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A Phase I Study of Imatinib Mesylate in Combination With Temozolomide in Patients With Malignant Glioma


Phase 1
18 Years
N/A
Not Enrolling
Both
Brain and Central Nervous System Tumors

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Trial Information

A Phase I Study of Imatinib Mesylate in Combination With Temozolomide in Patients With Malignant Glioma


OBJECTIVES:

- Determine the maximum tolerated dose and dose-limiting toxicity, if attainable, of
imatinib mesylate in combination with temozolomide in patients with malignant glioma.

- Characterize the safety and tolerability of imatinib mesylate, including acute and
chronic toxicities, in these patients.

- Determine the effect of temozolomide on the pharmacokinetics (PK) of imatinib mesylate
at each dose level.

- Evaluate the impact of enzyme-inducing anti-epileptic drug (EIAED) coadministration on
the PK of imatinib mesylate using a population-based PK approach.

- Evaluate the antitumor activity of imatinib mesylate plus temozolomide.

OUTLINE: This is a dose-escalation study of imatinib mesylate. Patients are stratified
according to concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, phenobarbital,
carbamazepine, fosphenytoin, primidone, oxcarbazepine) (yes vs no).

Patients receive oral imatinib mesylate once or twice daily on days 1-8 and oral
temozolomide once daily on days 4-8. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

Cohorts of patients receive escalating doses of imatinib mesylate until the maximum
tolerated dose is determined.

On days 1 and 8 of course 1, blood is drawn for pharmacokinetic studies.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed malignant glioma

- Any of the following subtypes:

- Glioblastoma multiforme

- Gliosarcoma

- Anaplastic astrocytoma

- Anaplastic oligodendroglioma

- Anaplastic oligoastrocytoma

- Previous histologic diagnosis of a lower grade of glioma allowed if there is
histologic evidence of progression to a diagnosis of malignant glioma

- Multifocal disease allowed

- Must have undergone prior conventional external-beam radiation therapy

- Stable disease, disease recurrence, or relapsed disease

- Must not have received any systemic therapy for this recurrence or relapse

- No prior progressive disease

- No central/systemic fluid collections (pericardial effusion, pulmonary effusion,
ascites) ≥ grade 2

- No evidence of intratumor hemorrhage on pretreatment diagnostic imaging, except for
stable post-operative grade 1 hemorrhage

PATIENT CHARACTERISTICS:

- Karnofsky performance status 70-100%

- Absolute neutrophil count > 1,500/mm³

- Hemoglobin > 9 g/dL

- Platelet count > 100,000/mm³

- AST and ALT < 2.5 times upper limit of normal (ULN)

- Bilirubin < 1.5 times ULN

- Creatinine < 1.5 times ULN

- No chronic renal disease

- No active uncontrolled infection

- No uncontrolled diabetes

- No excessive risk of bleeding, as defined by occurrence of any of the following:

- Stroke within the past 6 months

- History of CNS or intraocular bleed

- Septic endocarditis

- No history of labile hypertension

- No congestive heart failure

- No poorly controlled hypertension

- No myocardial infarction within the past 6 months

- No history of poor compliance with antihypertensive regimen

- No other severe and/or uncontrolled medical disease that would preclude study
participation

- No peripheral edema ≥ grade 2

- No gastrointestinal bleeding

- No gross hematuria

- No other active systemic bleeding

- Patients must not have experienced toxicity ≥ grade 3 with prior treatment with
either temozolomide or imatinib mesylate

- No other primary malignancy within the past 5 years except basal cell skin cancer or
carcinoma in situ of the cervix or other cancer not currently clinically significant
nor requiring active interventions

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy

- Prior surgical resection(s) allowed

- At least 2 weeks since prior surgery

- At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas)

- At least 2 weeks since prior external-beam radiotherapy

- At least 2 weeks since prior investigational drugs

- More than 1 week since prior biologic, immunotherapeutic, or cytostatic agents

- No concurrent warfarin

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Safety Issue:

Yes

Principal Investigator

David A. Reardon, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Duke Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

Pro00004364

NCT ID:

NCT00354068

Start Date:

July 2004

Completion Date:

November 2008

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult anaplastic oligodendroglioma
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • adult mixed glioma
  • adult anaplastic astrocytoma
  • recurrent adult brain tumor
  • adult glioblastoma
  • Glioma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Duke Cancer InstituteDurham, North Carolina  27710