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


Phase 1/Phase 2
3 Years
21 Years
Not Enrolling
Both
Brain and Central Nervous System Tumors

Thank you

Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

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

Outcome 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

Outcome 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.

Outcome Time Frame:

Day 1 of Imatinib Mesylate Therapy to Week 8

Safety Issue:

Yes

Principal Investigator

Ian F. Pollack, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital of Pittsburgh

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03019

NCT ID:

NCT00021229

Start Date:

May 2001

Completion Date:

August 2008

Related Keywords:

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

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
Texas Children's Cancer Center and Hematology Service at Texas Children's HospitalHouston, Texas  77030-2399