Clinical trial NCT00613132: Ph I Gleevec in Combo w RAD001 + Hydroxyurea for Pts w Recurrent MG
Official title: Phase I Dose Escalation of Gleevec in Combination With RAD001 Plus Hydroxyurea for Patients With Recurrent Malignant Glioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioblastoma
Gliosarcoma
Keywords: Glioblastoma
Gliosarcoma
GBM
Brain tumor
RAD0001
Hydroxyurea
Gleevec
Imatinib
Droxia
Everolimus
Hydrea
Hydroxycarbamide
Recurrent GBM
Imatinib mesylate
Glioblastoma multiforme
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2008-02-12
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Primary objective To determine maximum tolerated dose \& dose limiting toxicity of imatinib mesylate \& RAD001 when combined w fixed doses of hydroxyurea among pts w recurrent GBM who are on \& not on enzyme-inducing anti-convulsants including pts not on anti-epileptic drugs Secondary objective To assess safety \& tolerability of imatinib mesylate in combo w RAD001 \& hydroxyurea in this population To characterize single-dose \& repeated-dose pharmacokinetic profiles of imatinib mesylate \& RAD001 combo therapy in this pt population.

To assess antiangiogenic effects, pre- and post-treatment, of imatinib mesylate, RAD001 \& hydroxyurea combo therapy, using DCE-MRI to evaluate changes in extent of vascular permeability, perfusion \& relative tumor blood volume; to explore assessment of tumor cellularity \& tumor cell death by changes in DWI-MRI as quantitated by apparent diffusion coefficient maps.

Detailed description: This is open-label, single center, 1-arm ph I dose-escalation study of continuous, daily doses of imatinib mesylate \& RAD001 administered orally in combination w fixed doses of hydroxyurea in adult pts w recurrent or relapsing glioblastoma multiforme. Study format includes classical "3+3" dose escalation design to determine MTD \& DLT of imatinib mesylate + RAD001 when combined w hydroxyurea among GBM pts. Pts will be stratified based on whether they who are receiving EIACD \& each stratum will independently dose escalate. Additionally, study will characterize safety, tolerability, biologic activity, \& pharmacokinetic profile of this combo therapy.

Eligibility criteria: Inclusion Criteria:

* Pts w confirmed GBM, GS, AA, AO \& AOA are presenting in 1st, 2nd/3rd recurrence/relapse
* Pts without tumor biopsy \<1 wk/surgical resection \<2 wks prior to starting study drug
* For stratum of non-EIAED pts, each pts off all enzyme inducing anticonvulsants for \>2 wks prior to starting study drug
* Pts should be on non-increasing dose of steroids for \>7 days prior to obtaining baseline Gd-MRI of brain
* Pts should be on non-increasing dose of steroids for \>7 days prior to starting study drug
* Pts w previous implantation of Gliadel may be eligible after discussion between investigator \& sponsor
* Multifocal disease is eligible
* Age \>18 yrs
* KPS \>70
* Hematology: ANC\>1.5 x 10\^9/L, Hgb\>9 g/dL, Platelets\>100 x 10\^9/L
* Biochemistry: K≥ LLN/correctable w supplement, Total Ca≥ LLN/correctable w supplement, Mg≥ LLN/correctable w supplement, P≥ LLN/correctable w supplement, AST/SGOT \& ALT/SGPT \<2.5 x ULN, Serum bilirubin \<1.5 x ULN, Serum creatinine \<1.5 x ULN/measured 24hr CrCl\<0 mL/min/1.73m2, \& Cholesterol≤ 00 mg/dL \& triglyceride≤2.5 ULN
* Life expectancy ≥12wks
* Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

* Pts w any peripheral neuropathy ≥CTCAE gr2
* Pts w unresolved diarrhea ≥CTCAE gr2
* History of impaired cardiac function
* Obligate use of cardiac pacemaker, Congenital long QT syndrome, History or presence of ventricular or atrial tachyarrhythmias, Clinically significant resting bradycardia , Right bundle branch block + left anterior hemiblock
* Other clinically significant cardiac diseases
* Uncontrolled Db
* Active or uncontrolled infection requiring intravenous antibiotics
* Impairment of GI function/GI disease that may significantly alter absorption of Gleevec, hydroxyurea and/or RAD001
* Acute/chronic liver/renal disease
* Other concurrent severe and/or uncontrolled medical condition that could cause unacceptable safety risks/compromise compliance w protocol
* Treatment w any hematopoietic colony-stimulating factor ≤2wks prior to starting study drug. Erythropoietin is allowed
* Pts w history of CHF/arrhythmias who are receiving treatment w digoxin/verapamil, \& treatment cannot be discontinued/switched to different drug prior to starting study drug
* Pts taking warfarin sodium
* Pts received treatment w PDGF/mTOR directed therapies
* Pts received chemo ≤ 4wks prior to starting study drug/have not recovered from side effects of such therapy
* Pts received immunotherapy ≤2 wks prior to starting study drug/have not recovered from side effects of such therapy
* Pts received investigational drugs ≤4 wks prior to starting study drug/have not recovered from side effects of such therapy
* Pts received XRT ≤4 wks prior to starting study drug/have not recovered from side effects of such therapy
* Pts undergone major non-CNS surgery ≤2 wks prior to starting study drug/pts have not recovered from side effects of such therapy
* Cardiac pacemaker, Ferromagnetic metal implants other than those approved as safe for use in MR scanners, Claustrophobia, Obesity
* Female pts are pregnant/breast feeding,/adults of reproductive potential not employing effective method of birth control. Barrier contraceptives must be used throughout trial in both sexes. Oral, implantable/injectable contraceptives may be affected by cytochrome P450 interactions, \& are therefore not considered effective for study. Women of childbearing potential have negative serum pregnancy test 48hrs prior to administration of Gleevec, hydroxyurea and/or RAD001.
* Known diagnosis of HIV infection
* Pts w history of another primary malignancy that is currently clinically significant/currently requires active intervention
* Pts unwilling to/unable to comply w protocol

Primary outcomes:
measure: To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM
timeFrame: 6 months
Secondary outcomes:
measure: To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea
timeFrame: 6 months
measure: To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs
timeFrame: 6 months
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
role: PRINCIPAL_INVESTIGATOR
References: