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

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.

• Authors: J Martin-Liberal, M Gil-Martín, M Sáinz-Jaspeado, N Gonzalo, R Rigo, H Colom, C Muñoz, O M Tirado, X García del Muro
• Journal: British journal of cancer (Br J Cancer) Vol. 111 Issue 5 Pg. 858-65 (Aug 26 2014) ISSN: 1532-1827 [Electronic] England
• PMID: 25003665 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Deoxycytidine
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Sirolimus
• Gemcitabine

Topics

• Adult
• Aged
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Female
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Sirolimus (administration & dosage)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Gemcitabine