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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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Related in: MedlinePlus

(A) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 1. (B) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 21.
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fig1: (A) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 1. (B) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 21.

Mentions: The plasma concentration vs time profiles of gemcitabine at days 1 and 21 are displayed in Figure 1. It should be noted that quantifiable gemcitabine concentrations were found up to 2.5–4 h post administration in both occasions. The PK of gemcitabine after intravenous infusion of 10 mg m−2 min−1 in the target population was best described by a two-open-compartment model with first-order elimination. All recorded covariates were tested in the PK parameters, plasma clearance (CL) and central compartment distribution volume (Vc), with NONMEM, but no statistically significant relationship could be identified in any case. No statistically significant effect of anthropometric covariates (WGT, HGT and BSA) and age on the PK parameters was found (P>0.05) and no specific trends were observed between CL or Vc values and sirolimus concentrations (Supplementary Figure 1). The estimated PK parameters with final model (NONMEN) listed in Supplementary Table 1 were in agreement with those previously reported in the literature (Keith et al, 2003; Lin et al, 2004). Between-patient variability could be associated to CL (14.6%) and Vc (98.2%), meanwhile between-occasion variability could be to Vc (47.1%).


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)

(A) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 1. (B) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 21.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: (A) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 1. (B) Observed gemcitabine plasma concentrations (μg l−1) vs time (h) after intravenous infusion of 10 mg m−2 min−1 on day 21.
Mentions: The plasma concentration vs time profiles of gemcitabine at days 1 and 21 are displayed in Figure 1. It should be noted that quantifiable gemcitabine concentrations were found up to 2.5–4 h post administration in both occasions. The PK of gemcitabine after intravenous infusion of 10 mg m−2 min−1 in the target population was best described by a two-open-compartment model with first-order elimination. All recorded covariates were tested in the PK parameters, plasma clearance (CL) and central compartment distribution volume (Vc), with NONMEM, but no statistically significant relationship could be identified in any case. No statistically significant effect of anthropometric covariates (WGT, HGT and BSA) and age on the PK parameters was found (P>0.05) and no specific trends were observed between CL or Vc values and sirolimus concentrations (Supplementary Figure 1). The estimated PK parameters with final model (NONMEN) listed in Supplementary Table 1 were in agreement with those previously reported in the literature (Keith et al, 2003; Lin et al, 2004). Between-patient variability could be associated to CL (14.6%) and Vc (98.2%), meanwhile between-occasion variability could be to Vc (47.1%).

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