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A Phase II, Open-label, Multicenter Study Evaluating the Efficacy of Imatinib Plus Hydroxyurea (HU) in Patients With Progressive Glioblastoma Multiforme (GBM) Receiving or Not Receiving Enzyme-inducing Anticonvulsant Drugs (EIACDs)

Phase 2
18 Years
Not Enrolling
Recurrent Glioblastoma Multiforme (GBM)

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Trial Information

A Phase II, Open-label, Multicenter Study Evaluating the Efficacy of Imatinib Plus Hydroxyurea (HU) in Patients With Progressive Glioblastoma Multiforme (GBM) Receiving or Not Receiving Enzyme-inducing Anticonvulsant Drugs (EIACDs)

This record includes the results from two studies (Novartis protocol IDs
CSTI571H2201 and CSTI571H2202) which were conducted separately but reported together in a
single clinical study report. Both studies were phase II, open-label, multicenter,
single-arm studies that evaluated the efficacy of imatinib mesylate plus hydroxyurea in
subjects with progressive glioblastoma multiforme. The studies were identical in design with
two exceptions: Patients in study CSTI571H2201 received a dose of imatinib 600 mg once daily
and were not allowed concomitant use of enzyme-inducing anticonvulsant drugs (EIACDs);
patients in study CSTI571H2202 received a dose of imatinib 500 mg twice daily and were
allowed concomitant use of EIACDs.

Inclusion Criteria

Inclusion criteria:

- Males and females ≥ 18 years old.

- Histologically-confirmed diagnosis of progressive primary glioblastoma multiforme
(GBM) based on original diagnosis. Patients with prior low-grade glioma were eligible
if histological re-assessment demonstrated transformation to GBM.

- No more than one prior episode of progressive disease following previously received
surgery and/or radiation and only one prior chemotherapy exposure of either
temozolomide (TMZ) or nitrosourea including the application of polifeprosan
(Gliadel®) wafers.

- Presence of measurable disease on gadolinium-enhanced magnetic resonance imaging

- Patients taking steroids must have been on a stable dose for ≥ 7 days.

- Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2.

- Hemoglobin ≥ 10 g/dL (or hematocrit > 29%), absolute neutrophil count (ANC) > 1500
cells/L, platelets > 100,000 cells/L.

- Serum creatinine < 1.5 mg/dL, blood urea nitrogen (BUN) < 25 mg/dL, serum aspartate
aminotransferase (AST) and bilirubin < 1.5 x upper limit of normal (ULN).

- Sexually-active male and female patients were required to use double-barrier
contraception (oral contraceptive plus barrier contraceptive) or must have undergone
clinically documented total hysterectomy, ovariectomy, or tubal ligation.

- Female patients of childbearing potential must have had a negative pregnancy test
within 48 hours prior to start of study drug.

- Life expectancy ≥ 8 weeks.

- Signed informed consent by the patient prior to patient entry and any study

Exclusion Criteria:

- Receipt of imatinib or hydroxyurea (HU) prior to study entry or receipt of any
investigational agent within the last 6 months.

- Patients who had received a second course of chemotherapy or radiotherapy, unless
given as a single localized application of radio surgery.

- In study STI571H2201 only, receipt of enzyme-inducing anticonvulsant drugs (EIACDs),
eg, carbamazepine, phenobarbital, phenytoin, fosphenytoin, oxcarbazepine, or
primidone. Previous EIACD should have been interrupted 4 weeks prior to study start.

- Grade ≥ 2 peripheral edema or pulmonary or pericardial effusions or ascites of any

- Presence of any uncontrolled systemic infection.

- Patients who were not a minimum of 12 weeks from completion of conventional external
beam radiotherapy unless:

1. There was new radiographical enhancement outside the field of radiation, or

2. There was new pathological confirmation of recurrent tumor, or

3. Progressive radiographical enhancement noted on post-radiotherapy/TMZ continue
to worsen after an additional course of TMZ.

- Evidence of intra-tumor hemorrhage on pretreatment diagnostic imaging, except for
stable post-operative Grade 1 hemorrhage, patients with an excessive risk of an
intracranial hemorrhagic event, and patients with history of central nervous system
(excluding post-operative Grade 1) or intraocular bleed.

- Patients who had undergone major surgery within 2 weeks prior to study entry or who
had not recovered from prior major surgery, patients who had received chemotherapy
within 4 weeks prior to study start, or who have not recovered from toxic effects of
such therapy.

- Impairment of gastrointestinal function or gastrointestinal disease that could
significantly alter the absorption of imatinib.

- Patients taking warfarin sodium.

- Known history of human immunodeficiency virus (HIV) seropositivity; testing for HIV
was not required at study entry.

- For the purposes of MRI, patients with a pacemaker, ferromagnetic metal implants
other than those approved as safe for use in MR scanners (eg, some types of aneurysm
clips, shrapnel), patients suffering from uncontrollable claustrophobia, or those
physically unable to fit into the machine (eg, obesity).

- Patients considered by the investigator as unlikely to be compliant with the study,
take the study medications, travel for the necessary assessment visits, or have other
medical conditions likely to interfere with the study assessments.

- Patients with another primary malignancy treated within the prior 3 years except
excised squamous cell carcinomas of the skin and carcinoma in situ lesions of other
organs which had been treated for cure.

- Patients not able to provide reliable informed consent and who did not have a legal
representative for healthcare decisions on their behalf.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percentage of Patients With an Objective Overall Response (OOR)

Outcome Description:

Patients with an OOR were those whose best response to treatment was a complete response (CR) or a partial response (PR) assessed with magnetic resonance imaging. A patient had a CR if the target tumors disappeared. A patient had a PR if there was a ≥ 50% reduction in the sum of the products of the largest perpendicular diameters of the target tumors compared to the baseline value. A best response of CR required at least 2 determinations of CR at least 4 weeks apart. A best response of PR required at least 2 determinations of PR or better at least 4 weeks apart (and not qualifying for CR).

Outcome Time Frame:

Baseline to end of study (Month 24)

Safety Issue:


Principal Investigator

David Reardon, Dr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

February 2006

Completion Date:

August 2008

Related Keywords:

  • Recurrent Glioblastoma Multiforme (GBM)
  • imatinib mesylate
  • hydroxyurea
  • protein tyrosine kinases
  • glioma
  • glioblastoma multiforme
  • recurrent glioblastoma multiforme
  • GBM
  • MacDonald criteria
  • Glioblastoma



Duke University Medical CenterDurham, North Carolina  27710