Phase II Study of Gemcitabine Plus Sirolimus in Previously Treated Patients with Advanced Soft-Tissue Sarcoma: a Spanish Group for Research on Sarcomas (GEIS) Study
- 146 Downloads
Gemcitabine plus sirolimus enhances apoptosis in vitro and increases anti-tumor efficacy in vivo in soft-tissue sarcoma (STS) models.
The objective of this study was to evaluate the activity and toxicity of the combination of gemcitabine plus sirolimus in patients with STS after failure of standard chemotherapy.
Patients and Methods
Advanced STS patients, previously treated with doxorubicin and/or ifosfamide, were included in this single-arm phase II study. Patients received gemcitabine 800 mg/m2 intravenously (iv) at 10 mg/m2/min on days 1 and 8 every 3 weeks plus sirolimus 5 mg daily orally (po). After enrolment of the first 12 patients, the study protocol was amended due to toxicity and the starting dose of sirolimus was reduced to 3 mg daily po. Archival tumor samples were analyzed for extracellular signal-regulated kinase 1 and 2 (ERK1/2) expression and correlated with outcome. The primary endpoint was progression-free rate (PFR) at 3 months.
From May 2012 to May 2013, 28 patients were enrolled at eight centers. PFR at 3 and 6 months was 44% and 20%, respectively, with 12 patients being free of progression at 3 months. Median progression-free survival (PFS) was 1.85 months (95% confidence interval [CI] 0.73–2.97) and median overall survival (OS) was 9.2 months (95% CI 5.8–12.5). No responses were observed. The most common grade 3–4 hematologic toxicities were neutropenia (48%) and leukopenia (41%) and the most frequent grade 3 non-hematologic toxicities were infection (18.5%), transaminitis (15%), fatigue (11%), and pneumonitis (11%). ERK1/2 expression was significantly correlated with PFS (p = 0.026).
Compliance with Ethical Standards
This work was supported by Grant TRA-163 from the Spanish Ministry of Health.
Conflict of Interest
The authors declare no conflict of interest.
- 1.Van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, et al. 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(1):150–7.CrossRefPubMedGoogle Scholar
- 2.van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, et al. 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(18):2397–406.CrossRefPubMedGoogle Scholar
- 3.Leahy M, Garcia Del Muro X, Reichardt P, Judson I, Staddon A, Verweij J, et al. 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(10):2763–70.CrossRefPubMedGoogle Scholar
- 10.Pautier P, Floquet A, Penel N, Piperno-Neumann S, Isambert N, Rey A, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a federation Nationale des Centres de Lutte Contre le cancer (FNCLCC) French sarcoma group study (TAXOGEM study). Oncologist. 2012;17(9):1213–20.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, et al. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on sarcomas study. J Clin Oncol. 2011;29(18):2528–33.CrossRefPubMedGoogle Scholar
- 13.Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, 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 [corrected]. J Clin Oncol. 2007;25(19):2755–63.CrossRefPubMedGoogle Scholar
- 16.Demetri GD, Chawla SP, Ray-Coquard I, Le Cesne A, Staddon AP, Milhem MM, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol. 2013;31(19):2485–92.CrossRefPubMedGoogle Scholar
- 22.Martin-Broto J, Redondo A, Valverde C, et al. Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS). Ann Oncol. Epub 2017 Sep 25. https://doi.org/10.1093/annonc/mdx536.