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

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Brain and Central Nervous System Tumors
Interventions:	Drug: imatinib mesylate Radiation: local irradiation therapy

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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 Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Stratum I: Radiation + Imatinib Mesylate	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.
Stratum IIA: Imatinib Mesylate	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.
Stratum IIB: Imatinib Mesylate	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.

Description

Stratum I: Radiation + Imatinib Mesylate

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.

Stratum IIA: Imatinib Mesylate

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.

Stratum IIB: Imatinib Mesylate

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.

Participant Flow: Overall Study

	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate
STARTED	36	33	16
Enrolled in Phase I	35	33	16
Maximum Tolerated Dose (MTD) Estimation	23 ^[1]	20 ^[2]	12 ^[3]
Enrolled in Phase II	14 ^[4]	0 ^[5]	0 ^[6]
COMPLETED	1 ^[7]	0	0
NOT COMPLETED	35	33	16
Adverse Event	10	5	2
Death	0	1	0
Withdrawal by Subject	7	7	1
Progressive Disease	15	19	12
Protocol Violation	1	1	0
Physician Decision	0	0	1
Punctate hemmorrhage post RT	2	0	0

[1]	12 participants enrolled in the Phase I part did not complete the 8 week MTD estimation period.
[2]	13 participants enrolled in the Phase I part did not complete the 8 week MTD estimation period.
[3]	4 participants enrolled in the Phase I part did not complete the 8 week MTD estimation period.
[4]	Thirteen participants treated at the MTD in the phase I were also part of the phase II.
[5]	Participants from stratum IIA did not participate in the phase II part of the study.
[6]	Participants from stratum IIB did not participate in the phase II part of the study.
[7]	1 participant completed 13 courses of therapy

Baseline Characteristics

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Reporting Groups

	Description
Stratum I: Radiation + Imatinib Mesylate	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.
Stratum IIA: Imatinib Mesylate	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.
Stratum IIB: Imatinib Mesylate	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.

Description

Stratum I: Radiation + Imatinib Mesylate

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.

Stratum IIA: Imatinib Mesylate

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.

Stratum IIB: Imatinib Mesylate

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.

Baseline Measures

	Stratum I: Radiation + Imatinib Mesylate	Stratum IIA: Imatinib Mesylate	Stratum IIB: Imatinib Mesylate	Total
Number of Participants [units: participants]	36	33	16	85
Age [units: participants]
<=18 years	36	30	15	81
Between 18 and 65 years	0	3	1	4
>=65 years	0	0	0	0
Age [units: years] Mean ± Standard Deviation	8.05 ± 4.3	10.9 ± 5.4	14.1 ± 4.7	10.3 ± 5.3
Gender [units: participants]
Female	18	20	9	47
Male	18	13	7	38
Region of Enrollment [units: participants]
United States	36	33	16	85

Outcome Measures

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1. Primary:

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 [ Time Frame: Day 1 of Imatinib Mesylate Therapy to Week 8 ]

Show Outcome Measure 1

2. Primary:

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 [ Time Frame: Day 1 of Imatinib Mesylate Therapy to Week 8 ]

Show Outcome Measure 2

3. Primary:

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

Show Outcome Measure 3

4. Secondary:

Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post completion of radiation ]

Show Outcome Measure 4

5. Secondary:

Peak Concentration (Cmax) [ Time Frame: Day 1 of Course 1 ]

Show Outcome Measure 5

6. Secondary:

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

Show Outcome Measure 6

7. Secondary:

Pre-treatment Basic Fibroblast Growth Factor Values From Urine [ Time Frame: Pre-treatment ]

Show Outcome Measure 7

8. Secondary:

Pre-treatment Basic Fibroblast Growth Factor Values From Plasma [ Time Frame: Pre-treatment ]

Show Outcome Measure 8

9. Secondary:

Pre-treatment Vascular Endothelial Growth Factor From Urine [ Time Frame: Pre-treatment ]

Show Outcome Measure 9

10. Secondary:

Pre-treatment Vascular Endothelial Growth Factor Values From Plasma [ Time Frame: Pre-treatment ]

Show Outcome Measure 10

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

Name/Title: Pediatric Brain Tumor Consortium (James M. Boyett, Ph.D)
Organization: Pediatric Brain Tumor Consortium
phone: 901-595-4986
e-mail: james.boyett@stjude.org

Publications of Results:

Williams G, Fahey FH, Treves ST, Kocak M, Pollack IF, Boyett JM, Kun LE, Poussaint TY. Exploratory evaluation of two-dimensional and three-dimensional methods of FDG PET quantification in pediatric anaplastic astrocytoma: a report from the Pediatric Brain Tumor Consortium (PBTC). Eur J Nucl Med Mol Imaging. 2008 Apr 19; [Epub ahead of print]

Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW, Phillips P, Kun LE, Friedman H, Packer R, Banerjee A, Geyer JR, Goldman S, Poussaint TY, Krasin MJ, Wang Y, Hayes M, Murgo A, Weiner S, Boyett JM. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro-oncol. 2007 Apr;9(2):145-60. Epub 2007 Feb 9.

Responsible Party:	James M. Boyett/PBTC Operations and Biostatistics Center Executive Director, Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00021229 History of Changes
Other Study ID Numbers:	CDR0000068761, PBTC-006, U01CA081457
Study First Received:	July 11, 2001
Results First Received:	February 9, 2010
Last Updated:	June 29, 2011
Health Authority:	United States: Food and Drug Administration