Imatinib Mesylate With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma - Full Text View

Sponsor:	Pediatric Brain Tumor Consortium
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00021229

Purpose

RATIONALE: 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.

PURPOSE: 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.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: imatinib mesylate Radiation: local irradiation therapy	Phase I Phase II

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Imatinib Imatinib mesylate

U.S. FDA Resources

Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:

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 ] [ Designated as safety issue: Yes ]
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.
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 ] [ Designated as safety issue: Yes ]
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.
Median Progression-free Survival (PFS) [ Time Frame: Assessed pre-radiation, before the first dose of imatinib, and then every 8 weeks ] [ Designated as safety issue: No ]
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:

Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post completion of radiation ] [ Designated as safety issue: No ]
This study attempted to investigate in an exploratory manner the effect of 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.
Peak Concentration (Cmax) [ Time Frame: Day 1 of Course 1 ] [ Designated as safety issue: No ]
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.
Median Overall Survival [ Time Frame: Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks. ] [ Designated as safety issue: No ]
Overall Survival (OS) is defined as the interval from initiation of treatment to death or date of last contact for surviving patients.
Pre-treatment Basic Fibroblast Growth Factor Values From Urine [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
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.
Pre-treatment Basic Fibroblast Growth Factor Values From Plasma [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
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.
Pre-treatment Vascular Endothelial Growth Factor From Urine [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
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.
Pre-treatment Vascular Endothelial Growth Factor Values From Plasma [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
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.

Enrollment:	85
Study Start Date:	May 2001
Study Completion Date:	August 2008
Primary Completion Date:	August 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Arms

Assigned Interventions

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.

Show Detailed Description

Eligibility

Ages Eligible for Study:	3 Years to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00021229

Locations

United States, California
UCSF Comprehensive Cancer Center
San Francisco, California, United States, 94143
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105-2794
United States, Texas
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
Houston, Texas, United States, 77030-2399
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105

Sponsors and Collaborators

Pediatric Brain Tumor Consortium

National Cancer Institute (NCI)

Investigators

Study Chair:

Ian F. Pollack, MD

Children's Hospital of Pittsburgh

More Information

Publications:

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

Keywords provided by Pediatric Brain Tumor Consortium:

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
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

Neoplasms by Site
Nervous System Diseases
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 12, 2012