Clinical trial NCT00290771: Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Recurrent Glioblastoma Multiforme (GBM)
Keywords: imatinib mesylate
hydroxyurea
protein tyrosine kinases
glioma
glioblastoma multiforme
recurrent glioblastoma multiforme
GBM
MacDonald criteria
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-02-13
Enrollment: 231
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: This ClinicalTrials.gov 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.

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.

Primary outcomes:
measure: Percentage of Patients With an Objective Overall Response (OOR)
timeFrame: Baseline to end of study (Month 24)
Secondary outcomes:
measure: Duration of Objective Overall Response (OOR)
timeFrame: Baseline to end of study (Month 24)
measure: Percentage of Patients Who Had Clinical Benefit
timeFrame: Baseline to end of study (Month 24)
measure: Percentage of Patients With Progression-free Survival at Months 6 and 12
timeFrame: Months 6 and 12
measure: Percentage of Patients Surviving at Months 6, 12, and 24
timeFrame: Months 6, 12, and 24
measure: Number of Patients With at Least 1 Adverse Event
timeFrame: Baseline to end of study (Month 24)
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: David Reardon, Dr.
role: PRINCIPAL_INVESTIGATOR
References: