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Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Martin-Liberal J, Gil-Martín M, Sáinz-Jaspeado M, Gonzalo N, Rigo R, Colom H, Muñoz C, Tirado OM, García del Muro X - Br. J. Cancer (2014)

Bottom Line: Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis.Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed.A phase II study is currently ongoing.

View Article: PubMed Central - PubMed

Affiliation: The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

ABSTRACT

Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.

Methods: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.

Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.

Conclusions: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.

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Immunohistochemistry of pS6 in leiomyosarcoma xenograft samples. Sirolimus is able to reverse the hyperactivation of the mTOR pathway caused by gemcitabine in leiomyosarcoma xenografts. GEM=gemcitabine; SIR=sirolimus.
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fig4: Immunohistochemistry of pS6 in leiomyosarcoma xenograft samples. Sirolimus is able to reverse the hyperactivation of the mTOR pathway caused by gemcitabine in leiomyosarcoma xenografts. GEM=gemcitabine; SIR=sirolimus.

Mentions: Strong pS6 staining in tumours treated with gemcitabine alone was observed. In contrast, that staining was dramatically absent in tumours treated with the combination, indicating that the addition of sirolimus is able to reverse pS6 induction also in vivo (Figure 4).


Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Martin-Liberal J, Gil-Martín M, Sáinz-Jaspeado M, Gonzalo N, Rigo R, Colom H, Muñoz C, Tirado OM, García del Muro X - Br. J. Cancer (2014)

Immunohistochemistry of pS6 in leiomyosarcoma xenograft samples. Sirolimus is able to reverse the hyperactivation of the mTOR pathway caused by gemcitabine in leiomyosarcoma xenografts. GEM=gemcitabine; SIR=sirolimus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150275&req=5

fig4: Immunohistochemistry of pS6 in leiomyosarcoma xenograft samples. Sirolimus is able to reverse the hyperactivation of the mTOR pathway caused by gemcitabine in leiomyosarcoma xenografts. GEM=gemcitabine; SIR=sirolimus.
Mentions: Strong pS6 staining in tumours treated with gemcitabine alone was observed. In contrast, that staining was dramatically absent in tumours treated with the combination, indicating that the addition of sirolimus is able to reverse pS6 induction also in vivo (Figure 4).

Bottom Line: Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis.Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed.A phase II study is currently ongoing.

View Article: PubMed Central - PubMed

Affiliation: The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

ABSTRACT

Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.

Methods: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.

Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.

Conclusions: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.

Show MeSH
Related in: MedlinePlus