Clinical trial NCT00615927: Phase II Imatinib + Hydroxyurea in Treatment of Patients With Recurrent/Progressive Grade II Low-Grade Glioma (LGG)
Official title: Phase II Study of Imatinib Mesylate Plus Hydroxyurea in the Treatment of Patients With Recurrent / Progressive Grade II Low-Grade Glioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma
Gliosarcoma
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
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2008-02-14
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 12-month Progression Free Survival (PFS)
timeFrame: 12 months
Secondary outcomes:
measure: Median Progression-free Survival
timeFrame: 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
measure: Median Overall Survival (OS)
timeFrame: Time in weeks from the start of cycle 1 to date of death due to any cause, assessed up to 156 weeks
measure: Objective Response Rate
timeFrame: 156 weeks
measure: Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas
timeFrame: 156 weeks
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
Study officials:
affiliation: Duke Health
name: Annick Desjardins, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
References: