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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


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Brain and Central Nervous System Tumors

Thank you

Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and dose-limiting toxicity of AEE788

Safety Issue:

Yes

Principal Investigator

Novartis Pharmaceuticals

Investigator Role:

Study Director

Investigator Affiliation:

Novartis Pharmaceuticals

Authority:

United States: Food and Drug Administration

Study ID:

CAEE788A2106

NCT ID:

NCT00107237

Start Date:

October 2003

Completion Date:

June 2006

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult glioblastoma
  • recurrent adult brain tumor
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Jonsson Comprehensive Cancer Center at UCLALos Angeles, California  90095-1781
MD Anderson Cancer Center/University of TexasHouston, Texas  77030
Duke Univaersity Medical CenterDurham, North Carolina  27710