Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study

替西罗莫司 医学 内科学 胃肠病学 毒性 最大值 养生 西罗莫司 癌症 药理学 肿瘤科 外科 药代动力学 PI3K/AKT/mTOR通路 mTOR抑制剂的发现与发展 生物化学 化学 细胞凋亡
作者
Evanthia Galanis,Jan C. Buckner,Matthew J. Maurer,Jeffrey I. Kreisberg,Karla V. Ballman,Joseph Boni,Josep Maria Peralba,Robert B. Jenkins,Shaker R. Dakhil,Roscoe F. Morton,Kurt A. Jaeckle,Bernd W. Scheithauer,Janet Dancey,Manuel Hidalgo,Daniel J. Walsh
出处
期刊:Journal of Clinical Oncology [Lippincott Williams & Wilkins]
卷期号:23 (23): 5294-5304 被引量:684
标识
DOI:10.1200/jco.2005.23.622
摘要

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).Recurrent GBM patients with < or = 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly.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 (Cmax), and sirolimus Cmax 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).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.

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