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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

A Phase I/II Trial Of STI571 In Children With Newly Diagnosed Poor Prognosis Brainstem Gliomas And Recurrent Intracranial Malignant Gliomas

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00021229
• Other study ID #: NCI-2012-03019
• Secondary ID: PBTC-006U01CA081
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: July 11, 2001
• Last updated: July 25, 2014
• Start date: May 2001
• Est. completion date: August 2008

Study information

• Verified date: February 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 85
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 21 Years

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

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.

Locations

Country	Name	City	State
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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 d — View 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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	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.	Day 1 of Imatinib Mesylate Therapy to Week 8	Yes
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	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.	Day 1 of Imatinib Mesylate Therapy to Week 8	Yes
Primary	Median Progression-free Survival (PFS)	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.	Assessed pre-radiation, before the first dose of imatinib, and then every 8 weeks	No
Secondary	Change From Baseline in Volume FLAIR at Two Weeks After 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.	Baseline and two weeks post completion of radiation	No
Secondary	Peak Concentration (Cmax)	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.	Day 1 of Course 1	No
Secondary	Median Overall Survival	Overall Survival (OS) is defined as the interval from initiation of treatment to death or date of last contact for surviving patients.	Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks.	No
Secondary	Pre-treatment Basic Fibroblast Growth Factor Values From Urine	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	No
Secondary	Pre-treatment Basic Fibroblast Growth Factor Values From Plasma	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	No
Secondary	Pre-treatment Vascular Endothelial Growth Factor From Urine	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	No
Secondary	Pre-treatment Vascular Endothelial Growth Factor Values From Plasma	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.	Pre-treatment	No