Galanis, E. et al. North Central Cancer Treatment Group. Phase II trail of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294-5304

Johns Hopkins University, Baltimore, Maryland, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2005; 23(23):5294-304. DOI: 10.1200/JCO.2005.23.622
Source: PubMed


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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    • "Further predictive response stratification may be possible through baseline measurements of downstream mTOR activators such as s6 kinase (96). Similarly in GBM patients, levels of phosphorylated Akt have been shown to be predictive of clinical response to erlotinib in EGFR amplified tumors (97, 98). "
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    • "Inhibition of the pathway using rapamycin resulted in paradoxical activation of Akt through loss of negative feedback in a subset of patients, which in turn was related to shorter time-to-progression during postsurgical maintenance rapamycin therapy [24]. The limited single-agent activity of rapamycin analogs in several GBM trials [25,26] provides a rationale for ongoing clinical trials with dual PI3K/mTOR inhibitors in GBM. A clinical trial of a dual PI3K/m-TOR inhibitor, XL765, in combination with TMZ is currently underway for GBM [27]. "
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    • "However, the use of a single agent for newly diagnosed or recurrent GBM does not effectively improve treatment efficacy [3, 10]. In previous clinical studies, monotherapy using temsirolimus (CCI-779), a small-molecule inhibitor of the mammalian target of rapamycin (mTOR), was found to promote 6-month progression-free survival (PFS6) rates of 2.3–7.8% in phase II trials [11, 12]. The standard therapy of adding the adjuvant sorafenib to the treatment of newly diagnosed GBM patients also does not improve treatment efficacy [13]. "
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