Glioblastoma, Gliosarcoma
Conditions
Keywords
Glioblastoma, Gliosarcoma, glioblastoma multiforme (GBM), GBM, Imatinib Mesylate, Gleevec, Hydroxyurea, Droxia, Hydrea, Hydroxycarbamide, Imatinib, Brain tumor, Malignant brain tumor, Recurrent glioblastoma multiforme, Progressive glioblastoma multiforme
Brief summary
Primary objective: * To evaluate activity of imatinib mesylate and hydroxyurea among patients with progressive/recurrent grade II low-grade glioma (LGG) as measured by 12-month progression free survival Secondary objectives: * To evaluate progression-free survival (PFS), overall survival and objective response rate among patients with progressive/recurrent grade II LGG treated with imatinib mesylate plus hydroxyurea * To assess safety and tolerability of imatinib mesylate + hydroxyurea in this population
Detailed description
This is an open-label, single stage, uncontrolled, non-randomized Phase II study of continuous, daily doses of imatinib mesylate & hydroxyurea in adult patients with progressive/recurrent Grade II low-grade glioma (LGG). The treatment cycle is defined as imatinib mesylate & hydroxyurea administered daily for 28 days for purpose of scheduling evaluations. All patients who receive 1 or more doses of either imatinib mesylate or hydroxyurea will be evaluable for toxicity, whereas all patients who receive a minimum of 14 consecutive days of study regimen will be evaluable for response. Patients who discontinue therapy prior to receiving 14 consecutive days of study regimen will be regarded as ineligible for evaluation of response and will be replaced.
Interventions
DRUGImatinib Mesylate & Hydroxyurea
Imatinib administered orally on daily. Imatinib is local irritant & must be taken in sitting position; mini of 2hrs should be allowed between last drug intake & going to bed. Imatinib doses 400mg/600mg administered once daily, whereas daily doses of 800mg/\> administered as equally divided dose taken twice day. Dose for imatinib: Pts not receiving p450-inducing antiepileptic drugs: 400 mg/day. Pts receiving p450-inducing antiepileptic drugs: 500 mg twice day. It is recommended that pts take their prescribed imatinib mesylate at same time that they take their prescribed hydroxyurea, however, 30-60min interval between agents is acceptable if required for practical/other compliance issues. Hydroxyurea administered orally twice day. Dosing will begin on day 1 of cycle 1 & continue daily. Drug is approximately 80 percent bioavailable. Dose will be 500mg twice day for all pts.
Sponsors
Novartis Pharmaceuticals
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Patients with grade II LGG that is recurrent/progressive following prior surgical resection while on non-decreasing dose of corticosteroids * \> 25percent enlargement of bidimensional measure/new lesions on sequential imaging new &/or worsening neurologic deficits * Patients with progressive/recurrent optic pathway tumors * Patients have measurable disease on MRI/CT * Interval of \> 4 wks between prior external beam radiation therapy (XRT)/chemo,& enrollment on protocol unless there is unequivocal evidence of tumor progression & patient has recovered from all expected toxicities associated with prior therapy. Patients treated w chemo agents such as VP-16 who would normally be retreated after shorter intervals may be treated at usual starting time even if \< 4 wks from last prior dose of chemo * Patients not have had tumor biopsy \< 1 wk/surgical resection \< 2 wks prior to starting study drug * Patients enrolling on arm B must be on \> 1 enzyme inducing anticonvulsants for \>2 wks prior to starting study drug * Patients should be on non-increasing dose of steroids for \> 7 days prior to obtaining baseline Gd-MRI of brain * Patients should be on non-increasing dose of steroids for \> 7 days prior to starting study drug * Multifocal disease is eligible * Age \> 18 yrs old * Karnofsky Performance Status (KPS) of \> 60 * absolute neutrophil count (ANC) \> 1.5 x 10 9/L * Hgb \> 9 g/dL * Platelets \> 100 x 10 9/L * K ≥ lower limit of normal (LLN)/correctable with supplements * Ca ≥ LLN/correctable with supplements * P ≥ LLN/correctable with supplements * aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) & Alanine transaminase (ALT)/ Serum Glutamic Pyruvate Transaminase (SGPT} \< 2.5 x ULN * Serum bilirubin \< 1.5 x upper limit of normal (ULN) * Serum creatinine \< 1.5 x ULN/measured 24hr Creatinine Clearance \> 50 mL/min/1.73m2 * Life expectancy ≥ 12wks * Written informed consent obtained prior to screening procedures
Exclusion criteria
* Prior progressive disease/toxicity grade ≥ 3 with prior hydroxyurea therapy * Prior treatment with imatinib/other platelet derived growth factor (PDGF)-directed therapy * Excessive risk of bleeding as defined by stroke \< 6 months, history of central nervous system (CNS)/intraocular bleed, or septic endocarditis * Evidence of intratumor hemorrhage on pretreatment diagnostic imaging, except for stable post-operative gr1 hemorrhage * Pregnant/breast feeding, /adults of reproductive potential not employing effective method of birth control * Concurrent severe and/or uncontrolled medical disease that could compromise participation in study * Acute/chronic liver disease * Confirmed diagnosis of HIV infection * Impairment of GI function/GI disease that may significantly alter absorption of imatinib * Patients taking Coumadin * Patients have received investigational drugs \< 2wks prior to entry on study/have not recovered from toxic effects of such therapy * Patients have received biologic, immunotherapeutic/cytostatic agents \< 1 wk prior to entry on study/have not recovered from toxic effects of such therapy * Patient \> 5 yrs free of another primary malignancy except: if other primary malignancy is not currently clinically significant/requiring active intervention, or if other primary malignancy is basal cell skin cancer/ cervical carcinoma in situ. Existence of any other malignant disease is not allowed * Patients have had any surgery other than resection of brain tumor \< 2 wks prior to entry on study/have not recovered from side effects of such therapy * Patients unwilling to/unable to comply with protocol * Active systemic bleeding, such as GI bleeding/gross hematuria * Gr2 /\> peripheral edema/central/systemic fluid collections * Patients who enroll on arm A must have not received any EIAC for \> 2 wks prior to starting study regimen * Any of following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 12-month Progression Free Survival (PFS) | 12 months | Percentage of participants surviving twelve months from the start of cycle 1 without progression of disease. PFS was defined as the time from the cycle 1 start date to the date of the first documented progression according to modified Macdonald criteria, or to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 156 weeks | Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria. |
| Median Progression-free Survival | Time in weeks from the start of cycle 1 to the date of first progression according to modified Macdonald criteria or to death due to any cause, assessed up to 156 weeks | Time in weeks from the start of cycle 1 to the date of first progression according to modified Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. |
| Median Overall Survival (OS) | Time in weeks from the start of cycle 1 to date of death due to any cause, assessed up to 156 weeks | Time in weeks from the start of cycle 1 to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve. |
| Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas | 156 weeks | The number of patients experiencing any serious adverse event or other (non-serious) adverse event during the study participation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Astrocytoma Grade II Astrocytoma | 32 |
| Oligodendroglioma Grade II Oligodendroglioma or oligoastrocytomas | 32 |
| Total | 64 |
Baseline characteristics
| Characteristic | Astrocytoma | Oligodendroglioma | Total |
|---|---|---|---|
| Age Continuous | 42.6 years STANDARD_DEVIATION 16.6 | 46.6 years STANDARD_DEVIATION 11.8 | 44.6 years STANDARD_DEVIATION 14.4 |
| Sex: Female, Male Female | 12 Participants | 13 Participants | 25 Participants |
| Sex: Female, Male Male | 20 Participants | 19 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 32 | 28 / 32 |
| serious Total, serious adverse events | 10 / 32 | 3 / 32 |
Outcome results
Primary
12-month Progression Free Survival (PFS)
Percentage of participants surviving twelve months from the start of cycle 1 without progression of disease. PFS was defined as the time from the cycle 1 start date to the date of the first documented progression according to modified Macdonald criteria, or to death due to any cause.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Astrocytoma | 12-month Progression Free Survival (PFS) | 43.8 percentage of participants |
| Oligodendroglioma | 12-month Progression Free Survival (PFS) | 34.4 percentage of participants |
Secondary
Median Overall Survival (OS)
Time in weeks from the start of cycle 1 to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time frame: Time in weeks from the start of cycle 1 to date of death due to any cause, assessed up to 156 weeks
Population: Median overall survival was not estimable for either arm as not enough events of death occurred
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Astrocytoma | Median Overall Survival (OS) | NA weeks |
| Oligodendroglioma | Median Overall Survival (OS) | NA weeks |
Secondary
Median Progression-free Survival
Time in weeks from the start of cycle 1 to the date of first progression according to modified Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time frame: Time in weeks from the start of cycle 1 to the date of first progression according to modified Macdonald criteria or to death due to any cause, assessed up to 156 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Astrocytoma | Median Progression-free Survival | 43.5 weeks |
| Oligodendroglioma | Median Progression-free Survival | 43.3 weeks |
Secondary
Objective Response Rate
Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria.
Time frame: 156 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Astrocytoma | Objective Response Rate | 0 participants |
| Oligodendroglioma | Objective Response Rate | 0 participants |
Secondary
Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas
The number of patients experiencing any serious adverse event or other (non-serious) adverse event during the study participation.
Time frame: 156 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Astrocytoma | Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas | Experienced any Serious Adverse Event | 10 participants |
| Astrocytoma | Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas | Experienced any (non-serious) Adverse Event | 28 participants |
| Oligodendroglioma | Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas | Experienced any Serious Adverse Event | 3 participants |
| Oligodendroglioma | Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas | Experienced any (non-serious) Adverse Event | 28 participants |