Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma.
Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.
Department of Medicine, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Edward.Pan@UTSouthwestern.edu.
Edward
E
Pan
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Jeffrey G
JG
Supko
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Thomas J
TJ
Kaley
Department of Neurological Surgery, University of California, San Francisco, CA, USA.
Nicholas A
NA
Butowski
Department of Neurology, University of California, Los Angeles, CA, USA.
Timothy
T
Cloughesy
Neuro-Oncology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Jinkyu
J
Jung
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Serena
S
Desideri
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Stuart
S
Grossman
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Xiaobu
X
Ye
Neuro-Oncology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. deric.park@nih.gov.
Deric M
DM
Park
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D005466:Fluorocarbons
D000970:Antineoplastic Agents; D001552:Benzazepines; D000068258:Bevacizumab; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons
Bevacizumab; Clinical trial; Gamma secretase; Glioma; Notch