Phase I Pharmacodynamic and "High Content" Study of the Gamma-Secretase Inhibitor RO4929097 in Patients With Recurrent Malignant Gliomas (MGs) Targeting p75NTR to Inhibit Brain Tumor Initiating Cells (BTICs) and Recurrent Invasive Gliomas
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.
Interventional
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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
21 days
Yes
Peter Forsyth
Principal Investigator
University Health Network-Princess Margaret Hospital
United States: Food and Drug Administration
NCI-2011-02565
NCT01269411
July 2011
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