A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer

被引：18

作者：

Desar, I. M. E. ^{[1
]}

Timmer-Bonte, J. N. H. ^{[1
]}

Burger, D. M. ^{[2
]}

van der Graaf, W. T. A. ^{[1
]}

van Herpen, C. M. L. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Dept Med Oncol 452, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Dept Clin Pharm, Med Ctr, NL-6500 HB Nijmegen, Netherlands

来源：

BRITISH JOURNAL OF CANCER | 2010年 / 103卷 / 11期

关键词：

phase I; sorafenib; sirolimus; tyrosine kinase inhibitor; mTOR inhibitor; COMBINATION TARGETED THERAPY; SUNITINIB; TEMSIROLIMUS; INHIBITOR; TOXICITY; PATHWAY;

D O I：

10.1038/sj.bjc.6605777

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically. METHODS: A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination. RESULTS: Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC((0-96)) and C-max of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1mg q.d. CONCLUSION: The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination. British Journal of Cancer (2010) 103, 1637-1643. doi:10.1038/sj.bjc.6605777 www.bjcancer.com Published online 2 November 2010 (C) 2010 Cancer Research UK

引用

页码：1637 / 1643

页数：7

共 27 条

[1] The mammalian target of rapamycin signaling pathway: Twists and turns in the road to cancer therapy [J].

Abraham, Robert T. ;

Gibbons, James J. .

CLINICAL CANCER RESEARCH, 2007, 13 (11) :3109-3114

[2] Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity [J].

Azad, Nilofer S. ;

Posadas, Edwin M. ;

Kwitkowski, Virginia E. ;

Steinberg, Seth M. ;

Jain, Lokesh ;

Annunziata, Christina M. ;

Minasian, Lori ;

Sarosy, Gisele ;

Kotz, Herbert L. ;

Premkumar, Ahalya ;

Cao, Liang ;

McNally, Deborah ;

Chow, Catherine ;

Chen, Helen X. ;

Wright, John J. ;

Kohn, Elise C. .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (22) :3709-3714

[3] Hand-Foot Skin Reaction Increases with Cumulative Sorafenib Dose and with Combination Anti-Vascular Endothelial Growth Factor Therapy [J].

Azad, Nilofer S. ;

Aragon-Ching, Jeanny B. ;

Dahut, William L. ;

Gutierrez, Martin ;

Figg, William D. ;

Jain, Lokesh ;

Steinberg, Seth M. ;

Turner, Maria L. ;

Kohn, Elise C. ;

Kong, Heidi H. .

CLINICAL CANCER RESEARCH, 2009, 15 (04) :1411-1416

[4] Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma [J].

Bhojani, Naeem ;

Jeldres, Claudio ;

Patard, Jean-Jacques ;

Perrotte, Paul ;

Suardi, Nazareno ;

Hutterer, Georg ;

Patenaude, Francois ;

Oudard, Stephane ;

Karakiewicz, Pierre I. .

EUROPEAN UROLOGY, 2008, 53 (05) :917-930

[5]

Cen P, 2009, J CLIN ONCOL, V27

[6] Synergistic combinations of signaling pathway inhibitors: Mechanisms for improved cancer therapy [J].

Dent, Paul ;

Curiel, David T. ;

Fisher, Paul B. ;

Grant, Steven .

DRUG RESISTANCE UPDATES, 2009, 12 (03) :65-73

[7] Sorafenib in advanced clear-cell renal-cell carcinoma [J].

Escudier, Bernard ;

Eisen, Tim ;

Stadler, Walter M. ;

Szczylik, Cezary ;

Oudard, Stephane ;

Siebels, Michael ;

Negrier, Sylvie ;

Chevreau, Christine ;

Solska, Ewa ;

Desai, Apurva A. ;

Rolland, Frederic ;

Demkow, Tomasz ;

Hutson, Thomas E. ;

Gore, Martin ;

Freeman, Scott ;

Schwartz, Brian ;

Shan, Minghua ;

Simantov, Ronit ;

Bukowski, Ronald M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (02) :125-134

[8] The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; A review [J].

Eskens, Ferry A. L. M. ;

Verweij, Jaap .

EUROPEAN JOURNAL OF CANCER, 2006, 42 (18) :3127-3139

[9] Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer [J].

Faivre, S ;

Delbaldo, C ;

Vera, K ;

Robert, C ;

Lozahic, S ;

Lassau, N ;

Bello, C ;

Deprimo, S ;

Brega, A ;

Massimini, G ;

Armand, JP ;

Scigalla, P ;

Raymond, E .

JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (01) :25-35

[10]

Forsythe JA, 1996, MOL CELL BIOL, V16, P4604

← 1 2 3 →