A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas - PubMed (original) (raw)

Clinical Trial

. 2006 Nov 6;95(9):1148-54.

doi: 10.1038/sj.bjc.6603419. Epub 2006 Oct 10.

J Kortmansky, D Singh, H Hirte, W Kocha, G Goss, L Le, A Oza, T Nicklee, J Ho, D Birle, G R Pond, D Arboine, J Dancey, S Aviel-Ronen, M-S Tsao, D Hedley, L L Siu

Affiliations

Clinical Trial

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

I Duran et al. Br J Cancer. 2006.

Abstract

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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Figures

Figure 1

Figure 1

Maximal percentages of tumour reduction for target lesion(s) by RECIST criteria (Note: some patients with PD progressed owing to new or increasing non-target lesions, or by symptomatic progression).

Figure 2

Figure 2

Time to progression for entire study cohort.

Figure 3

Figure 3

Overall survival for entire study cohort.

Figure 4

Figure 4

Pre- and post-treatment liver biopsies. Tissue sections were first immunofluorescence-labelled for S235/236-S6 ribosomal protein, imaged, and then restained with H&E. The grey scale images of pS6 are unenhanced, at original resolution.

Figure 5

Figure 5

PI3K/AKT/mTOR pathway showing the mTOR protein complexes, mTOR/RAPTOR and mTOR/RICTOR, and the feedback loop involving IGF-IR. Arrows indicate activation; bars indicate inhibition.

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References

    1. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML (2004) 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. J Clin Oncol 22: 909–918 - PubMed
    1. Baselga J, Fumoleau P, Gil M, Colomer R, Roche H, Cortes-Funes H, Burstein H, Kaufman P, Kong S, Moore L (2004) Phase II, 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results. Proc Am Soc Clin Oncol 23: 13
    1. Bukowski RM, Tangen CM, Peterson RF, Taylor SA, Rinehart JJ, Eyre HJ, Rivkin SE, Fleming TR, Macdonald JS (1994) Phase II trial of dimethyltriazenoimidazole carboxamide in patients with metastatic carcinoid. A Southwest Oncology Group study. Cancer 73: 1505–1508 - PubMed
    1. Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, Eiermann W, Hess D, Morant R, Semiglazov V, Borner M, Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy-Bouxin N, Boni J, Kong S, Cincotta M, Moore L (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23: 5314–5322 - PubMed
    1. Cheng PN, Saltz LB (1999) Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 86: 944–948 - PubMed

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