Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study
I. To establish the maximum-tolerated dose and the recommended phase II dose of
gamma-secretase inhibitor RO4929097 (RO4929097) in combination with temozolomide and
radiotherapy in patients with newly diagnosed glioblastoma multiforme, anaplastic
astrocytoma, gliosarcoma, or other malignant gliomas.
I. To evaluate the pharmacokinetics of RO4929097 and temozolomide in these patients.
II. To evaluate brain and tumor penetration by this regimen, including radiotherapy, in
I. To evaluate pharmacodynamic effects of RO4929097 in the resected specimens from these
patients in comparison with specimens obtained from untreated patients.
II. To evaluate the effects of RO4929097 on the cancer stem cells of these patients.
III. To evaluate the effects of RO4929097 on angiogenesis (microvascular density and
expression of tumor vascular markers, including vascular E-cadherin, CD146, CD31, VEGF
ligands and receptors, and pericyte markers).
IV. To evaluate the combined effects of this regimen in explants established from tumor
specimens of these patients and controls.
V. To evaluate the effects of RO4929097 on MRI parameters, including DCE-MRI perfusion,
diffusion-weighted imaging, and volumetric analysis.
VI. To evaluate, preliminarily, the efficacy of this regimen at 6 months in these patients.
VII. To determine, preliminarily, the median progression-free survival and overall survival
of patients treated with this regimen.
VIII. To evaluate potential biomarkers of RO4929097and Notch inhibition activity in plasma
and hair follicle samples.
OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor
Pre-surgery treatment: Patients receive oral gamma-secretase inhibitor RO4929097 (RO4929097)
once daily on days 1-7 of week 1 and day 1 of week 2.
Surgery: Patients undergo surgery 2-3 hours after administration of RO4929097 on day 1 of
Treatment concurrent with radiotherapy: Beginning 3-4 weeks after surgery, patients undergo
conventional focal (intensity-modulated or 3-D conformal) radiotherapy 5 days a week for
approximately 6 weeks. Patients also receive oral RO4929097 once daily for approximately 10
weeks beginning the day of radiotherapy and oral temozolomide once daily for approximately 6
weeks beginning the day before radiotherapy.
Adjuvant treatment following radiotherapy: Approximately 4 weeks after completion of
radiotherapy, patients receive oral RO4929097 once daily on days 1-28 and oral temozolomide
once daily on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of
disease progression or unacceptable toxicity.
Blood and tumor tissue samples are analyzed for pharmacokinetics on days 0-2 of week 1 and
day 1 of week 5. Other biomarker studies are conducted on blood and hair follicle samples.
After completion of study therapy, patients are followed up for 4 weeks and periodically
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose defined as the highest dose studied for which the incidence of DLT is less than 33% using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|
|University of Virginia||Charlottesville, Virginia 22908|