This phase I trial is studying the side effects and best dose of RO4929097 in treating patients with recurrent invasive gliomas. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
PRIMARY OBJECTIVES: I. Determine, in patients with recurrent MGs (many of whom receive dexamethasone, a moderate CYP3A4 inducer), the safety and maximum-tolerated dose of RO4909297 administered at 2 dose levels. II. Determine the pharmacokinetics, intratumoral drug concentration, target modulation, and evidence of any treatment effect in the malignant glioma tumor tissue by R04929097 administered at the dose found in Part A. SECONDARY OBJECTIVES: I. Determine the pharmacokinetic (PK) profile of RO4909297 in patients with recurrent MGs (many of whom receive dexamethasone, a moderate CYP3A4 inducer). II. Determine the progression-free survival of patients with recurrent malignant glioma following treatment with R04929097. III. Determine if the RPTD dose of RO4929097 significantly inhibits p75\^NTR cleavage and processing. IV. Determine the effects of RO4929097 on the establishment and growth of BTIC cultures in neurosphere growth conditions, effects on proliferation, ability to self-renewal, and ability to differentiate along lineage-specific pathways. V. Determine the ability of RO4929097 to inhibit Notch signaling, by assessing downstream target activation, in glioma tissue of patients with recurrent MG. VI. Determine the association between a number of serum, tumor, and BTIC markers and response to R04929097. OUTLINE: This is a multicenter, dose-escalation (part A) study followed by an open-label (part B) study. PART A: Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. PART B: Patients receive oral RO4929097 once daily on days 1-7 and undergo surgery on day 8. Beginning 28 days later, patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Post resection tumor specimens are collected for correlative studies, including pharmacokinetic and biomarker assays. After completion of study therapy, patients are followed up at 30 days and then every 3 month for up to 6-12 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada
Maximum-tolerated dose (MTD) defined as the dose level in which less than or equal to 1 out of 6 patients experience dose limiting toxicity (DLT) assessed using NCI CTCAE version 4.0
Time frame: 21 days
Pharmacokinetic (PK) profile of RO4909297
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours
Progression-free survival following treatment with R04929097
The Kaplan-Meier method will be used.
Time frame: From registration to time of progression or death, whichever occurs first, assessed up to 12 months
Inhibition of p75NTR cleavage and processing
Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients. The Wilcoxon signed-rank and rank sum tests will be used.
Time frame: Up to 12 months
Establishment and growth of BTIC cultures in neurosphere growth conditions, effects on proliferation, ability to self-renewal, and ability to differentiate along lineage-specific pathways
Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients. The Wilcoxon signed-rank and rank sum tests will be used.
Time frame: Up to 12 months
Inhibition of Notch signaling, by assessing downstream target activation
Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients. The Wilcoxon signed-rank and rank sum tests will be used.
Time frame: Up to 12 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
TREATMENT
Masking
NONE
Enrollment
22
Correlative