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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Recurrent Glioblastoma Multiforme (GBM)

Intervention / Treatment
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* Drug: Imatinib tablets
* Drug: Hydroxyurea capsules


Participation Criteria
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Eligibility Criteria
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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: 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib 600 mg + hydroxyurea 1000 mg<br>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<br>* Imatinib was supplied as 100 and 400 mg tablets by Novartis.<br>* Other names: Glivec®;Drug: Hydroxyurea capsules<br>* Hydroxyurea was supplied locally as 500 mg capsules.<br>|
| Experimental: Imatinib 1000 mg + hydroxyurea 1000 mg<br>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<br>* Imatinib was supplied as 100 and 400 mg tablets by Novartis.<br>* Other names: Glivec®;Drug: Hydroxyurea capsules<br>* Hydroxyurea was supplied locally as 500 mg capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Objective Overall Response (OOR) | 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. | Baseline to end of study (Month 24) | 
| Percentage of Patients Who Had Clinical Benefit | 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. | Baseline to end of study (Month 24) | 
| Percentage of Patients With Progression-free Survival at Months 6 and 12 | 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. | Months 6 and 12 | 
| Percentage of Patients Surviving at Months 6, 12, and 24 | Patients not known to have died were censored at the time of last survival follow-up. | Months 6, 12, and 24 | 
| Number of Patients With at Least 1 Adverse Event | 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. | Baseline to end of study (Month 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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imatinib mesylate, hydroxyurea, protein tyrosine kinases, glioma, glioblastoma multiforme, recurrent glioblastoma multiforme, GBM, MacDonald criteria