Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

AEE788 and Everolimus in Treating Patients With Recurrent or Relapsed Glioblastoma Multiforme

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00107237
First received: April 5, 2005
Last updated: June 11, 2013
Last verified: June 2013
  Purpose

RATIONALE: AEE788 and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving AEE788 together with everolimus may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of AEE788 when given together with everolimus and to see how well they work in treating patients with recurrent or relapsed glioblastoma multiforme.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Drug: AEE788
Drug: everolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase IB/II Multicenter, Two-Arm, Dose-Escalation Study of Oral AEE788 Administered in Combination With Oral RAD001 on a Continuous Once Daily Dosing Schedule in Adult Patients With First or Second Recurrent or Relapsing Glioblastoma Multiforme

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Maximum tolerated dose and dose-limiting toxicity of AEE788 [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Safety [ Designated as safety issue: Yes ]
  • Tolerability [ Designated as safety issue: Yes ]
  • Single-dose and repeated-dose pharmacokinetic profile [ Designated as safety issue: No ]
  • Efficacy (response rate, progression-free survival, and overall survival) [ Designated as safety issue: No ]
  • Antiangiogenic effects [ Designated as safety issue: No ]

Enrollment: 16
Study Start Date: October 2003
Study Completion Date: June 2006
Primary Completion Date: June 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AEE788 200 mg + RAD001 5 mg
AEE788 200 mg qd, RAD001 5 mg qd
Drug: AEE788
AEE788 was available in the form of a hard gelatin capsule of 50 mg or 100 mg strengths and packaged in bottles.
Drug: everolimus
Everolimus was formulated as tablets of 2.5 mg and 5 mg strength and supplied in blister packs.
Other Name: RAD001
Experimental: AEE788 150 mg + RAD001 5mg
AEE788 150 mg qd, RAD001 5 mg qod
Drug: AEE788
AEE788 was available in the form of a hard gelatin capsule of 50 mg or 100 mg strengths and packaged in bottles.
Drug: everolimus
Everolimus was formulated as tablets of 2.5 mg and 5 mg strength and supplied in blister packs.
Other Name: RAD001

Detailed Description:

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose and dose-limiting toxicity of AEE788 when administered in combination with 1 of 2 different doses of everolimus in patients with recurrent or relapsed glioblastoma multiforme.

Secondary

  • Determine the safety and tolerability of this regimen, including acute and chronic toxic effects, in these patients.
  • Determine the single-dose and repeated-dose pharmacokinetic profile of this regimen in these patients.
  • Determine, preliminarily, the efficacy of this regimen, in terms of response rate, progression-free survival, and overall survival, in these patients. (Phase II)
  • Determine the antiangiogenic effects of this regimen in these patients.

OUTLINE: This is an open-label, multicenter, dose-escalation study of AEE788.

  • Phase I: Patients are assigned to 1 of 2 treatment groups.

    • Group 1: Patients receive oral AEE788 once daily and oral everolimus once daily on days 1-28.
    • Group 2: Beginning at the first occurrence of dose-limiting toxicity in group 1, patients receive AEE788 as in group 1 and a higher-dose of oral everolimus once daily on days 1-28.

In both groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients per group receive escalating doses of AEE788 until the maximum tolerated dose is determined.

  • Phase II: Patients are assigned to 1 of 2 treatment groups according to eligibility for surgery.

    • Group 1 (eligible for tumor biopsy, surgical resection, or tumor debulking): Patients receive oral AEE788 once daily at the MTD and oral everolimus once daily for 5-9 days. Patients then undergo surgery. Beginning 15-21 days after surgery, patients receive oral AEE788 and oral everolimus once daily on days 1-28.
    • Group 2 (ineligible for surgery): Patients receive oral AEE788 once daily at the MTD and oral everolimus once daily on days 1-28.

In both groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. In both phases, if treatment with AEE788 or everolimus is stopped due to toxicity, patients may continue to receive AEE788 or everolimus alone once daily.

After the completion of study treatment, patients are followed every 3 months for as long as the investigator deems necessary.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed glioblastoma multiforme, meeting 1 of the following criteria:

    • Phase I

      • In first or second recurrence or relapse
      • At least 1 measurable or evaluable enhancing lesion by gadolinium MRI (Gd-MRI) of the brain within the past 3 weeks
    • Phase II, group 1

      • In first or second recurrence or relapse by Gd-MRI of the brain within the past 3 weeks
      • Requires tumor biopsy OR surgical resection for tumor debulking or for confirmation of recurrence
    • Phase II, group 2

      • In first recurrence or relapse
      • At least 1 bidimensionally measurable enhancing lesion (≥ 1.5 cm^2 using product of the largest perpendicular diameters) by Gd-MRI of the brain within the past 3 weeks
  • Multifocal disease allowed

PATIENT CHARACTERISTICS:

Performance status

  • Karnofsky 70-100%

Life expectancy

  • At least 12 weeks

Hematopoietic

  • Absolute neutrophil count ≥ 1,500/mm^3
  • Hemoglobin ≥ 9 g/dL
  • Platelet count ≥ 100,000/mm^3

Hepatic

  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • No acute or chronic liver disease

Renal

  • Total calcium (corrected) normal*
  • Creatinine ≤ 1.5 times ULN OR
  • Creatinine clearance ≥ 50 mL/min
  • No proteinuria by dipstick OR
  • Total urinary protein ≤ 500 mg AND creatinine clearance ≥ 50 mL/min by 24-hour urine collection
  • No acute or chronic renal disease NOTE: *Supplements allowed

Cardiovascular

  • LVEF ≥ 45% by MUGA or echocardiogram
  • No complete left bundle branch block
  • No requirement for a cardiac pacemaker
  • No congenital long QT syndrome
  • No ventricular or atrial tachyarrhythmias
  • No clinically significant resting bradycardia, defined as < 50 beats per minute
  • QTc ≤ 480 msec by ECG
  • No right bundle branch block and left anterior hemiblock (bifascicular block)
  • No uncontrolled hypertension OR history of labile hypertension
  • No unstable angina pectoris OR angina pectoris occurrence within the past 3 months
  • No congestive heart failure
  • No acute myocardial infarction within the past 3 months
  • No history of poor compliance with an antihypertensive regimen
  • No other impaired cardiac function or clinically significant cardiac disease

Gastrointestinal

  • No unresolved diarrhea ≥ grade 2
  • No impairment of gastrointestinal (GI) function or GI disease that would significantly alter absorption of study drugs, including any of the following:

    • Ulcerative disease
    • Uncontrolled nausea
    • Vomiting
    • Malabsorption syndrome

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective barrier contraception
  • Potassium normal*
  • Magnesium normal*
  • Phosphorus normal*
  • Cholesterol ≤ 300 mg/dL (treatment allowed)
  • Triglycerides ≤ 2.5 times ULN (treatment allowed)
  • No known HIV positivity
  • No peripheral neuropathy ≥ grade 2
  • No uncontrolled diabetes
  • No active or uncontrolled infection
  • No other severe and/or uncontrolled medical condition that would preclude study participation or compliance
  • No contraindication to MRI, including any of the following:

    • Cardiac pacemaker
    • Ferromagnetic metal implants other than those approved as safe for use with magnetic resonance scanners (e.g., some types of aneurysm clips or shrapnel)
    • Claustrophobia
    • Obesity exceeding magnetic resonance equipment limits
  • No other clinically significant primary malignancy requiring active intervention NOTE: *Supplements allowed

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • More than 2 weeks since prior hematopoietic colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) except epoetin alfa
  • More than 2 weeks since prior immunotherapy and recovered
  • No concurrent biologic therapy
  • No concurrent prophylactic hematopoietic growth factors (e.g., G-CSF or GM-CSF) unless approved by the study sponsor

Chemotherapy

  • More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
  • Prior polifeprosan 20 with carmustine implant (Gliadel® wafer) allowed
  • No other concurrent chemotherapy

Endocrine therapy

  • Must be on stable or deceasing doses of steroids for at least 7 days before baseline Gd-MRI of the brain and before starting study drug
  • No concurrent tamoxifen

Radiotherapy

  • More than 4 weeks since prior radiotherapy and recovered
  • No concurrent radiotherapy

Surgery

  • More than 1 week since prior tumor biopsy
  • More than 2 weeks since prior surgical resection
  • More than 2 weeks since prior major non-CNS surgery and recovered
  • No prior small bowel resection

Other

  • At least 2 weeks since prior and no concurrent enzyme-inducing anticonvulsant drugs
  • More than 4 weeks since prior investigational drugs and recovered
  • No prior epidermal growth factor receptor- or ErbB-2-directed therapy (phase II only)
  • No prior vascular endothelial growth factor (VEGF) or VEGF receptor-directed therapy (phase II only)
  • No prior mTOR-directed therapy (phase II only)
  • No concurrent therapeutic warfarin
  • No concurrent treatment with any medication that may prolong QT interval, including any of the following:

    • Quinidine
    • Procainamide
    • Disopyramide
    • Amiodarone
    • Sotalol
    • Bretylium
    • Ibutilide
    • Thioridazine
    • Mesoridazine
    • Chlorpromazine
    • Amitriptyline
    • Imipramine
    • Desipramine
    • Doxepin
    • Erythromycin
    • Clarithromycin
    • Ketoconazole
    • Halofantrine
    • Quinine
    • Chloroquine
    • Mefloquine
    • Moxifloxacin
    • Gatifloxacin
    • Pimozide
    • Risperidone
    • Ziprasidone
    • Venlafaxine
    • Maprotiline
    • Lithium
    • Pentamidine
    • Droperidol
    • Dolasetron
  • No concurrent digoxin or verapamil
  • No concurrent tacrolimus
  • No other concurrent investigational agents
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00107237

Locations
United States, California
Jonsson Comprehensive Cancer Center at UCLA
Los Angeles, California, United States, 90095-1781
United States, North Carolina
Duke Univaersity Medical Center
Durham, North Carolina, United States, 27710
United States, Texas
MD Anderson Cancer Center/University of Texas
Houston, Texas, United States, 77030
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00107237     History of Changes
Other Study ID Numbers: CAEE788A2106, UCLA-0409004-01, CDR0000422335
Study First Received: April 5, 2005
Last Updated: June 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
adult glioblastoma
recurrent adult brain tumor
adult giant cell glioblastoma
adult gliosarcoma

Additional relevant MeSH terms:
Central Nervous System Neoplasms
Glioblastoma
Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Nervous System Diseases
Neuroectodermal Tumors
Everolimus
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014