gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Phase I trial of sorafenib (BAY 43-9006) combined with dacarbazine (DTIC) in patients with metastatic melanoma

Meeting Abstract

  • corresponding author presenting/speaker Tim Eisen - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House, Sutton, Surrey, United Kingdom
  • T. Ahmad - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House
  • R. Marais - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House
  • I. Gibbens - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House
  • M. James - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House
  • A. Affolter - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House
  • D. Chao - The Royal Free Hospital, London, United Kingdom
  • L. Bergamini - BayerSpA, Milan, Italy
  • B. Schwartz - Bayer Pharmaceuticals Corporation, West Haven, CT, USA
  • M.E. Gore - Urology, Skin and Lung Units, The Royal Marsden Hospital, Sycamore House

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO451

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dkk2006/06dkk561.shtml

Veröffentlicht: 20. März 2006

© 2006 Eisen et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Background: B-Raf mutations occur in about 70% of melanomas, and are associated with hyperactive Raf/MEK/ERK signalling activity. Sorafenib (BAY 43–9006) inhibits the Raf/MEK/ERK pathway at the level of Raf kinase (Raf-1, wild-type B-Raf, V599E B-Raf) and the receptor tyrosine kinases VEGFR-2 and PDGFR-β, to mediate effects on both the tumor and vasculature. In PhaseI/II trials, sorafenib was generally well tolerated as a single agent or with concomitant chemotherapy. Sorafenib, in combination with carboplatin/paclitaxel, has shown preliminary anti-tumor activity against melanoma.

Patients and methods: This single-centre, open-label, PhaseI, dose-escalation study was performed to determine the safety profile and maximum tolerated dose (MTD) of sorafenib administered at 200 (cohort1) or 400 mg bid (cohort2) in combination with repeated 21-day cycles of DTIC 1000 mg/m2. In an extension phase (cohort3), patients received the MTD of sorafenib plus DTIC 1000 mg/m2.

Results: Patients with metastatic melanoma (ECOG PS 0–1) were enrolled into cohorts1 (n = 3), 2 (n = 6) and 3 (n = 9). One patient in cohort2 experienced dose-limiting grade 3 hand–foot skin reaction. The MTD of sorafenib in combination with DTIC was defined as 400 mg bid. Common drug-related adverse events in cohort1 and cohorts2–3, generally grade1–2 in severity, included nausea (100% and 40% of patients), fatigue (67% and 60%), constipation (33% and 67%), alopecia (67% and 13%) and rash (67% and 53%). Grade3–4 adverse events were rare, and mostly resolved. Frequent grade3–4 AEs included abnormal lipase (1 patient in cohort1 and 2 patients in cohorts2–3), fatigue (2 patients in cohort2–3) and febrile neutropenia (3 patients in cohorts2–3). One patient died due to progressive disease after Cycle1. Of the 10 patients evaluable for change from baseline in tumor diameter at 12 weeks, 3 patients had a >30% reduction, 5 patients remained within 20% and 2 patients had a >40% increase. Two patients are ongoing. B-Raf mutation status did not predict response. Ras mutations were not found.

Conclusions: The MTD of this combination is continuous oral sorafenib 400 mg bid plus DTIC 1000 mg/m2. This combination is safe and well tolerated, and shows preliminary anti-tumor activity in patients with metastatic melanoma.