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

Sponsor

Annick Desjardins (Other)

Overall Status

Completed

CT.gov ID

NCT00613132

Collaborator

Novartis Pharmaceuticals (Industry)

Enrollment

Location

Arms

92.1

Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Gliosarcoma	Drug: Gleevec, RAD001, and Hydroxyurea	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

78 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2005

Actual Primary Completion Date :

Aug 1, 2008

Actual Study Completion Date :

Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Pts receiving EIACDs	Drug: Gleevec, RAD001, and Hydroxyurea Dose of Gleevec will be 400 mg in 1st cohort & will be increased to 600 mg po/day & then to 400 mg bid in successive cohorts. Prescribed dose should be administered orally, w large glass of water. Pts should not eat large or high fat meal within 1 hour before or after gleevec dosing. Doses of 600 mg or less should be administered once daily, whereas doses greater than 600 mg should be administered as equal doses twice day. It is recommended that pts take their prescribed Gleevec at same time that they take their prescribed RAD001 & hydroxyurea, however, 30-60 minute interval between agents is acceptable if required for practical or other compliance issues. Other Names: Gleevec-Imatinib-Imatinib mesylate RAD001-Everolimus Hydroxyurea-Droxia-Hydrea-Hydroxycarbamide
Experimental: 2 Pts not receiving EIACDs	Drug: Gleevec, RAD001, and Hydroxyurea Dose of Gleevec will be 400 mg in 1st cohort & will be increased to 600 mg po/day & then to 400 mg bid in successive cohorts. Prescribed dose should be administered orally, w large glass of water. Pts should not eat large or high fat meal within 1 hour before or after gleevec dosing. Doses of 600 mg or less should be administered once daily, whereas doses greater than 600 mg should be administered as equal doses twice day. It is recommended that pts take their prescribed Gleevec at same time that they take their prescribed RAD001 & hydroxyurea, however, 30-60 minute interval between agents is acceptable if required for practical or other compliance issues. Other Names: Gleevec-Imatinib-Imatinib mesylate RAD001-Everolimus Hydroxyurea-Droxia-Hydrea-Hydroxycarbamide

Arm

Intervention/Treatment

Experimental: 1

Pts receiving EIACDs

Drug: Gleevec, RAD001, and Hydroxyurea

Dose of Gleevec will be 400 mg in 1st cohort & will be increased to 600 mg po/day & then to 400 mg bid in successive cohorts. Prescribed dose should be administered orally, w large glass of water. Pts should not eat large or high fat meal within 1 hour before or after gleevec dosing. Doses of 600 mg or less should be administered once daily, whereas doses greater than 600 mg should be administered as equal doses twice day. It is recommended that pts take their prescribed Gleevec at same time that they take their prescribed RAD001 & hydroxyurea, however, 30-60 minute interval between agents is acceptable if required for practical or other compliance issues.

Other Names:

Gleevec-Imatinib-Imatinib mesylate

RAD001-Everolimus

Hydroxyurea-Droxia-Hydrea-Hydroxycarbamide

Experimental: 2

Pts not receiving EIACDs

Drug: Gleevec, RAD001, and Hydroxyurea

Other Names:

Gleevec-Imatinib-Imatinib mesylate

RAD001-Everolimus

Hydroxyurea-Droxia-Hydrea-Hydroxycarbamide

Outcome Measures

Primary Outcome Measures

To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM [6 months]

Secondary Outcome Measures

To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea [6 months]
To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs [6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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