arm/Group Description	Tipifarnib 100 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study only.	Tipifarnib 125 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. The 125 mg/m2 dose level was determined to be the MTD and therefore the recommended phase II dose. Of the 40 participants treated at this dose level, six were enrolled on the phase I part of the study and 34 were enrolled to the phase II.	Tipifarnib 150 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study only.
Period Title: Overall Study
STARTED	5	40	6
Enrolled in Phase I	5	6	6
Maximum Tolerated Dose (MTD) Estimation	3	6	5
Enrolled in Phase II	0	40	0
COMPLETED	0	1	0
NOT COMPLETED	5	39	6

Baseline Characteristics

Arm/Group Title	Tipifarnib 100-mg/m2	Tipifarnib 125-mg/m2	Tipifarnib 150-mg/m2	Total
Arm/Group Description	Tipifarnib 100 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study only.	Tipifarnib 125 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. The 125 mg/m2 dose level was determined to be the MTD and therefore the recommended phase II dose. Of the 40 participants treated at this dose level, six were enrolled on the phase I part of the study and 34 were enrolled to the phase II.	Tipifarnib 150 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study only.	Total of all reporting groups
Overall Participants	5	40	6	51
Age (Count of Participants)
<=18 years	5 100%	40 100%	6 100%	51 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	5.87	5.48	5.84	5.72
Sex: Female, Male (Count of Participants)
Female	1 20%	25 62.5%	5 83.3%	31 60.8%
Male	4 80%	15 37.5%	1 16.7%	20 39.2%
Region of Enrollment (participants) [Number]
United States	5 100%	40 100%	6 100%	51 100%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Day 1 of tipifarnib therapy to week 8

Outcome Measure Data

Analysis Population Description

Per protocol, participants included phase I participants who developed dose-limiting toxicities during the maximum tolerated dose (MTD) estimation period (courses 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without dose-limiting toxicities.

Arm/Group Title	Tipifarnib 100-mg/m2	Tipifarnib 125-mg/m2	Tipifarnib 150-mg/m2
Arm/Group Description	Tipifarnib 100 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study.	Tipifarnib 125 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. The 125 mg/m2 dose level was determined to be the MTD and therefore the recommended phase II dose. Of the 40 participants treated at this dose level, six were enrolled on the phase I part of the study and 34 were enrolled to the phase II.	Tipifarnib 150 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study.
Measure Participants	3	6	5
Number [Participants]	0 0%	1 2.5%	4 66.7%

2. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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.
Time Frame	Assessed before the first dose of tipifarnib, every 8 weeks for the first 48 weeks, and then every 12 weeks.

Outcome Measure Data

Analysis Population Description

Per protocol 40 participants who received at least one dose of tipifarnib were needed for this objective. The analysis population consists of phase I participants treated at the maximum tolerated dose (MTD) and the participants enrolled to the phase II part.

Arm/Group Title	Tipifarnib 125-mg/m2
Arm/Group Description	Tipifarnib 125 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. The 125 mg/m2 dose level was determined to be the MTD and therefore the recommended phase II dose. Of the 40 participants treated at this dose level, six were enrolled on the phase I part of the study and 34 were enrolled to the phase II.
Measure Participants	40
Median (Full Range) [Months]	6.8

3. Secondary Outcome

Title	Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation
Description	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.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

The analysis population consists of participants, from both the phase I part and the phase II part, treated at any dose level who had a baseline perfusion ratio value and a second perfusion ratio value measured at approximately 8 weeks after starting treatment.

Arm/Group Title	Tipifarnib - Any Dose Level
Arm/Group Description	Participants treated at any dose level who had the baseline and on treatment (two weeks post completion of radiation) MRI perfusion scan.
Measure Participants	19
Median (Full Range) [Ratio]	-.42

4. Secondary Outcome

Title	Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation.
Description	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.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

The analysis population consists of participants, from both the phase I part and the phase II part, treated at any dose level who had a baseline diffusion ratio value and a second diffusion ratio value measured at approximately 8 weeks after starting treatment.

Arm/Group Title	Tipifarnib - All Dose Levels
Arm/Group Description	Participants treated at any dose level who had the baseline and on treatment (two weeks post completion of radiation) MRI diffusion scan.
Measure Participants	35
Median (Full Range) [Ratio]	-.13

5. Secondary Outcome

Title	Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation
Description	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.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

The analysis population consists of participants, from both the phase I part and the phase II part, treated at any dose level who had a baseline volume FLAIR value and a second volume FLAIR value measured at approximately 8 weeks after starting treatment.

Arm/Group Title	Tipifarnib - All Dose Levels
Arm/Group Description	Participants treated at any dose level who had the baseline and on treatment (two weeks post completion of radiation) MRI scan.
Measure Participants	33
Median (Full Range) [cubic centimeters]	-12.45

6. Secondary Outcome

Title	Mean Tumor to Gray Matter Ratio Measured at Baseline
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The analysis population consists of participants, from both the phase I part and the phase II part, treated at any dose level who had a baseline PET scan.

Arm/Group Title	Tipifarnib - All Dose Levels
Arm/Group Description	Participants treated at any dose level who had a baseline positron emission tomography (PET) scan.
Measure Participants	14
Median (Full Range) [Ratio]	.64

7. Secondary Outcome

Title	Mean Tumor to White Matter Ratio Measured at Baseline
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The analysis population consists of participants, from both the phase I part and the phase II part, treated at any dose level who had a baseline PET scan.

Arm/Group Title	Tipifarnib - All Dose Levels
Arm/Group Description	Participants treated at any dose level who had a baseline positron emission tomography (PET) scan.
Measure Participants	14
Median (Full Range) [Ratio]	1.44

Adverse Events

Time Frame	Clinical and laboratory studies to assess adverse events were scheduled pre-treatment, weekly during the first 8 weeks, every 2 weeks for courses 3 -13, and every 12 weeks for courses 14-26. Additional studies were done at the investigator's discretion.
Arm/Group Title	Tipifarnib 100-mg/m2		Tipifarnib 125-mg/m2		Tipifarnib 150-mg/m2
Arm/Group Description	Tipifarnib 100 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study only.		Tipifarnib 125 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. The 125 mg/m2 dose level was determined to be the MTD and therefore the recommended phase II dose. Of the 40 participants treated at this dose level, six were enrolled on the phase I part of the study and 34 were enrolled to the phase II.		Tipifarnib 150 mg/m2 twice a day for 6 weeks concurrent with radiation therapy followed by a two week rest period. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks). Tipifarnib was continued at 200 mg/m2 twice a day, starting at course 3, for 21 days followed by 7 days of rest. Treatment repeats every 4 weeks for up to 24 additional courses. Local radiation (RT) was initiated 1-2 days following the first dose of tipifarnib and was administered once daily, five days per week , at 180 cGy/day fractions for six weeks to a total dose of 5580 cGy. All participants treated at this dose level were enrolled to the phase I part of the study only.
All Cause Mortality
	Tipifarnib 100-mg/m2		Tipifarnib 125-mg/m2		Tipifarnib 150-mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tipifarnib 100-mg/m2		Tipifarnib 125-mg/m2		Tipifarnib 150-mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		29/40 (72.5%)		3/6 (50%)
Blood and lymphatic system disorders
Lymphopenia	0/5 (0%)		13/40 (32.5%)		0/6 (0%)
Neutrophils/granulocytes (ANC/AGC)	0/5 (0%)		2/40 (5%)		1/6 (16.7%)
Cardiac disorders
Hypertension	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Eye disorders
Eyelid dysfunction	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Gastrointestinal disorders
Dysphagia (difficulty swallowing)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
General disorders
Pain - Head/Headache	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Death not associated with CTCAE term	2/5 (40%)		5/40 (12.5%)		0/6 (0%)
Death not associated with CTCAE term	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		3/40 (7.5%)		1/6 (16.7%)
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe	0/5 (0%)		2/40 (5%)		0/6 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils	1/5 (20%)		0/40 (0%)		0/6 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Potassium, serum-low (hypokalemia)	1/5 (20%)		2/40 (5%)		0/6 (0%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	0/5 (0%)		2/40 (5%)		0/6 (0%)
Alkalosis (metabolic or respiratory)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Bicarbonate, serum-low	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
GGT (gamma-Glutamyl transpeptidase)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Glucose, serum-high (hyperglycemia)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Phosphate, serum-low (hypophosphatemia)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Sodium, serum-low (hyponatremia)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)	1/5 (20%)		0/40 (0%)		0/6 (0%)
Nervous system disorders
Hemorrhage, CNS	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Ataxia (incoordination)	1/5 (20%)		3/40 (7.5%)		0/6 (0%)
Hydrocephalus	1/5 (20%)		3/40 (7.5%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Neuropathy: motor	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Seizure	0/5 (0%)		2/40 (5%)		0/6 (0%)
Speech impairment (e.g., dysphasia or aphasia)	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Apnea	1/5 (20%)		0/40 (0%)		0/6 (0%)
Encephalopathy	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Laryngeal nerve dysfunction	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Neurology - Other (Specify, __)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		0/40 (0%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		0/40 (0%)		0/6 (0%)
Psychiatric disorders
Somnolence/depressed level of consciousness	3/5 (60%)		4/40 (10%)		0/6 (0%)
Mood alteration	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Renal and urinary disorders
Hemorrhage, GU	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Pain - Kidney	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Obstruction, GU	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Urinary retention (including neurogenic bladder)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/5 (0%)		2/40 (5%)		1/6 (16.7%)
Aspiration	0/5 (0%)		2/40 (5%)		0/6 (0%)
Pneumonitis/pulmonary infiltrates	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Cough	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Dyspnea (shortness of breath)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Urticaria (hives, welts, wheals)	0/5 (0%)		1/40 (2.5%)		0/6 (0%)
Surgical and medical procedures
Hemorrhage/bleeding associated with surgery, intra-operative or postoperative	1/5 (20%)		0/40 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Tipifarnib 100-mg/m2		Tipifarnib 125-mg/m2		Tipifarnib 150-mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		40/40 (100%)		5/6 (83.3%)
Blood and lymphatic system disorders
Lymphopenia	3/5 (60%)		29/40 (72.5%)		2/6 (33.3%)
Leukocytes (total WBC)	4/5 (80%)		25/40 (62.5%)		4/6 (66.7%)
Hemoglobin	1/5 (20%)		20/40 (50%)		3/6 (50%)
Platelets	3/5 (60%)		12/40 (30%)		3/6 (50%)
Neutrophils/granulocytes (ANC/AGC)	2/5 (40%)		10/40 (25%)		2/6 (33.3%)
Cardiac disorders
Hypertension	0/5 (0%)		7/40 (17.5%)		1/6 (16.7%)
Endocrine disorders
Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae)	2/5 (40%)		13/40 (32.5%)		2/6 (33.3%)
Eye disorders
Ophthalmoplegia/diplopia (double vision)	1/5 (20%)		13/40 (32.5%)		1/6 (16.7%)
Nystagmus	1/5 (20%)		10/40 (25%)		0/6 (0%)
Vision-blurred vision	1/5 (20%)		1/40 (2.5%)		1/6 (16.7%)
Ocular surface disease	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Vision-photophobia	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Gastrointestinal disorders
Vomiting	3/5 (60%)		30/40 (75%)		3/6 (50%)
Nausea	1/5 (20%)		17/40 (42.5%)		2/6 (33.3%)
Dysphagia (difficulty swallowing)	1/5 (20%)		10/40 (25%)		2/6 (33.3%)
Diarrhea	1/5 (20%)		10/40 (25%)		1/6 (16.7%)
Anorexia	0/5 (0%)		8/40 (20%)		3/6 (50%)
Mucositis/stomatitis (clinical exam)	1/5 (20%)		7/40 (17.5%)		2/6 (33.3%)
Constipation	2/5 (40%)		18/40 (45%)		4/6 (66.7%)
Gastritis (including bile reflux gastritis)	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Heartburn/dyspepsia	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
General disorders
Fatigue (asthenia, lethargy, malaise)	2/5 (40%)		18/40 (45%)		3/6 (50%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	0/5 (0%)		3/40 (7.5%)		1/6 (16.7%)
Weight gain	1/5 (20%)		2/40 (5%)		1/6 (16.7%)
Weight loss	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Pain - Head/headache	2/5 (40%)		23/40 (57.5%)		4/6 (66.7%)
Pain - Abdomen NOS	1/5 (20%)		8/40 (20%)		2/6 (33.3%)
Pain - Extremity-limb	2/5 (40%)		5/40 (12.5%)		2/6 (33.3%)
Pain - Throat/pharynx/larynx	0/5 (0%)		4/40 (10%)		0/6 (0%)
Pain - Back	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Pain - Middle ear	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Pain - Eye	1/5 (20%)		1/40 (2.5%)		1/6 (16.7%)
Pain - Muscle	0/5 (0%)		1/40 (2.5%)		2/6 (33.3%)
Pain - Stomach	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Sweating	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Pain - Chest/thorax NOS	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Pain - Neck	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/5 (20%)		10/40 (25%)		3/6 (50%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils	1/5 (20%)		3/40 (7.5%)		0/6 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils	1/5 (20%)		4/40 (10%)		0/6 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils	1/5 (20%)		2/40 (5%)		0/6 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Infection with normal ANC or Grade 1 or 2 neutrophils	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Febrile neutropenia (fever of unknown origin)	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Infection with normal ANC or Grade 1 or 2 neutrophils	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Infection with unknown ANC	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Opportunistic infection associated with >=Grade 2 Lymphopenia	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	3/5 (60%)		22/40 (55%)		3/6 (50%)
Albumin, serum-low (hypoalbuminemia)	3/5 (60%)		16/40 (40%)		3/6 (50%)
Glucose, serum-high (hyperglycemia)	2/5 (40%)		17/40 (42.5%)		3/6 (50%)
Magnesium, serum-high (hypermagnesemia)	3/5 (60%)		11/40 (27.5%)		2/6 (33.3%)
Sodium, serum-low (hyponatremia)	2/5 (40%)		13/40 (32.5%)		1/6 (16.7%)
Calcium, serum-low (hypocalcemia)	4/5 (80%)		8/40 (20%)		3/6 (50%)
Potassium, serum-low (hypokalemia)	2/5 (40%)		12/40 (30%)		1/6 (16.7%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/5 (20%)		12/40 (30%)		1/6 (16.7%)
Glucose, serum-low (hypoglycemia)	1/5 (20%)		10/40 (25%)		0/6 (0%)
Calcium, serum-high (hypercalcemia)	0/5 (0%)		8/40 (20%)		1/6 (16.7%)
Bicarbonate, serum-low	0/5 (0%)		7/40 (17.5%)		1/6 (16.7%)
GGT (gamma-Glutamyl transpeptidase)	0/5 (0%)		5/40 (12.5%)		0/6 (0%)
Magnesium, serum-low (hypomagnesemia)	0/5 (0%)		4/40 (10%)		0/6 (0%)
Potassium, serum-high (hyperkalemia)	0/5 (0%)		4/40 (10%)		0/6 (0%)
Bilirubin (hyperbilirubinemia)	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Metabolic/Laboratory - Other (Specify, __)	2/5 (40%)		1/40 (2.5%)		1/6 (16.7%)
Sodium, serum-high (hypernatremia)	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Phosphate, serum-low (hypophosphatemia)	3/5 (60%)		14/40 (35%)		3/6 (50%)
Alkaline phosphatase	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)	1/5 (20%)		3/40 (7.5%)		0/6 (0%)
Muscle weakness, generalized or specific area (not due to neuropathy)	0/5 (0%)		4/40 (10%)		0/6 (0%)
Muscle weakness, generalized or specific area (not due to neuropathy)	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Extremity-lower (gait/walking)	1/5 (20%)		0/40 (0%)		0/6 (0%)
Extremity-upper (function)	1/5 (20%)		0/40 (0%)		0/6 (0%)
Muscle weakness, generalized or specific area (not due to neuropathy)	1/5 (20%)		0/40 (0%)		0/6 (0%)
Nervous system disorders
Hemorrhage, CNS	0/5 (0%)		6/40 (15%)		0/6 (0%)
Ataxia (incoordination)	2/5 (40%)		29/40 (72.5%)		3/6 (50%)
Neuropathy: cranial	3/5 (60%)		21/40 (52.5%)		2/6 (33.3%)
Neuropathy: cranial	1/5 (20%)		21/40 (52.5%)		3/6 (50%)
Neuropathy: motor	1/5 (20%)		12/40 (30%)		3/6 (50%)
Dizziness	0/5 (0%)		8/40 (20%)		2/6 (33.3%)
Speech impairment (e.g., dysphasia or aphasia)	1/5 (20%)		8/40 (20%)		1/6 (16.7%)
Neuropathy: cranial	2/5 (40%)		6/40 (15%)		0/6 (0%)
Neuropathy: cranial	2/5 (40%)		4/40 (10%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		5/40 (12.5%)		0/6 (0%)
Neuropathy: sensory	1/5 (20%)		4/40 (10%)		1/6 (16.7%)
Pyramidal tract dysfunction (e.g., increased tone, hyperreflexia, positive Babinski, decreased fine	1/5 (20%)		5/40 (12.5%)		0/6 (0%)
Neuropathy: cranial	2/5 (40%)		3/40 (7.5%)		0/6 (0%)
Tremor	1/5 (20%)		4/40 (10%)		0/6 (0%)
Neuropathy: cranial	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Neuropathy: cranial	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Neuropathy: cranial	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Neuropathy: cranial	1/5 (20%)		1/40 (2.5%)		0/6 (0%)
Psychiatric disorders
Mood alteration - Depression	0/5 (0%)		3/40 (7.5%)		1/6 (16.7%)
Somnolence/depressed level of consciousness	1/5 (20%)		4/40 (10%)		1/6 (16.7%)
Personality/behavioral	0/5 (0%)		2/40 (5%)		2/6 (33.3%)
Mood alteration - Agitation	0/5 (0%)		5/40 (12.5%)		1/6 (16.7%)
Renal and urinary disorders
Urinary retention (including neurogenic bladder)	1/5 (20%)		4/40 (10%)		1/6 (16.7%)
Incontinence, urinary	1/5 (20%)		2/40 (5%)		0/6 (0%)
Urinary frequency/urgency	0/5 (0%)		2/40 (5%)		1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Hemorrhage, pulmonary/upper respiratory	1/5 (20%)		2/40 (5%)		1/6 (16.7%)
Cough	2/5 (40%)		8/40 (20%)		3/6 (50%)
Pulmonary/Upper Respiratory - Other (Specify, __)	0/5 (0%)		1/40 (2.5%)		1/6 (16.7%)
Dyspnea (shortness of breath)	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Hiccoughs (hiccups, singultus)	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Pneumonitis/pulmonary infiltrates	0/5 (0%)		0/40 (0%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
Rash/desquamation	3/5 (60%)		15/40 (37.5%)		2/6 (33.3%)
Hair loss/alopecia (scalp or body)	2/5 (40%)		7/40 (17.5%)		2/6 (33.3%)
Rash: acne/acneiform	0/5 (0%)		7/40 (17.5%)		1/6 (16.7%)
Dry skin	1/5 (20%)		5/40 (12.5%)		1/6 (16.7%)
Pruritus/itching	0/5 (0%)		5/40 (12.5%)		2/6 (33.3%)
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	1/5 (20%)		1/40 (2.5%)		1/6 (16.7%)
Flushing	0/5 (0%)		3/40 (7.5%)		0/6 (0%)
Rash: hand-foot skin reaction	1/5 (20%)		0/40 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.