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Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with
J Martin-Liberal1, M Gil-Martín2, M Sáinz-Jaspeado3
1The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
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.
Insights
The recommended dose for sirolimus and gemcitabine combination therapy in advanced solid tumors is 5mg daily and 800mg/m² respectively. This combination demonstrated significant preclinical antitumor activity and mTOR pathway inhibition.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Phase I study of advanced solid tumors.
- Investigating the combination of sirolimus and gemcitabine.
- Assessing recommended dose, pharmacokinetics (PK), pharmacodynamics, and preclinical efficacy.
Purpose of the Study:
- Determine the recommended dose of sirolimus and gemcitabine.
- Evaluate PK and pharmacodynamic activity.
- Assess preclinical antitumour efficacy.
Main Methods:
- 19 patients with advanced solid tumors treated with varying doses of sirolimus and gemcitabine.
- Dose escalation based on dose-limiting toxicity (DLT).
- Pharmacodynamic assessment of mTOR inhibition via pS6 in skin biopsies; PK analysis; in vitro and in vivo preclinical efficacy studies.
Main Results:
- Recommended dose: sirolimus 5 mg/24h plus gemcitabine 800 mg/m².
- Observed DLTs included transaminitis and thrombocytopenia.
- Demonstrated mTOR inhibition, no PK interaction between drugs, and significant inhibition of tumor growth in preclinical sarcoma models.
Conclusions:
- Sirolimus 5 mg plus gemcitabine 800 mg/m² is the recommended dose.
- Combination therapy shows preclinical antitumour activity and mTOR signaling inhibition.
- A Phase II study is currently underway.
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