Imatinib Mesylate With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00021229
• Collaborator: (none)
• Enrollment: 85
• Locations: 10
• Arm: 1
• Duration (Months): 87
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Phase I/II trial to estimate the maximum tolerated dose of imatinib mesylate in newly diagnosed brain stem gliomas and recurrent high grade gliomas and to assess the effectiveness of imatinib mesylate in treating young patients who have newly diagnosed intrinsic brain stem glioma. Imatinib mesylate may interfere with the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining imatinib mesylate with radiation therapy may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: imatinib mesylate; Radiation: local irradiation therapy	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the maximum tolerated dose (MTD) of imatinib mesylate after completion of radiation in children with newly diagnosed poor prognosis brainstem gliomas. (Phase I, strata I closed to accrual as of 5/28/04.) II. Determine the maximum tolerated dose (MTD) of imatinib mesylate in children with recurrent high-grade intracranial glioma stratified according to the use of enzyme-inducing anticonvulsant drugs (EIACDs). (Phase I, strata IIA and IIB closed to accrual as of 8/15/03 and 8/15/04, respectively) III. Determine the safety and efficacy of this drug in patients with newly diagnosed diffuse intrinsic brainstem gliomas. (Phase II)

SECONDARY OBJECTIVES:

1. Explore neuroimaging and biological correlatives of therapeutic activity of this regimen in these patients. (Phase I, all strata closed to accrual as of 8/15/04) II. Determine the pharmacokinetics of these regimens in these patients overall and by enzyme-inducing anticonvulsant drugs (EIACDs) (Phase I, all strata closed to accrual as of 8/15/04.) III. Estimate the progression-free survival (PFS) and overall survival (OS) of newly diagnosed diffuse intrinsic brainstem gliomas treated with this drug. (Phase I and II)

OUTLINE: This is a phase I dose-escalation, multicenter study followed by a phase II. Patients are stratified according to tumor type (newly diagnosed intrinsic brainstem glioma vs recurrent/refractory intracranial high-grade glioma). Patients in stratum II (phase I only) are further stratified according to concurrent use of enzyme-inducing anticonvulsant drugs (EIACDs) (yes vs no). Patients are assigned to one of three strata in the phase I study.

• Phase I

• Stratum I (newly diagnosed brainstem glioma): Patients undergo radiotherapy once daily five days a week for 6 weeks. Beginning 1-3 weeks after completion of radiotherapy, patients without evidence of intratumoral bleed receive oral imatinib mesylate twice daily. Imatinib mesylate treatment repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity. (Closed to accrual as of 5/28/04.)

• Stratum II A (recurrent or refractory high-grade intracranial gliomas/no concurrent EIACDs): Patients receive imatinib mesylate as in stratum I. (Closed to accrual as of 8/15/03.)

• Stratum II B (recurrent or refractory high-grade intracranial gliomas and concurrent EIACDs): Patients receive imatinib mesylate as in stratum I. (Closed to accrual as of 8/15/04.)

Cohorts of 2-3 patients receive escalating doses of imatinib mesylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which it is estimated that 20% of patients will experience dose-limiting toxicity. MTDs are independently estimated in each strata. For stratum I, newly diagnosed brain stem gliomas, the dose level which at least 5 of 6 patients experience no dose-limiting toxicity will be the dose used in the efficacy and safety phase (phase II).

• Phase II: (Open to accrual as of 5/28/04.)

• Stratum I only: Patients undergo radiotherapy as in phase I. Patients receive imatinib mesylate at the MTD established in phase I.

Patients enrolled in the phase I portion and not treated at the MTD are to be followed for the shortest of 1) three months after the last protocol based treatment or 2) the date other therapy is initiated. Stratum I patients treated at the MTD in the phase I portion and all patients in the phase II portion of the study are to be followed until death or withdrawal from the study

PROJECTED ACCRUAL: Approximately 140 patients will be accrued for this study within 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial Of STI571 In Children With Newly Diagnosed Poor Prognosis Brainstem Gliomas And Recurrent Intracranial Malignant Gliomas
• Study Start Date: May 1, 2001
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Imatinib mesylate

Drug: imatinib mesylate; Phase 1 Stratum I: Starting dose level of 350 mg/m2/day every 28 days X 13 courses (dose escalation) Phase I Stratum IIA: Starting dose level of 465 mg/m2/day every 28 days X 13 courses (dose escalation) Phase I Stratum IIB: Starting dose level of 465 mg/m2/day every 28 days X 13 courses (dose escalation) Phase II: Phase I Stratum I determined dose (Maximum tolerated dose) every 28 days X 13 courses.; Radiation: local irradiation therapy; Phase I Stratum I: Total dose of 5580 cGy using conventional or conformal volume-based delivery techniques once daily, 5 days/week for six weeks prior to receiving imatinib. Phase II: Total dose of 5580 cGy using conventional or conformal volume-based delivery techniques once daily, 5 days/week for six weeks prior to receiving imatinib.

Outcome Measures

Primary Outcome Measures

1. Number of Participants in Phase I Stratum I With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy [Day 1 of Imatinib Mesylate Therapy to Week 8]

   The dose limiting toxicity (DLT) analysis population consists of phase I stratum I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 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. The estimated MTD based on the 23 participants who either had a DLT during course 1 or 2 or completed courses 1 and 2 without DLT is 265 mg/m2/day.

2. Number of Participants in Phase I Stratum II With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy [Day 1 of Imatinib Mesylate Therapy to Week 8]

   The dose limiting toxicity (DLT) analysis population consisted of phase I stratum II 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. The estimated MTD based on the DLT analysis population of 20 in stratum IIA was 465 mg/m2/day. An MTD was not established in stratum IIB as no DLTs were observed at the higher dose levels of 620 and 800 mg/m2/day.

3. Median Progression-free Survival (PFS) [Assessed pre-radiation, before the first dose of imatinib, and then every 8 weeks]

   Progression-free survival is 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 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 radiation (RT) on changes in various neuroimaging variables in pediatric brainstem gliomas (stratum I). 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 (pre-radiation) and within two (+/- one) weeks after completion of RT.

2. Peak Concentration (Cmax) [Day 1 of Course 1]

   Peak concentration (cmax) is a pharmacokinetic measure defined as the highest concentration of a drug measured after the drug is administered. The cmax of imatinib mesylate on day 1 of course 1 is reported. Two milliliter (0.5 ml for children under the age of 5) blood samples were collected immediately prior to imatinib mesylate administration on Day 1 of Course 1 and at the following timepoints following drug administration: 0.5, 1, 1.5, 2, 4, 10 and 12 hours after the morning dose.

3. Median Overall Survival [Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks.]

   Overall Survival (OS) is defined as the interval from initiation of treatment to death or date of last contact for surviving patients.

4. Pre-treatment Basic Fibroblast Growth Factor Values From Urine [Pre-treatment]

   This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine bFGF values.

5. Pre-treatment Basic Fibroblast Growth Factor Values From Plasma [Pre-treatment]

   This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma bFGF values.

6. Pre-treatment Vascular Endothelial Growth Factor From Urine [Pre-treatment]

   This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine VEGF values.

7. Pre-treatment Vascular Endothelial Growth Factor Values From Plasma [Pre-treatment]

   This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma VEGF values.

Eligibility Criteria

Criteria

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

Inclusion Criteria

• Age 3 to 21

• Performance status of Karnofsky 50-100% OR Lansky 50-100%

• Absolute neutrophil count greater than 1,000/mm3

• Platelet count greater than 100,000/mm3 (transfusion independent)

• Hemoglobin greater than 8 g/dL (transfusion allowed)

• Bilirubin no greater than 1.5 times normal for age

• SGPT less than 3 times normal for age

• Albumin at least 2 g/dL

• Creatinine less than 1.5 times normal for age OR Glomerular filtration rate greater than 70 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception during and for 6 months after study participation

• Stratum I

• Newly diagnosed diffuse intrinsic brainstem malignant glioma

• No disseminated disease

• No radiographic evidence of intratumoral hemorrhage before or during radiotherapy

• No prior chemotherapy (beyond routine corticosteroids)

• No prior irradiation

• Must not be receiving enzyme-inducing anticonvulsant drugs

• Stratum II

• Histologically confirmed recurrent or refractory anaplastic astrocytoma, glioblastoma multiforme, or other high-grade glioma (including recurrent brain stem glioma

• No intratumoral hemorrhage unrelated to prior surgical procedure

• No myelosuppressive chemotherapy within 3 weeks (6 weeks if a nitrosourea agent) of study entry

• No prior imatinib mesylate

• At least 3 months since prior craniospinal radiotherapy (18 Gy or more)

• At least 8 weeks since prior local radiotherapy to primary tumor

• At least 2 weeks since prior focal radiotherapy for symptomatic

• At least 3 months since prior bone marrow transplantation

• Neurological deficits allowed if stable for at least 1 week prior to study

Exclusion Criteria

• Receiving other anticancer or experimental drug therapy.

• Ongoing uncontrolled infection.

• Significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or psychiatric disease.

• Deep venous or arterial thrombosis within 6 weeks of registration.

• Taking warfarin.

• Newly diagnosed diffuse intrinsic brainstem malignant glioma with disseminated disease (stratum I)

• Intratumoral hemorrhage

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Comprehensive Cancer Center	San Francisco	California	United States	94143
2	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
3	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
4	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
5	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-4318
7	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
8	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105-2794
9	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas	United States	77030-2399
10	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Study Chair: Ian F. Pollack, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00021229
• Other Study ID Numbers: NCI-2012-03019; PBTC-006; U01CA081457; CDR0000068761
• First Posted: Jan 27, 2003
• Last Update Posted: Jul 31, 2014
• Last Verified: Feb 1, 2013

• Keywords provided by National Cancer Institute (NCI): childhood central nervous system germ cell tumor; childhood high-grade cerebral astrocytoma; untreated childhood brain stem glioma; recurrent childhood brain stem glioma; recurrent childhood cerebral astrocytoma
• Additional relevant MeSH terms: Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Imatinib Mesylate

Study Results

Participant Flow

Recruitment Details	Participants from PBTC member institutions were enrolled on the phase I component between 09May2001 and 28MAY2004 (stratum I), 15AUG2003 (stratum IIA), and 15AUG2004 (stratum IIB). The phase II component of the study opened on 28MAY2004 and was terminated on 13APR2005 due to poor accrual.
Pre-assignment Detail	The intent of the phase I part of the study was to estimate the maximum tolerated dose (MTD) independently in stratum I, in stratum IIA, and in stratum IIB. The estimated MTD from stratum I was the recommended dose for the phase II part. Phase I participants in stratum I who received study drug at the MTD contributed to the phase II objectives.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Period Title: Overall Study
STARTED	36	33	16
Enrolled in Phase I	35	33	16
Maximum Tolerated Dose (MTD) Estimation	23	20	12
Enrolled in Phase II	14	0	0
COMPLETED	1	0	0
NOT COMPLETED	35	33	16

Baseline Characteristics

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate	Total
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Total of all reporting groups
Overall Participants	36	33	16	85
Age (Count of Participants)
<=18 years	36 100%	30 90.9%	15 93.8%	81 95.3%
Between 18 and 65 years	0 0%	3 9.1%	1 6.3%	4 4.7%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.05 (4.3)	10.9 (5.4)	14.1 (4.7)	10.3 (5.3)
Sex: Female, Male (Count of Participants)
Female	18 50%	20 60.6%	9 56.3%	47 55.3%
Male	18 50%	13 39.4%	7 43.8%	38 44.7%
Region of Enrollment (participants) [Number]
United States	36 100%	33 100%	16 100%	85 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants in Phase I Stratum I With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy
Description	The dose limiting toxicity (DLT) analysis population consists of phase I stratum I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 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. The estimated MTD based on the 23 participants who either had a DLT during course 1 or 2 or completed courses 1 and 2 without DLT is 265 mg/m2/day.
Time Frame	Day 1 of Imatinib Mesylate Therapy to Week 8

Outcome Measure Data

Analysis Population Description

Per protocol, participants included phase I stratum 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	Stratum I: Radiation + Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.
Measure Participants	23
Number [Participants]	5 13.9%

2. Primary Outcome

Title	Number of Participants in Phase I Stratum II With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy
Description	The dose limiting toxicity (DLT) analysis population consisted of phase I stratum II 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. The estimated MTD based on the DLT analysis population of 20 in stratum IIA was 465 mg/m2/day. An MTD was not established in stratum IIB as no DLTs were observed at the higher dose levels of 620 and 800 mg/m2/day.
Time Frame	Day 1 of Imatinib Mesylate Therapy to Week 8

Outcome Measure Data

Analysis Population Description

Per protocol, participants included phase I stratum II participants who developed dose-limiting toxicities (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.

Arm/Group Title	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Measure Participants	20	12
Number [Participants]	2 5.6%	0 0%

3. Primary Outcome

Title	Median Progression-free Survival (PFS)
Description	Progression-free survival is 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 pre-radiation, before the first dose of imatinib, and then every 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol, 40 participants who received at least one dose of drug were needed for this objective. The analysis population consists of stratum I participants enrolled at the maximum tolerated dose (phase 1) and the participants enrolled to the phase II part. The study was terminated because of poor accrual and the objective was not met.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.
Measure Participants	0

4. 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 radiation (RT) on changes in various neuroimaging variables in pediatric brainstem gliomas (stratum I). 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 (pre-radiation) and within two (+/- one) weeks after completion of RT.
Time Frame	Baseline and two weeks post completion of radiation

Outcome Measure Data

Analysis Population Description

The analysis population consists of Stratum I patients enrolled who had both pre and post radiation (RT) volume FLAIR measures. Stratum II participants did not receive RT and thus were not included.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.
Measure Participants	24
Mean (Full Range) [cubic centimeters]	7.62

5. Secondary Outcome

Title	Peak Concentration (Cmax)
Description	Peak concentration (cmax) is a pharmacokinetic measure defined as the highest concentration of a drug measured after the drug is administered. The cmax of imatinib mesylate on day 1 of course 1 is reported. Two milliliter (0.5 ml for children under the age of 5) blood samples were collected immediately prior to imatinib mesylate administration on Day 1 of Course 1 and at the following timepoints following drug administration: 0.5, 1, 1.5, 2, 4, 10 and 12 hours after the morning dose.
Time Frame	Day 1 of Course 1

Outcome Measure Data

Analysis Population Description

The analysis population consists of participants who enrolled at the maximum tolerated dose (MTD) of the phase I component and who submitted day 1 course 1 samples for the PK studies. An MTD was not estimated in stratum IIB. For this stratum, reported are values at the stratum IIA MTD to allow comparison.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Measure Participants	3	9	3
Mean (Full Range) [µg/ml]	1.3	2.6	1.3

6. Secondary Outcome

Title	Median Overall Survival
Description	Overall Survival (OS) is defined as the interval from initiation of treatment to death or date of last contact for surviving patients.
Time Frame	Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks.

Outcome Measure Data

Analysis Population Description

The analysis population consists of the stratum I participants who received imatinib mesylate at or above the maximum tolerated dose. The median survival reported is based on these 20 participants.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.
Measure Participants	20
Median (95% Confidence Interval) [Days]	324.5 (8.7)

7. Secondary Outcome

Title	Pre-treatment Basic Fibroblast Growth Factor Values From Urine
Description	This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine bFGF values.
Time Frame	Pre-treatment

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment urine samples for the biomarker study.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Measure Participants	16	17	10
Mean (Standard Deviation) [pg/ml]	5665 (4006)	10322 (14443)	5312 (6262)

8. Secondary Outcome

Title	Pre-treatment Basic Fibroblast Growth Factor Values From Plasma
Description	This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma bFGF values.
Time Frame	Pre-treatment

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment blood samples for the biomarker study.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Measure Participants	19	16	10
Mean (Standard Deviation) [pg/ml]	8.69 (7.16)	32.3 (64.5)	11.3 (12.2)

9. Secondary Outcome

Title	Pre-treatment Vascular Endothelial Growth Factor From Urine
Description	This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine VEGF values.
Time Frame	Pre-treatment

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment urine samples for the biomarker study.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Measure Participants	16	17	10
Mean (Standard Deviation) [pg/ml]	79 (69.9)	86.1 (93.9)	45.3 (38.0)

10. Secondary Outcome

Title	Pre-treatment Vascular Endothelial Growth Factor Values From Plasma
Description	This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma VEGF values.
Time Frame	Pre-treatment

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment blood samples for the biomarker study.

Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Measure Participants	19	16	10
Mean (Standard Error) [pg/ml]	119.9 (168.5)	155.2 (229.7)	78.2 (59.4)

Adverse Events

Time Frame	Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment.
Adverse Event Reporting Description	Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Arm/Group Title	Stratum I: Radiation + Imatinib Mesylate		Stratum IIA: Imatinib Mesylate		Stratum IIB: Imatinib Mesylate
Arm/Group Description	Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.		Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.		Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
All Cause Mortality
	Stratum I: Radiation + Imatinib Mesylate		Stratum IIA: Imatinib Mesylate		Stratum IIB: Imatinib Mesylate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Stratum I: Radiation + Imatinib Mesylate		Stratum IIA: Imatinib Mesylate		Stratum IIB: Imatinib Mesylate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/36 (36.1%)		13/33 (39.4%)		5/16 (31.3%)
Blood and lymphatic system disorders
Edema	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Hemoglobin (Hgb)	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Leukocytes (total WBC)	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Lymphopenia	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Neutrophils/granulocytes (ANC/AGC)	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Platelets	0/36 (0%)		1/33 (3%)		0/16 (0%)
Thrombosis/embolism	0/36 (0%)		0/33 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Abdominal pain or cramping	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Colitis	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Constipation	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Dehydration	0/36 (0%)		0/33 (0%)		1/16 (6.3%)
Diarrhea without colostomy	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Melena/GI bleeding	0/36 (0%)		1/33 (3%)		0/16 (0%)
Nausea	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Vomiting	1/36 (2.8%)		1/33 (3%)		2/16 (12.5%)
General disorders
Fatigue	2/36 (5.6%)		3/33 (9.1%)		0/16 (0%)
Fever (in the absence of neutropenia)	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Inpatient Hospital Days	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Pain - other	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Hepatobiliary disorders
Hypoalbuminemia	2/36 (5.6%)		1/33 (3%)		0/16 (0%)
Infections and infestations
Infection without neutropenia	3/36 (8.3%)		0/33 (0%)		0/16 (0%)
Metabolism and nutrition disorders
Bicarbonate	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Hyperglycemia	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Hypocalcemia	0/36 (0%)		1/33 (3%)		0/16 (0%)
Hypokalemia	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Hyponatremia	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Hypophosphatemia	0/36 (0%)		2/33 (6.1%)		0/16 (0%)
Metabolic/Laboratory- Other	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal - Other	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Nervous system disorders
CNS hemorrhage/bleeding	7/36 (19.4%)		7/33 (21.2%)		2/16 (12.5%)
Confusion	0/36 (0%)		0/33 (0%)		1/16 (6.3%)
Depressed level of consciousness	1/36 (2.8%)		1/33 (3%)		1/16 (6.3%)
Headache	3/36 (8.3%)		3/33 (9.1%)		3/16 (18.8%)
Memory loss	0/36 (0%)		0/33 (0%)		1/16 (6.3%)
Neurology - Other	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Neuropathy - Motor	1/36 (2.8%)		1/33 (3%)		1/16 (6.3%)
Neuropathy - cranial	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Neuropathy - sensory	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Seizures	1/36 (2.8%)		0/33 (0%)		1/16 (6.3%)
Speech impairment	1/36 (2.8%)		1/33 (3%)		0/16 (0%)
Tremor	0/36 (0%)		1/33 (3%)		0/16 (0%)
Renal and urinary disorders
Creatinine	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Hematuria	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Incontinence	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Renal/Genitourinary - Other	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Pleural effusion (non-malignant)	1/36 (2.8%)		0/33 (0%)		0/16 (0%)
Skin and subcutaneous tissue disorders
Pigmentation changes	0/36 (0%)		1/33 (3%)		0/16 (0%)
Rash/desquamation	0/36 (0%)		1/33 (3%)		0/16 (0%)
Vascular disorders
Hematemesis	0/36 (0%)		1/33 (3%)		0/16 (0%)
Hypertension	1/36 (2.8%)		2/33 (6.1%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Stratum I: Radiation + Imatinib Mesylate		Stratum IIA: Imatinib Mesylate		Stratum IIB: Imatinib Mesylate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/36 (91.7%)		31/33 (93.9%)		14/16 (87.5%)
Blood and lymphatic system disorders
Hemoglobin	17/36 (47.2%)		10/33 (30.3%)		7/16 (43.8%)
Leukocytes	18/36 (50%)		9/33 (27.3%)		6/16 (37.5%)
Lymphopenia	19/36 (52.8%)		8/33 (24.2%)		7/16 (43.8%)
Neutrophils/granulocytes	15/36 (41.7%)		8/33 (24.2%)		4/16 (25%)
Platelets	8/36 (22.2%)		6/33 (18.2%)		5/16 (31.3%)
Transfusions: pRBCs	0/36 (0%)		1/33 (3%)		1/16 (6.3%)
Ear and labyrinth disorders
Earache (otalgia)	5/36 (13.9%)		0/33 (0%)		1/16 (6.3%)
External auditory canal	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Inner ear/hearing	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Endocrine disorders
Cushingnoid appearance	8/36 (22.2%)		1/33 (3%)		0/16 (0%)
Eye disorders
Conjunctivitis	3/36 (8.3%)		0/33 (0%)		0/16 (0%)
Ocular/Visual - Other	1/36 (2.8%)		3/33 (9.1%)		0/16 (0%)
Vision - blurred vision	2/36 (5.6%)		2/33 (6.1%)		0/16 (0%)
Vision - double vision	9/36 (25%)		2/33 (6.1%)		2/16 (12.5%)
Gastrointestinal disorders
Abdominal pain or cramping	8/36 (22.2%)		2/33 (6.1%)		2/16 (12.5%)
Constipation	14/36 (38.9%)		3/33 (9.1%)		1/16 (6.3%)
Diarrhea without colostomy	7/36 (19.4%)		6/33 (18.2%)		1/16 (6.3%)
Dyspepsia/heartburn	6/36 (16.7%)		3/33 (9.1%)		0/16 (0%)
Dysphagia, esophagitis, odynophagia (painful swallowing)	2/36 (5.6%)		1/33 (3%)		0/16 (0%)
Flatulence	2/36 (5.6%)		1/33 (3%)		0/16 (0%)
Gastrointestinal-Other	1/36 (2.8%)		2/33 (6.1%)		0/16 (0%)
Nausea	12/36 (33.3%)		10/33 (30.3%)		7/16 (43.8%)
Stomatitis/pharyngitis	3/36 (8.3%)		2/33 (6.1%)		1/16 (6.3%)
Vomiting	23/36 (63.9%)		13/33 (39.4%)		8/16 (50%)
General disorders
Constitutional symptoms - Other	2/36 (5.6%)		4/33 (12.1%)		0/16 (0%)
Fatigue	13/36 (36.1%)		11/33 (33.3%)		4/16 (25%)
Fever (in the absence of neutropenia)	5/36 (13.9%)		2/33 (6.1%)		0/16 (0%)
Irritability (<3 years of age)	3/36 (8.3%)		1/33 (3%)		0/16 (0%)
Neuropathic pain	1/36 (2.8%)		2/33 (6.1%)		0/16 (0%)
Pain - other	6/36 (16.7%)		4/33 (12.1%)		5/16 (31.3%)
Hepatobiliary disorders
Bilirubin	3/36 (8.3%)		1/33 (3%)		0/16 (0%)
Hepatic-Other	1/36 (2.8%)		0/33 (0%)		2/16 (12.5%)
Hypoalbuminemia	5/36 (13.9%)		4/33 (12.1%)		6/16 (37.5%)
SGOT (AST)	14/36 (38.9%)		8/33 (24.2%)		4/16 (25%)
SGPT (ALT)	15/36 (41.7%)		9/33 (27.3%)		4/16 (25%)
Infections and infestations
Infection without neutropenia	10/36 (27.8%)		5/33 (15.2%)		1/16 (6.3%)
Infection/Febrile Neutropenia-Other	0/36 (0%)		1/33 (3%)		1/16 (6.3%)
Investigations
Alkaline phosphatase	1/36 (2.8%)		2/33 (6.1%)		1/16 (6.3%)
Creatinine	3/36 (8.3%)		1/33 (3%)		0/16 (0%)
GGT	1/36 (2.8%)		0/33 (0%)		3/16 (18.8%)
Weight gain	5/36 (13.9%)		4/33 (12.1%)		1/16 (6.3%)
Weight loss	2/36 (5.6%)		0/33 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Anorexia	10/36 (27.8%)		5/33 (15.2%)		1/16 (6.3%)
Bicarbonate	4/36 (11.1%)		3/33 (9.1%)		0/16 (0%)
Dehydration	1/36 (2.8%)		1/33 (3%)		1/16 (6.3%)
Hypercholesterolemia	0/36 (0%)		0/33 (0%)		2/16 (12.5%)
Hyperglycemia	11/36 (30.6%)		9/33 (27.3%)		5/16 (31.3%)
Hyperkalemia	3/36 (8.3%)		1/33 (3%)		3/16 (18.8%)
Hypermagnesemia	6/36 (16.7%)		3/33 (9.1%)		2/16 (12.5%)
Hypernatremia	3/36 (8.3%)		0/33 (0%)		1/16 (6.3%)
Hypertriglyceridemia	1/36 (2.8%)		0/33 (0%)		1/16 (6.3%)
Hyperuricemia	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Hypocalcemia	10/36 (27.8%)		7/33 (21.2%)		5/16 (31.3%)
Hypoglycemia	5/36 (13.9%)		1/33 (3%)		2/16 (12.5%)
Hypokalemia	9/36 (25%)		7/33 (21.2%)		3/16 (18.8%)
Hypomagnesemia	1/36 (2.8%)		2/33 (6.1%)		0/16 (0%)
Hyponatremia	10/36 (27.8%)		3/33 (9.1%)		8/16 (50%)
Hypophosphatemia	16/36 (44.4%)		10/33 (30.3%)		6/16 (37.5%)
Metabolic/Laboratory - Other	5/36 (13.9%)		1/33 (3%)		2/16 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia (joint pain)	3/36 (8.3%)		0/33 (0%)		1/16 (6.3%)
Muscle weakness	3/36 (8.3%)		3/33 (9.1%)		0/16 (0%)
Musculoskeletal-Other	2/36 (5.6%)		1/33 (3%)		1/16 (6.3%)
Myalgia (muscle pain)	4/36 (11.1%)		0/33 (0%)		0/16 (0%)
Nervous system disorders
Ataxia (incoordination)	8/36 (22.2%)		5/33 (15.2%)		3/16 (18.8%)
CNS hemorrhage/bleeding	3/36 (8.3%)		0/33 (0%)		0/16 (0%)
Cognitive/disturbance/learning problems	1/36 (2.8%)		1/33 (3%)		1/16 (6.3%)
Depressed level of consciousness	1/36 (2.8%)		1/33 (3%)		2/16 (12.5%)
Dizziness/light-headedness	4/36 (11.1%)		0/33 (0%)		1/16 (6.3%)
Headache	18/36 (50%)		16/33 (48.5%)		9/16 (56.3%)
Neurology - other	3/36 (8.3%)		3/33 (9.1%)		0/16 (0%)
Neuropathy - cranial	7/36 (19.4%)		3/33 (9.1%)		0/16 (0%)
Neuropathy - motor	9/36 (25%)		9/33 (27.3%)		6/16 (37.5%)
Neuropathy - sensory	3/36 (8.3%)		3/33 (9.1%)		1/16 (6.3%)
Nystagmus	2/36 (5.6%)		2/33 (6.1%)		2/16 (12.5%)
Seizure(s)	1/36 (2.8%)		4/33 (12.1%)		5/16 (31.3%)
Speech impairment	5/36 (13.9%)		2/33 (6.1%)		1/16 (6.3%)
Tremor	3/36 (8.3%)		2/33 (6.1%)		1/16 (6.3%)
Psychiatric disorders
Insomnia	5/36 (13.9%)		1/33 (3%)		0/16 (0%)
Mood alteration - anxiety, agitation	3/36 (8.3%)		1/33 (3%)		0/16 (0%)
Mood alteration - depression	2/36 (5.6%)		3/33 (9.1%)		1/16 (6.3%)
Personality/behavioral	2/36 (5.6%)		2/33 (6.1%)		1/16 (6.3%)
Renal and urinary disorders
Dysuria	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Incontinence	2/36 (5.6%)		2/33 (6.1%)		0/16 (0%)
Renal/Genitourinary-Other	0/36 (0%)		2/33 (6.1%)		1/16 (6.3%)
Urinary frequency/urgency	1/36 (2.8%)		1/33 (3%)		2/16 (12.5%)
Urinary retention	3/36 (8.3%)		1/33 (3%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	4/36 (11.1%)		1/33 (3%)		0/16 (0%)
Epistaxis	1/36 (2.8%)		2/33 (6.1%)		2/16 (12.5%)
Pulmonary-Other	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Skin and subcutaneous tissue disorders
Alopecia	3/36 (8.3%)		0/33 (0%)		0/16 (0%)
Dermatology/skin -Other	4/36 (11.1%)		5/33 (15.2%)		1/16 (6.3%)
Dry skin	0/36 (0%)		0/33 (0%)		3/16 (18.8%)
Pruritus	4/36 (11.1%)		0/33 (0%)		1/16 (6.3%)
Rash/desquamation	7/36 (19.4%)		8/33 (24.2%)		5/16 (31.3%)
Rash/Dermatitis	2/36 (5.6%)		0/33 (0%)		0/16 (0%)
Vascular disorders
Edema	1/36 (2.8%)		2/33 (6.1%)		3/16 (18.8%)
Hypertension	2/36 (5.6%)		0/33 (0%)		1/16 (6.3%)

Limitations/Caveats

The phase II component of the trial was terminated because of poor accrual. Only one patient enrolled to the phase II component and did not receive the investigational drug.

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.