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)
- 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
- 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
- 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
- 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.