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
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
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.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is an open-label, multicenter, dose-escalation study of AEE788.
Phase I: Patients are assigned to 1 of 2 treatment groups.
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.
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.
DISEASE CHARACTERISTICS:
Histologically confirmed glioblastoma multiforme, meeting 1 of the following criteria:
Phase I
Phase II, group 1
Phase II, group 2
Multifocal disease allowed
PATIENT CHARACTERISTICS:
Performance status
Life expectancy
Hematopoietic
Hepatic
Renal
Cardiovascular
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:
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:
No other clinically significant primary malignancy requiring active intervention NOTE: *Supplements allowed
PRIOR CONCURRENT THERAPY:
Biologic therapy
Chemotherapy
Endocrine therapy
Radiotherapy
Surgery
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:
No concurrent digoxin or verapamil
No concurrent tacrolimus
No other concurrent investigational agents