Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)
Condition: Recurrent Glioblastoma Multiforme (GBM)
MeSH terms: Glioblastoma; Recurrence
Intervention: Imatinib tablets; Hydroxyurea capsules
Intervention description: Imatinib was supplied as 100 and 400 mg tablets by Novartis.; Hydroxyurea was supplied locally as 500 mg capsules.
Intervention MeSH terms: Imatinib Mesylate; Hydroxyurea
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 231.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: imatinib mesylate; hydroxyurea; protein tyrosine kinases; glioma; glioblastoma multiforme; recurrent glioblastoma multiforme; GBM; MacDonald criteria

Summary:

      This was an investigational study to assess the objective overall response (OOR) rate
      (complete response [CR] + partial response [PR]) of imatinib mesylate and hydroxyurea
      (hydroxycarbamide) combination therapy in patients with recurrent glioblastoma multiforme
      (brain tumors). This study also evaluated the duration of tumor response (as per MacDonald
      criteria), clinical benefit, progression-free survival rate at 6 and 12 months, and the
      survival rate at 12 and 24 months.
    

Eligibility 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
             (MRI).

          -  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 procedure.

        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
             grade.

          -  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.