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

NCT00290771 | Terminated Phase 2 Results

• 2 other identifiers: CSTI571H2201CSTI571H2202
• Study Type: interventional
• Target: 231
• Locations: 1 country
• Sites: 1

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.

Conditions

Recurrent Glioblastoma Multiforme (GBM)

Keywords

imatinib mesylate; hydroxyurea; protein tyrosine kinases; glioma; glioblastoma multiforme; recurrent glioblastoma multiforme; GBM; MacDonald criteria

Outcome Measures

Primary Outcomes (1)

• Percentage of Patients With an Objective Overall Response (OOR)

  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).

  Baseline to end of study (Month 24)

Secondary Outcomes (5)

• Duration of Objective Overall Response (OOR)

  Baseline to end of study (Month 24)

• Percentage of Patients Who Had Clinical Benefit

  Baseline to end of study (Month 24)

• Percentage of Patients With Progression-free Survival at Months 6 and 12

  Months 6 and 12

• Percentage of Patients Surviving at Months 6, 12, and 24

  Months 6, 12, and 24

• Number of Patients With at Least 1 Adverse Event

  Baseline to end of study (Month 24)

Study Arms (2)

Imatinib 600 mg + hydroxyurea 1000 mg

EXPERIMENTAL

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; Drug: Hydroxyurea capsules

Imatinib 1000 mg + hydroxyurea 1000 mg

EXPERIMENTAL

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; Drug: Hydroxyurea capsules

Interventions

Imatinib tablets DRUG

Imatinib was supplied as 100 and 400 mg tablets by Novartis.

Also known as: Glivec®

Imatinib 1000 mg + hydroxyurea 1000 mg; Imatinib 600 mg + hydroxyurea 1000 mg

Hydroxyurea capsules DRUG

Hydroxyurea was supplied locally as 500 mg capsules.

Imatinib 1000 mg + hydroxyurea 1000 mg; Imatinib 600 mg + hydroxyurea 1000 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• There was new radiographical enhancement outside the field of radiation, or
• There was new pathological confirmation of recurrent tumor, or
• 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).

Sponsors & Collaborators

• Novartis: lead

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Glioblastoma; Glioma

Interventions

Imatinib Mesylate; Hydroxyurea

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Urea

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862 778-8300

Study Officials

• David Reardon, Dr.

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: February 10, 2006
• First Posted: February 13, 2006
• Study Start: February 1, 2006
• Primary Completion: August 1, 2008
• Study Completion: August 1, 2008
• Last Updated: May 16, 2011
• Results First Posted: May 16, 2011

Record last verified: 2011-04

Locations

US (1)