ArticleBritish journal of cancer2014
Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.
Article in British journal of cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed.
- Phase II Study of Gemcitabine Plus Sirolimus in Previously Treated Patients with Advanced Soft-Tissue Sarcoma: a Spanish Group for Research on Sarcomas (GEIS) Study.Targeted oncology · 2018Trial
- Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs.American journal of veterinary research · 2016Trial
- Case report: Responses to the combination of gemcitabine with sirolimus in two patients withFrontiers in oncology · 2023Article
- Targeting the VEGF Pathway in Osteosarcoma.Cells · 2021Review
- Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis.Cancers · 2020Article
- In vitro drug sensitivity (IDS) of patient-derived primary osteosarcoma cells as an early predictor of the clinical outcomes of osteosarcoma patients.Cancer chemotherapy and pharmacology · 2020Article
- Taming the Flames: Targeting White Adipose Tissue Browning in Hypermetabolic Conditions.Endocrine reviews · 2017Review
- Pilot study of sirolimus in patients with PIK3CA mutant/amplified refractory solid cancer.Molecular and clinical oncology · 2017Article
- Article
- Potential impact of mTOR inhibitors on cervical squamous cell carcinoma: A systematic review.Oncology letters · 2016Article
- Targeting protein kinases to reverse multidrug resistance in sarcoma.Cancer treatment reviews · 2016Review
- Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy.Paediatric drugs · 2015Review
- Potential Therapeutic Targets in Uterine Sarcomas.Sarcoma · 2015Review
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Authors and funding
9 authors.
Funding
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Abstract
backgroundWe 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.
methodsNineteen 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.
resultsThree 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.
conclusionsRecommended 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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