Phase II Imatinib + Hydroxyurea in Treatment of Patients With Recurrent/Progressive Grade II Low-Grade Glioma (LGG)

Phase 2

Completed

Conditions: Glioblastoma
Gliosarcoma

Interventions: Drug: Imatinib Mesylate & Hydroxyurea

Registration Number: NCT00615927

Lead Sponsor: Duke University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

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 exclusion criteria to MRI imaging:
- Cardiac pacemaker
- Ferromagnetic metal implants other than those approved as safe for use in magnetic resonance (MR) scanners
- Claustrophobia
- Obesity

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Astrocytoma	Imatinib Mesylate & Hydroxyurea	Grade II Astrocytoma
Oligodendroglioma	Imatinib Mesylate & Hydroxyurea	Grade II Oligodendroglioma or oligoastrocytomas

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
Objective Response Rate	156 weeks	Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria.
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.