Sorafenib Administered Using a High-dose, Pulsatile Regimen: a Phase I Exposure Escalation Study

Summary

Sorafenib is an oral anticancer drug and inhibits multiple protein kinases important for tumor growth and metastases, including VEGFR, PDGFR, and RAF kinases. In daily clinical practice it is currently used at a dose of 400 mg twice daily in a continuous schedule. In this phase I study patients will be treated with a new dosing schedule of sorafenib: i.e. a high-dose, pulsatile schedule. The tolerability and safety of this new schedule is examined in exposure escalation cohorts based on a target plasma AUC0-12h (area under the curve). Exposure escalation cohorts are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.

Timeline

Start

2015-09

Primary completion

2017-12-27

Completion

2017-12-27

Publications

• Background Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B, Awada A, Voigtmann R, Scheulen ME, Seeber S. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):965-72. doi: 10.1200/JCO.2005.06.124. Epub 2004 Dec 21.
• Background Pecuchet N, Lebbe C, Mir O, Billemont B, Blanchet B, Franck N, Viguier M, Coriat R, Tod M, Avril MF, Goldwasser F. Sorafenib in advanced melanoma: a critical role for pharmacokinetics? Br J Cancer. 2012 Jul 24;107(3):455-61. doi: 10.1038/bjc.2012.287. Epub 2012 Jul 5.
• Background Wang X, Zhang L, Goldberg SN, Bhasin M, Brown V, Alsop DC, Signoretti S, Mier JW, Atkins MB, Bhatt RS. High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma. J Transl Med. 2011 Dec 21;9:220. doi: 10.1186/1479-5876-9-220.
• Background Honeywell R, Yarzadah K, Giovannetti E, Losekoot N, Smit EF, Walraven M, Lind JS, Tibaldi C, Verheul HM, Peters GJ. Simple and selective method for the determination of various tyrosine kinase inhibitors used in the clinical setting by liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 May 1;878(15-16):1059-68. doi: 10.1016/j.jchromb.2010.03.010. Epub 2010 Mar 15.

Drugs

Indications