Clinical trial NCT00021229: Imatinib Mesylate With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma
Official title: A Phase I/II Trial Of STI571 In Children With Newly Diagnosed Poor Prognosis Brainstem Gliomas And Recurrent Intracranial Malignant Gliomas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Brain and Central Nervous System Tumors
Keywords: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Enrollment: 85
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: PRIMARY OBJECTIVES:

I. 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:

I. 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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Day 1 of Imatinib Mesylate Therapy to Week 8
measure: 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
timeFrame: Day 1 of Imatinib Mesylate Therapy to Week 8
measure: Median Progression-free Survival (PFS)
timeFrame: Assessed pre-radiation, before the first dose of imatinib, and then every 8 weeks
Secondary outcomes:
measure: Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation
timeFrame: Baseline and two weeks post completion of radiation
measure: Peak Concentration (Cmax)
timeFrame: Day 1 of Course 1
measure: Median Overall Survival
timeFrame: Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks.
measure: Pre-treatment Basic Fibroblast Growth Factor Values From Urine
timeFrame: Pre-treatment
measure: Pre-treatment Basic Fibroblast Growth Factor Values From Plasma
timeFrame: Pre-treatment
measure: Pre-treatment Vascular Endothelial Growth Factor From Urine
timeFrame: Pre-treatment
measure: Pre-treatment Vascular Endothelial Growth Factor Values From Plasma
timeFrame: Pre-treatment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
Study officials:
affiliation: University of Pittsburgh
name: Ian F. Pollack, MD
role: STUDY_CHAIR
References:
citation: 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 Sep;35(9):1651-8. doi: 10.1007/s00259-008-0780-7. Epub 2008 Apr 19.
citation: 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. doi: 10.1215/15228517-2006-031. Epub 2007 Feb 9.