SORAVE: Phase I study for the treatment of relapsed solid tumors with the combination of sorafenib and everolimus

Autor: Markus Dietlein, Ildiko Katay, Marc Bos, Noemi Muthen, Uwe Fuhr, Peter Mallmann, Matthias Scheffler, Max Schlaak, Fritz Soergel, Irini Papachristou, Roland Schnell, Deniz Kahraman, Juergen Wolf, Christian Mattonet, Masyar Gardizi, Lucia Nogova, Martina Kinzig, Carsten Kobe, Kerstin Rhiem, Denis Rokitta
Rok vydání: 2012
Předmět:
Zdroj: Journal of Clinical Oncology. 30:3044-3044
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2012.30.15_suppl.3044
Popis: 3044 Background: Dual inhibition of signaling pathways interfering with angiogenesis and cell proliferation may increase anti-tumor efficacy. We evaluated the combination of the VEGFR inhibitor sorafenib (S) and the mTOR inhibitor everolimus (E) and used FDG-PET to assess pharmacodynamic (PD) activity of E. Methods: Patients with relapsed solid tumors were treated with escalating doses of E 2.5-10.0mg/d p.o. in a 14 days monotherapy run in phase followed by combination therapy with a fixed dose of S 400mg bid from day 15. The primary aim was to define a safe and feasible combination treatment regimen for a subsequent phase II trial. DLT was defined as any drug related toxicity of CTC IV° or toxicity requiring hospitalization or interruption of therapy for more than 2 weeks within the first 29 days of treatment. Pharmacokinetic (PK) analyses were performed on day 5, 14 and 29 combined with explorative PD assessment of E by FDG-PET on days 1, 5 and 14 of treatment. Results: Nineteen patients were treated with the combination of E and S. The DLT was not reached according to protocol definition. However, at a dose level of E 10mg/d p.o. the following adverse events (AE) occurred in the non-DLT interval: Pneumonia III°, treatment delay due to leucopoenia/thrombopenia III° and sudden cardiac death probably due to arrhythmia. Based on these observations, the dose level of 7.5mg/day E p.o. in combination with 400mg S bid was defined as the MTD. The steady state of E alone was reached after 5 days of treatment and did not change until day 14. However, on day 29 everolimus plasma concentrations (AUC and Cmax) showed a significant 30 % reduction when co-administered with S. A metabolic response of the hottest lesion in PET on day 5 defined as ≤ 80% of baseline was seen in 4 of 15 evaluable patients. Median PFS and OS were 4.2 and 5.4 months, respectively. A patient with neuroendocrine carcinoma reached the longest PFS of 16.6 months. Conclusions: Treatment of patients with relapsed solid tumors with a combination of E 7.5mg/day and 400mg S bid is safe and feasible. The extension phase for confirmation of safety data, further PK and PD modeling and preliminary exploration of efficacy in KRAS mutant cancer patients will be performed at this dose level.
Databáze: OpenAIRE
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