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

  • Juan Martin-Liberal
  • Antonio López-Pousa
  • Javier Martínez-Trufero
  • Javier Martín-Broto
  • Ricardo Cubedo
  • Javier Lavernia
  • Andrés Redondo
  • José Antonio López-Martín
  • Nùria Mulet-Margalef
  • Xavier Sanjuan
  • Òscar M. Tirado
  • Xavier Garcia-del-Muro
Original Research Article

Abstract

Background

Gemcitabine plus sirolimus enhances apoptosis in vitro and increases anti-tumor efficacy in vivo in soft-tissue sarcoma (STS) models.

Objective

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.

Results

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).

Conclusions

The combination of gemcitabine and sirolimus is an active treatment in STS. Further investigation is warranted. ClinicalTrials.gov identifier: NCT01684449.

Notes

Compliance with Ethical Standards

Funding

This work was supported by Grant TRA-163 from the Spanish Ministry of Health.

Conflict of Interest

The authors declare no conflict of interest.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Juan Martin-Liberal
    • 1
    • 2
  • Antonio López-Pousa
    • 3
  • Javier Martínez-Trufero
    • 4
  • Javier Martín-Broto
    • 5
  • Ricardo Cubedo
    • 6
  • Javier Lavernia
    • 7
  • Andrés Redondo
    • 8
  • José Antonio López-Martín
    • 9
  • Nùria Mulet-Margalef
    • 1
    • 2
  • Xavier Sanjuan
    • 10
  • Òscar M. Tirado
    • 11
  • Xavier Garcia-del-Muro
    • 2
    • 11
    • 12
  1. 1.Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO)Vall d’Hebron University HospitalBarcelonaSpain
  2. 2.Sarcoma, Melanoma and Genitourinary Tumors UnitInstitut Català d’Oncologia L’HospitaletBarcelonaSpain
  3. 3.Cancer Medicine DepartmentHospital de la Santa Creu i Sant PauBarcelonaSpain
  4. 4.Medical Oncology DepartmentHospital Universitario Miguel ServetZaragozaSpain
  5. 5.Instituto de Biomedicina de Sevilla (IBiS)Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSevillaSpain
  6. 6.Medical Oncology DepartmentHospital Puerta de HierroMadridSpain
  7. 7.Medical Oncology DepartmentInstituto Valenciano de OncologíaValenciaSpain
  8. 8.Medical Oncology DepartmentHospital Universitario La PazMadridSpain
  9. 9.Medical Oncology DepartmentHospital 12 de OctubreMadridSpain
  10. 10.Pathology DepartmentBellvitge University HospitalBarcelonaSpain
  11. 11.Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), CIBERONCUniversitat de BarcelonaBarcelonaSpain
  12. 12.Universitat de BarcelonaBarcelonaSpain

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