Originally published as JCO Early Release 10.1200/JCO.2005.23.622 on July 5 2005

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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, 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

Address reprint requests to Evanthia Galanis, MD, DSc, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905; e-mail: galanis.evanthia{at}mayo.edu.

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 eligible. 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 improvement 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 progression (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 hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04).

CONCLUSION: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed 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.

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.

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