Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme

Chang, Susan M.; Wen, Patrick Y.; Cloughesy, Timothy F.; Greenberg, Harry S.; Schiff, David; Conrad, Charles A.; Fink, Karen; Robins, H. Ian; Angelis, Lisa De; Raizer, Jeffrey J.; Hess, Kenneth R.; Aldape, Ken; Lamborn, Kathleen R.; Kuhn, John G.; Dancey, Janet; Prados, Michael D.

doi:10.1007/s10637-005-1444-0

Cited by 375 publications

(197 citation statements)

References 18 publications

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…Notwithstanding the lower 5 mg dose administered in this study, the types of adverse events observed were not dissimilar to those seen in studies of temsirolimus in patients with cancer, although a greater percentage of cancer patients had thrombocytopaenia, rash, and mucositis (Atkins et al, 2004;Hidalgo et al, 2006) than did the healthy subjects in this study. Previous studies have suggested that the incidence and severity of some adverse events are proportional to the exposure to temsirolimus (Boni et al, 2005;Chang et al, 2005). In a population PK safety analysis of patients receiving 25, 75, or 250 mg of temsirolimus weekly, clinically interesting associations between AUC sum and adverse event severity were observed for thrombocytopaenia (P ¼ 0.007), pruritus (P ¼ 0.011), and hypertriglyceridaemia (P ¼ 0.040) (Boni et al, 2005).…”

Section: Discussionmentioning

confidence: 93%

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Leister¹,

Burns²,

Hug³

2008

Br J Cancer

View full text Add to dashboard Cite

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C max ) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC sum (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

show abstract

Section: Discussionmentioning

confidence: 93%

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Leister¹,

Burns²,

Hug³

2008

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Results have been reported from studies in metastatic breast (MBC), renal cell (RCC), 75 small cell lung, (SCLC), 76 endometrial carcinoma, 77 mantle cell lymphoma (MCL), 78 melanoma, 79 and glioblastoma multiforme (GBM). 80,81 The results of these studies are summarized in Table 2. The most promising activity has been seen in mantle cell lymphoma and endometrial carcinoma with objective tumor response rates of 30-40%.…”

Section: Temsirolimus (Cci-779)mentioning

confidence: 99%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

134

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

show abstract

“…In glioblastoma, attempts to target mTOR with rapamycin and its analogues have largely failed to show efficacy (7)(8)(9), mediated by difficulty in fully inhibiting mTORC1 signaling and by emergence of a feedback loop, that activates pro-growth, pro-survival Akt signaling (10). Rapamycin analogues also activate MAPK through a PI3K-dependent mechanism in other cancer types, suggesting additional potential mechanisms of clinical resistance and raising the need for alternative strategies to target mTOR signaling in patients (11).…”

mentioning

confidence: 99%

The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis

Guo¹,

Hildebrandt²,

Prins³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

211

224

View full text Add to dashboard Cite

The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by 18 fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.

show abstract

Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme

Cited by 375 publications

References 18 publications

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Therapeutic targets: MTOR and related pathways

The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis

Contact Info

Product

Resources

About