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

Glioblastoma Clinical Trial

Official title:

Phase II Study of Imatinib Mesylate Plus Hydroxyurea in the Treatment of Patients With Recurrent / Progressive Grade II Low-Grade Glioma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00615927
• Other study ID #: Pro00008799
• Status: Completed
• Phase: Phase 2
• First received: February 3, 2008
• Last updated: March 13, 2013
• Start date: February 2006
• Est. completion date: June 2012

Study information

• Verified date: December 2012
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: June 2012
• Est. primary completion date: April 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Glioblastoma
• Gliosarcoma

Intervention

Drug:
• Imatinib 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.

Locations

Country	Name	City	State
United States	Duke University Health System	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	12 months	No
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 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	No
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 in weeks from the start of cycle 1 to date of death due to any cause, assessed up to 156 weeks	No
Secondary	Objective Response Rate	Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria.	156 weeks	No
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.	156 weeks	Yes

External Links

•   The Preston Robert Tisch Brain Tumor Center at DUKE