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

Primary Purpose

Glioblastoma, Gliosarcoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Gleevec, RAD001, and Hydroxyurea
Sponsored by
Annick Desjardins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Glioblastoma, Gliosarcoma, GBM, Brain tumor, RAD0001, Hydroxyurea, Gleevec, Imatinib, Droxia, Everolimus, Hydrea, Hydroxycarbamide, Recurrent GBM, Imatinib mesylate, Glioblastoma multiforme

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Duke University Health System

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

1

2

Arm Description

Pts receiving EIACDs

Pts not receiving EIACDs

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
January 29, 2008
Last Updated
February 19, 2013
Sponsor
Annick Desjardins
Collaborators
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00613132
Brief Title
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

2. Study Status

Record Verification Date
February 2013
Overall Recruitment Status
Completed
Study Start Date
May 2005 (undefined)
Primary Completion Date
August 2008 (Actual)
Study Completion Date
January 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Annick Desjardins
Collaborators
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Gliosarcoma
Keywords
Glioblastoma, Gliosarcoma, GBM, Brain tumor, RAD0001, Hydroxyurea, Gleevec, Imatinib, Droxia, Everolimus, Hydrea, Hydroxycarbamide, Recurrent GBM, Imatinib mesylate, Glioblastoma multiforme

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
78 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Pts receiving EIACDs
Arm Title
2
Arm Type
Experimental
Arm Description
Pts not receiving EIACDs
Intervention Type
Drug
Intervention Name(s)
Gleevec, RAD001, and Hydroxyurea
Other Intervention Name(s)
Gleevec-Imatinib-Imatinib mesylate, RAD001-Everolimus, Hydroxyurea-Droxia-Hydrea-Hydroxycarbamide
Intervention Description
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.
Primary Outcome Measure Information:
Title
To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM
Time Frame
6 months
Secondary Outcome Measure Information:
Title
To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea
Time Frame
6 months
Title
To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annick Desjardins, MD
Organizational Affiliation
Duke Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Health System
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.cancer.duke.edu/btc/
Description
The Preston Robert Tisch Brain Tumor Center at DUKE

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

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