Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study Evanthia Galanis, Jan C. Buckner, Matthew J. Maurer, Jeffrey I. Kreisberg, Karla Ballman, J. Boni, Josep M. Peralba, Robert B. Jenkins, Shaker R. Dakhil, Roscoe F. Morton, Kurt A. Jaeckle, Bernd W. Scheithauer, Janet Dancey, Manuel Hidalgo, and Daniel J. Walsh From the North Central Cancer Treatment Group; Mayo Clinic College of Medicine, Rochester, MN; The Johns Hopkins University, Baltimore, MD; The University of Texas Health Science Center at San Antonio, San Antonio, TX; Wyeth, Collegeville, PA; Cancer Therapy Evaluation Program, Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Wichita Community Clinical Oncology Program, Wichita, KS; Iowa Oncology Research Association CCOP, Des Moines, IA; and the Mayo Clinic Jacksonville, Jacksonville, FL. Submitted April 12, 2005; accepted April 28, 2005. Supported by North Central Cancer Treatment Group grant CA25224, R21 CA99209, and General Clinical Research Centers grant MO1 RR00585-34. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors’ disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Evanthia Galanis, MD, DSc, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905; e-mail: galanis .evanthia@mayo.edu. 0732-183X/05/2323-5294/$20.00 DOI: 10.1200/JCO.2005.23.622 A B S T R A C T Background Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods Recurrent GBM patients with # 1 chemotherapy regimen for progressive disease were eli- gible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (C max ), and sirolimus C max and area under the concentration-time curve were decreased in patients receiving p450 enzyme–inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improve- ment in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to pro- gression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyper- lipidemia in the first two treatment cycles was associated with a higher percentage of ra- diographic response (71% v 31%; P Z .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P Z .04). Conclusion Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on tem- sirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was ob- served in 36% of temsirolimus–treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors. J Clin Oncol 23:5294-5304. INTRODUCTION Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a dismal prognosis with 12- to 15-month median survival despite the use of surgery, chemotherapy, and radi- ation therapy. Treatment options are lim- ited at recurrence. Although a variety of chemotherapy agents have been tried in this setting, response rates have been in VOLUME 23 d NUMBER 23 d AUGUST 10 2005 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT 5294 Downloaded from ascopubs.org by 18.232.181.18 on June 11, 2022 from 018.232.181.018 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.