Clinical Trial: RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study

Brief Summary: 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.

Detailed Summary:

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.

The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.



Original Primary Outcome: Maximum-tolerated dose and/or recommended phase II dose

Current Secondary Outcome:

  • Changes in MRI parameters [ Time Frame: Baseline to up to 4 years ]
    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.
  • Percent changes in serum YKL-40 levels and hair follicle HES1 levels [ Time Frame: Baseline to up to 4 years ]
    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.
  • Pharmacokinetic (PK) parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097 [ Time Frame: Pre-dose, 30 minutes, 1, 2, 4, 6, and 8 hours ]
    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.


Original Secondary Outcome: Pharmacokinetics

Information By: National Cancer Institute (NCI)

Dates:
Date Received: May 6, 2010
Date Started: May 2010
Date Completion:
Last Updated: September 28, 2015
Last Verified: June 2015