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

This study has been completed.
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Annick Desjardins, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00613132
First received: January 29, 2008
Last updated: February 19, 2013
Last verified: February 2013
  Purpose

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 Intervention Phase
Glioblastoma
Gliosarcoma
Drug: Gleevec, RAD001, and Hydroxyurea
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 78
Study Start Date: May 2005
Study Completion Date: January 2013
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00613132

Locations
United States, North Carolina
Duke University Health System
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Annick Desjardins
Novartis Pharmaceuticals
Investigators
Principal Investigator: Annick Desjardins, MD Duke University Health System
  More Information

Additional Information:
No publications provided

Responsible Party: Annick Desjardins, Assistant Professor of Medicine, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00613132     History of Changes
Other Study ID Numbers: Pro00005875, 7020-07-32
Study First Received: January 29, 2008
Last Updated: February 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Duke University:
Glioblastoma
Gliosarcoma
GBM
Brain tumor
RAD0001
Hydroxyurea
Gleevec
Imatinib
Droxia
Everolimus
Hydrea
Hydroxycarbamide
Recurrent GBM
Imatinib mesylate
Glioblastoma multiforme

Additional relevant MeSH terms:
Gliosarcoma
Glioblastoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Astrocytoma
Everolimus
Sirolimus
Imatinib
Hydroxyurea
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antisickling Agents
Hematologic Agents

ClinicalTrials.gov processed this record on September 16, 2014