Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)

This study has been terminated.
(Lack of efficacy)
Sponsor:
Information provided by:
Novartis
ClinicalTrials.gov Identifier:
NCT00290771
First received: February 10, 2006
Last updated: April 20, 2011
Last verified: April 2011
  Purpose

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.


Condition Intervention Phase
Recurrent Glioblastoma Multiforme (GBM)
Drug: Imatinib tablets
Drug: Hydroxyurea capsules
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of Patients With an Objective Overall Response (OOR) [ Time Frame: Baseline to end of study (Month 24) ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Duration of Objective Overall Response (OOR) [ Time Frame: Baseline to end of study (Month 24) ] [ Designated as safety issue: No ]
    Duration of OOR only included patients whose best overall response was complete response (CR) or partial response (PR). The start date was the date of the first documented response (CR or PR); the end date was the date of the first documented disease progression (PD) or death from any cause. (PD) was defined as ≥ 25% increase in size of the sum of the products of the largest perpendicular diameters of the target tumors compared to the smallest value recorded at or after baseline. If a patient had not progressed or died, the duration of OOR was censored at the time of the last OOR assessment.

  • Percentage of Patients Who Had Clinical Benefit [ Time Frame: Baseline to end of study (Month 24) ] [ Designated as safety issue: No ]
    Patients who had clinical benefit were patients with a best response of complete response (CR), partial response (PR), or stable disease (SD) lasting for more than 6 months from the start of treatment until the first documented disease progression (PD) or death from any cause. (PD) was defined as ≥ 25% increase in size of the sum of the products of the largest perpendicular diameters of the target tumors compared to the smallest value recorded at or after baseline. SD was defined as insufficient tumor shrinkage to qualify for PR or CR and no increase in lesions which would qualify as PD.

  • Percentage of Patients With Progression-free Survival at Months 6 and 12 [ Time Frame: Months 6 and 12 ] [ Designated as safety issue: No ]
    Progression-free survival (PFS) was defined as the time from the start of treatment to the date of the first documented disease progression (PD) or death due to any cause. (PD) was defined as ≥ 25% increase in size of the sum of the products of the largest perpendicular diameters of the target tumors compared to the smallest value recorded at or after baseline. If a patient had not progressed or died, progression-free survival was censored at the time of the last overall response assessment.

  • Percentage of Patients Surviving at Months 6, 12, and 24 [ Time Frame: Months 6, 12, and 24 ] [ Designated as safety issue: No ]
    Patients not known to have died were censored at the time of last survival follow-up.

  • Number of Patients With at Least 1 Adverse Event [ Time Frame: Baseline to end of study (Month 24) ] [ Designated as safety issue: Yes ]
    An adverse event (AE) is any undesirable sign, symptom, or medical condition occurring after starting study drug even if the event is not considered to be related to study drug. Study drug refers to imatinib or hydroxyurea. The study treatment is the combination of these two study drugs.


Enrollment: 231
Study Start Date: February 2006
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Imatinib 600 mg + hydroxyurea 1000 mg
Patients took imatinib 600 mg (1 imatinib 400 mg tablet and 2 imatinib 100 mg tablets) orally once daily with the morning meal. Patients were instructed to swallow the tablets while drinking a large glass of water. In addition to imatinib, patients took hydroxyurea 500 mg orally twice daily with the morning and evening meals. Patients were not allowed concomitant use of enzyme-inducing anticonvulsant drugs.
Drug: Imatinib tablets
Imatinib was supplied as 100 and 400 mg tablets by Novartis.
Other Name: Glivec®
Drug: Hydroxyurea capsules
Hydroxyurea was supplied locally as 500 mg capsules.
Experimental: Imatinib 1000 mg + hydroxyurea 1000 mg
Patients took imatinib 500 mg (1 imatinib 400 mg tablet and 1 imatinib 100 mg tablet) orally twice daily with the morning and evening meals. Patients were instructed to swallow the tablets while drinking a large glass of water. In addition to imatinib, patients took hydroxyurea 500 mg orally twice daily with the morning and evening meals. Patients were allowed concomitant use of enzyme-inducing anticonvulsant drugs.
Drug: Imatinib tablets
Imatinib was supplied as 100 and 400 mg tablets by Novartis.
Other Name: Glivec®
Drug: Hydroxyurea capsules
Hydroxyurea was supplied locally as 500 mg capsules.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00290771

Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Novartis
Investigators
Principal Investigator: David Reardon, Dr. Duke University
  More Information

No publications provided

Responsible Party: External Affairs, Novartis
ClinicalTrials.gov Identifier: NCT00290771     History of Changes
Obsolete Identifiers: NCT00292149
Other Study ID Numbers: CSTI571H2201, CSTI571H2202
Study First Received: February 10, 2006
Results First Received: December 20, 2010
Last Updated: April 20, 2011
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
Canada: Health Canada
Switzerland: Swissmedic
Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Novartis:
imatinib mesylate
hydroxyurea
protein tyrosine kinases
glioma
glioblastoma multiforme
recurrent glioblastoma multiforme
GBM
MacDonald criteria

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Anticonvulsants
Hydroxyurea
Imatinib
Antineoplastic Agents
Antisickling Agents
Central Nervous System Agents
Enzyme Inhibitors
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014