Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G et al.. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95: 1148-1154

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
British Journal of Cancer (Impact Factor: 4.84). 12/2006; 95(9):1148-54. DOI: 10.1038/sj.bjc.6603419
Source: PubMed


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=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=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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Available from: Ming-Sound Tsao, Jun 26, 2014
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    • "The single-agent activity of temsirolimus was evaluated in a multicenter phase II study of 37 patients with advanced, progressive neuroendocrine tumors [41]. Although the intent-to-treat response rate for the cohort was low (6 %), 54 % of patients experienced stable disease while on treatment with a median time to progression (TTP) of 6 months. "
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    • "Inhibiteurs de la voie mTOR Un essai de phase II a d'abord démontré 7 % de réponse objective dans 15 TNE du pancréas en progression traitées par le temsirolimus [122]. Par la suite, 9 % de réponses objectives et une survie sans progression de 9,7 mois ont été rapportées dans une étude de phase II évaluant l'évérolimus chez 115 patients ayant une TNE du pancréas en progression ou non [123]. "
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    • "International (11 countries) 115 Everolimus 10 mg/day, continuous daily dosing Histologically confirmed, well to moderately differentiated, advanced pNET ORR, PFS, duration of response, OS, safety 45 Everolimus 10 mg/day + octreotide LAR (630 mg) Duran 2006 [51] Full text USA, Canada 15 Temsirolimus 25 mg IV/week for 8 weeks Histological/cytological confirmed carcinoid/ pancreatic islet cell tumour with documented progressive metastatic disease ORR, SD, duration of SD, TTP, OS, safety Kulke 2010 [52] Abstract USA 24 Everolimus 5 mg or 10 mg qd with temozolomide 150 mg/ m2 qd given for 7 days, maximum of 6 4-week cycles Histologic evidence of pNET, not suitable for curative surgery Response (PR, SD, PD); safety Kulke 2008 [36] "
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