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Ph I Gleevec in Combo w RAD001 + Hydroxyurea for Pts w Recurrent MG

Information source: Duke University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Glioblastoma; Gliosarcoma

Intervention: Gleevec, RAD001, and Hydroxyurea (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Annick Desjardins

Official(s) and/or principal investigator(s):
Annick Desjardins, MD, Principal Investigator, Affiliation: Duke University Health System


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.

Clinical Details

Official title: Phase I Dose Escalation of Gleevec in Combination With RAD001 Plus Hydroxyurea for Patients With Recurrent Malignant Glioma

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

Primary outcome: To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM

Secondary outcome:

To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea

To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs

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.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria:

- Pts w confirmed GBM, GS, AA, AO & AOA are presenting in 1st, 2nd/3rd


- 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


- 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

Locations and Contacts

Duke University Health System, Durham, North Carolina 27710, United States
Additional Information

The Preston Robert Tisch Brain Tumor Center at DUKE

Starting date: May 2005
Last updated: February 19, 2013

Page last updated: August 23, 2015

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