title: Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study.
abstract: Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day(-1) escalated to 10 mg·day(-1)) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (-111-132) and 114 mL (11-217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL(-1) to 934.5 pg·mL(-1), and 103 ng·mL(-1) to 80.5 ng·mL(-1), respectively. Adverse events were mostly grade 1-2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe.
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA These authors share first authorship.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Goldberg
authors.affiliation: Dept of Medical Sciences, U. O. di Pneumologia, Ospedale San Giuseppe MultiMedica, Milano, Italy These authors share first authorship.
authors.forename: Sergio
authors.initials: S
authors.lastname: Harari
authors.affiliation: National Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France vincent.cottin@chu-lyon.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cottin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Dept of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Peters
authors.affiliation: Dept of Oncology, Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors.forename: Shibadas
authors.initials: S
authors.lastname: Biswal
authors.affiliation: Dept of Oncology, Beijing Novartis Pharma Co. Ltd., Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Dept of Oncology, Novartis Horsham Research Centre, Horsham, UK.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Khindri
authors.affiliation: Dept of Oncology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.affiliation: Dept of Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Ma
authors.affiliation: Division of Pulmonary and Critical Care, University of Cincinnati, Cincinnati, OH, USA These authors share last authorship.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.affiliation: Dept of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA These authors share last authorship.
authors.forename: Elizabeth Petri
authors.initials: EP
authors.lastname: Henske
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy* / Q000473:pathology; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018570:Risk Assessment; D016896:Treatment Outcome; D042643:Vascular Endothelial Growth Factor D / Q000097:blood / Q000187:drug effects*; D014797:Vital Capacity / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D042643:Vascular Endothelial Growth Factor D; D000068338:Everolimus