Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG)

Bernd Kasper, Peter Reichardt, Daniel Pink, Michaela Sommer, Monika Mathew, Geraldine Rauch, Peter Hohenberger, Bernd Kasper, Peter Reichardt, Daniel Pink, Michaela Sommer, Monika Mathew, Geraldine Rauch, Peter Hohenberger

Abstract

Background: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest.

Methods: We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose.

Results: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing.

Conclusion: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.

References

    1. Van Glabekke M., van Oosterom A.T., Oosterhuis J.W., Mouridsen H., Crowther D., Somers R., Verweij J., Santoro A., Buesa J., Tursz T. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: An analysis of 2.185 patients treated with anthracycline-containing first-line regimens—A European Organization for Research and treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J. Clin. Oncol. 1999;17:150–157.
    1. Van Oosterom A.T., Mouridsen H.T., Nielsen O.S., Dombernowsky P., Krzemieniecki K., Judson I., Svancarova L., Spooner D., Hermans C., van Glabbeke M., et al. EORTC Soft Tissue and Bone Sarcoma Group. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur. J. Cancer. 2002;38:2397–2406. doi: 10.1016/S0959-8049(02)00491-4.
    1. Leahy M., Garcia Del Muro X., Reichardt P., Judson I., Staddon A., Verweij J., Baffoe-Bonnie A., Jönsson L., Musayev A., Justo N., et al. SABINE Investigators. Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The Sarcoma treatment and Burden of Illness in North America and Europe (SABINE) study. Ann. Oncol. 2012;23:2763–2770. doi: 10.1093/annonc/mds070.
    1. Demetri G.D., Chawla S.P., von Mehren M., Ritch P., Baker L.H., Blay J.Y., Hande K.R., Keohan M.L., Samuels B.L., Schuetze S., et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J. Clin. Oncol. 2009;27:4188–4196. doi: 10.1200/JCO.2008.21.0088.
    1. Van der Graaf W.T.A., Blay J.Y., Chawla S.P., Kim D.W., Bui-Nguyen B., Casali P.G., Schöffski P., Aglietta M., Staddon A.P., Beppu Y., et al. EORTC Soft Tissue and Bone Sarcoma Group. PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–1886.
    1. Ducimetiere F., Lurkin A., Ranchere-Vince D., Decouvelaere A.V., Péocʼh M., Istier L., Chalabreysse P., Muller C., Alberti L., Bringuier P.P., et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6:e20294. doi: 10.1371/journal.pone.0020294.
    1. Garcia-Carbonero R., Supko J.G., Manola J., Seiden M.V., Harmon D., Ryan D.P., Quigley M.T., Merriam P., Canniff J., Goss G., et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J. Clin. Oncol. 2004;22:1480–1490. doi: 10.1200/JCO.2004.02.098.
    1. Le Cesne A., Blay J.Y., Judson I., van Oosterom A., Verweij J., Radford J., Lorigan P., Rodenhuis S., Ray-Coquard I., Bonvalot S., et al. Phase II study of ET-743 in advanced soft tissue sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J. Clin. Oncol. 2005;23:576–584.
    1. Hensley M.L., Maki R., Venkatraman E., Geller G., Lovegren M., Aghajanian C., Sabbatini P., Tong W., Barakat R., Spriggs D.R. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: Results of a phase II trial. J. Clin. Oncol. 2002;20:2824–2831. doi: 10.1200/JCO.2002.11.050.
    1. Maki R., Wathen J.K., Patel S.R., Priebat D.A., Okuno S.H., Samuels B., Fanucchi M., Harmon D.C., Schuetze S.M., Reinke D., et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: Results of sarcoma alliance for research through collaboration study 002. J. Clin. Oncol. 2007;25:2755–2763. doi: 10.1200/JCO.2006.10.4117.
    1. Messersmith W.A., Jimeno A., Ettinger D., Laheru D., Brahmer J., Lansey D., Khan Y., Donehower R.C., Elsayed Y., Zannikos P., et al. Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2008;63:181–188. doi: 10.1007/s00280-008-0733-7.
    1. Kasper B. Therapie des fortgeschrittenen Weichgewebesarkoms: Neue Perspektiven mit Trabectedin (Yondelis®) J. Med. Drug Rev. 2013;3:35–43.
    1. Sessa C., del Conte G., Christinat A., Cresta S., Perotti A., Gallerani E., Lardelli P., Kahatt C., Alfaro V., Iglesias J.L., et al. Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors. Invest. New Drugs. 2013;31:1236–1243. doi: 10.1007/s10637-013-9942-y.
    1. Blay J.Y., van Mehren M., Samuels B.L., Fanucchi M.P., Ray-Coquard I., Buckley B., Gilles L., Lebedinsky C., Elsayed Y.A., le Cesne A. Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma. Clin. Cancer Res. 2008;14:6656–6662. doi: 10.1158/1078-0432.CCR-08-0336.
    1. Pautier P., Chevreau C., le Cesne A., Penel N., Bui B., Guillemet C., Delcambre C., Rey A., Duffaud F. LMS-02: A phase II single-arm multicenter study to determine the efficacy of doxorubicin in combination with trabectedin as a 1st line treatment of metastatic and/or locally advanced leiomyosarcoma of uterine (U-LMS) or soft tissue (ST-LMS) origin: Results of the soft tissue group. Eur. J. Cancer. 2013;49:s3834.
    1. Broto J.M., Lopez-Pousa A., Garcia del Muro X., de Las Peñas R., Martinez-Trufero J., Cruz J., Alvarez R., Cubedo R., Redondo A., Poveda A. Randomized phase II trial of doxorubicin vs. trabectedin plus doxorubicin in first line treatment of patients with advanced non-resectable or metastatic soft tissue sarcomas: A Spanish Group for Sarcoma Research (GEIS) study. Eur. J. Cancer. 2013;49:s3800.
    1. Aapro M.S., Martin C., Hatty S. Gemcitabine—A safety review. Anticancer Drugs. 1998;9:191–201. doi: 10.1097/00001813-199803000-00001.

Source: PubMed

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