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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00613132
• Other study ID #: Pro00005875
• Secondary ID: 7020-07-32
• Status: Completed
• Phase: Phase 1
• First received: January 29, 2008
• Last updated: February 19, 2013
• Start date: May 2005
• Est. completion date: January 2013

Study information

• Verified date: February 2013
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: January 2013
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

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:
• 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.

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Annick Desjardins	Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM		6 months	No
Secondary	To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea		6 months	Yes
Secondary	To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs		6 months	No

External Links

•   The Preston Robert Tisch Brain Tumor Center at DUKE