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Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: a Spanish group for research on sarcomas (GEIS) study

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Summary

Background This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma. Methods Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m2 respectively). A 3 + 3 dose escalation design with cohorts of 3–6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted. Results Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m2 and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m2. Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro. Conclusions RD was sorafenib 400 mg bid plus ifosfamide 6 g/m2, allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing.

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Acknowledgments

This work was supported in part by Bayer España.

Disclosures

E. Brendel is an employee of Bayer Pharma AG in the department of Clinical Sciences/Clinical Pharmacology. The rest of the authors have declared no conflict of interest.

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Authors and Affiliations

  1. Sarcoma Unit, The Royal Marsden Hospital, Fulham Road, SW3 6JJ, London, UK

    J. Martín-Liberal

  2. Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain

    A. López-Pousa & O. Gallego

  3. Hospital Universitari Son Espases, 07010, Palma de Mallorca, Spain

    J. Martín Broto

  4. Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain

    R. Cubedo

  5. Bayer Pharma AG, Global Drug Discovery, Clinical Pharmacology, Wuppertal, Germany

    E. Brendel

  6. Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908, Barcelona, Spain

    O. M. Tirado

  7. Institut Català d’Oncologia, 08908, Barcelona, Spain

    X. García del Muro

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  1. J. Martín-Liberal
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Correspondence to J. Martín-Liberal.

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Martín-Liberal, J., López-Pousa, A., Broto, J.M. et al. Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: a Spanish group for research on sarcomas (GEIS) study. Invest New Drugs 32, 287–294 (2014). https://doi.org/10.1007/s10637-013-9989-9

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  • DOI: https://doi.org/10.1007/s10637-013-9989-9

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