Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients With Advanced Refractory Renal Cell Carcinoma

Atkins, Michael B.; Hidalgo, Manuel; Stadler, Walter M.; Logan, Theodore F.; Dutcher, Janice P.; Hudes, Gary R.; Park, Young; Liou, Song Heng; Marshall, Bonnie; Boni, Joseph; Dukart, Gary; Sherman, Matthew L.

doi:10.1200/jco.2004.08.185

Cited by 908 publications

(547 citation statements)

References 39 publications

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“…This interpretation is strengthened by our observation that confluency dramatically affected phospho-RPS6 levels in WT8 cells. Alternatively, mTOR may be activated in only a subset of RCCs in agreement with the observed 7% response rate to CCI-779 (Atkins et al, 2004).…”

Section: Discussionsupporting

confidence: 67%

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Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

et al. 2005

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Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFa) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel -Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHLdependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated posttranscriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.

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Section: Discussionsupporting

confidence: 67%

“…Tuberous sclerosis mutant cells have an exaggerated HIFa response to hypoxia, which is blocked by treatment with rapamycin. A rapamycin prodrug, CCI-779 (Wyeth), has been examined as a single agent in RCC (Atkins et al, 2004). The response rate was low (7%) but included one complete response.…”

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confidence: 99%

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

et al. 2005

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“…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.…”

Section: Temsirolimus (Cci-779)mentioning

confidence: 99%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

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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.

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“…Temsirolimus (sirolimus 42-ester 2,2-bis hydroxymethyl propionic-acid; CCI-779) is a more water-soluble ester derivative of its parent compound sirolimus, selected for development as an anticancer agent based on its more favourable pharmaceutical characteristics and superior therapeutic index. Temsirolimus has already been tested in phase I and II trials with promising activity and good safety profile (Atkins et al, 2004;Baselga et al, 2004;Raymond et al, 2004;Chan et al, 2005). In phase I studies, rash and mucositis were dose-limiting, and other adverse events (AE) observed include eczematous reactions, dry skin, herpes-type lesions, mild myelosupression, hypercholesterolaemia and hypertriglyceridemia (Atkins et al, 2004;Baselga et al, 2004;Raymond et al, 2004).…”

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confidence: 99%

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

et al. 2006

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Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6 -18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P ¼ 0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P ¼ 0.01) predicted for a better response. Increases in pAKT (P ¼ 0.041) and decreases in pmTOR (P ¼ 0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

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Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients With Advanced Refractory Renal Cell Carcinoma

Abstract: In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

Cited by 908 publications

References 39 publications

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

Therapeutic targets: MTOR and related pathways

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

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