This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) when given together with temozolomide and radiation therapy in treating patients with newly diagnosed malignant glioma. Enzyme inhibitors, such as gamma-secretase/Notch signalling pathway inhibitor RO4929097, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with temozolomide and radiation therapy may kill more tumor cells.
PRIMARY OBJECTIVES: I. To establish the maximum tolerated dose/recommended phase II dose of RO4929097 in combination with temozolomide and radiotherapy in patients with glioblastoma or malignant gliomas. SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetics of RO4929097 when given in combination with temozolomide (correlative study C1). II. To evaluate brain and tumor penetration of RO4929097 when given in recommended phase II single agent schedule and when given at the maximum tolerated dose (MTD) for the combination with radiotherapy and temozolomide (correlative study C2). TERTIARY OBJECTIVES: I. To evaluate pharmacodynamic effects of RO4929097 in the resected specimens, and comparison with specimens obtained from untreated patients. II. Effects of RO4929097 on the cancer stem cell population (correlative study C4). III. Effects of RO4929097 on angiogenesis (correlative study C5). IV. To evaluate the combined effects of RO4929097, radiation and temozolomide in explants established from patients' tumor specimens (correlative study C6). V. To evaluate the effects of RO4929097 on magnetic resonance imaging (MRI) parameters (correlative study C7), including dynamic contrast enhanced (DCE) MRI perfusion, diffusion weighted imaging and volumetric analysis. VI. Preliminary evaluation of efficacy of this treatment regimen: 6 month (6m) and median progression-free and overall survival, and response rates. VII. To evaluate potential biomarkers of gamma-secretase and Notch inhibition activity (correlative study C8). OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097. Patients are assigned to 1 of 2 treatment arms. PRE-SURGERY TREATMENT: Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) once daily (QD) on days 1-7 of week 1 and day 1 of week 2. SURGERY: Patients undergo surgery 2-3 hours after administration of gamma-secretase/Notch signalling pathway inhibitor RO4929097 on day 1 of week 2. TREATMENT CONCURRENT WITH RADIOTHERAPY: Beginning 3-4 weeks after surgery, patients undergo conventional focal (intensity-modulated radiation therapy \[IMRT\] or 3-D conformal) radiotherapy 5 days a week for approximately 6 weeks. Patients also receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD for approximately 10 weeks beginning the day of radiotherapy and temozolomide PO QD for approximately 6 weeks beginning the day before radiotherapy. ADJUVANT TREATMENT FOLLOWING RADIOTHERAPY: Approximately 4 weeks after completion of radiotherapy, patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-28 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 2 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Undergo 3-D conformal radiation therapy
Given PO
Undergo IMRT
Correlative studies
Correlative studies
Given PO
Undergo surgery
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
University of Virginia Cancer Center
Charlottesville, Virginia, United States
Maximum-tolerated dose defined as the highest dose studied for which the incidence of dose limiting toxicity is less than 33% using National Cancer Institute Common Toxicity Criteria
The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.
Time frame: 28 days
Changes in MRI parameters
Perfusion and diffusion-based MRI parameters including but not restricted to blood volume, mean and median apparent diffusion coefficient and structural volumes will be analyzed. Results will be summarized, and mean and median values at different time points will be tabulated. Changes in such parameters will be checked for statistical significance and correlated with the disease status.
Time frame: Baseline to up to 4 years
Percent changes in serum YKL-40 levels and hair follicle HES1 levels
Means and medians of all patients together will be calculated and tabulated for each time point, with depiction of standard deviations. A Wilcoxon test will be used to determine p value of changes in mean values of YKL-40 and hairy and enhancer of split 1, (Drosophila) (HES1), with a p value of less than 0.05 considered statistically significant.
Time frame: Baseline to up to 4 years
Pharmacokinetic (PK) parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097
Noncompartmental and/or compartmental methods will be used to calculate PK parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temozolomide from the plasma concentration-time data collected from each individual. Descriptive statistics (including number, mean and/or median, standard deviation, coefficient of variation, and range) for PK parameters will be tabulated by dose level.
Time frame: Pre-dose, 30 minutes, 1, 2, 4, 6, and 8 hours
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.