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Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas

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Abstract

Purpose: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. Methods: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2′,2′-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. Results: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1–18). Grade 3–4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or γ-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0–24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. Conclusions: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.

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Acknowledgments

Supported in part by a grant from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (Project 01/0319) and by a grant from Eli Lilly and Company, Spain. Supported by the Instituto Universitario de Oncología del Principado de Asturias (IUOPA)-Obra Social Cajastur. This study was conducted within the Programa 9 of the RTICCC from Instituto de Salud Carlos III (03/01), Spain.

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Authors and Affiliations

  1. Servicio de Oncología, Hospital Central de Asturias, 33006, Oviedo, Spain

    R. Losa, J. Fra, M. Sierra, A. Goitia, E. Uña, M. Gión, E. Esteban & José M. Buesa

  2. Hospital de Sant Pau, Barcelona, Spain

    A. López-Pousa & R. Nadal

  3. Instituto Catalán de Oncología, Hospitalet, Barcelona, Spain

    J. García del Muro

  4. Hospital Clínic, Barcelona, Spain

    J. Maurel

  5. Hospital Universitario Lozano Blesa, Zaragoza, Spain

    P. Escudero

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  1. R. Losa
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Correspondence to José M. Buesa.

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J. Fra and R. Losa contributed equally to this work.

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Losa, R., Fra, J., López-Pousa, A. et al. Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas. Cancer Chemother Pharmacol 59, 251–259 (2007). https://doi.org/10.1007/s00280-006-0263-0

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