title: Clinical outcomes and prognostic factors of patients with advanced mesothelioma treated in a phase I clinical trials unit.
abstract: We have previously reported a prognostic score for patients in phase I trials in the Drug Development Unit, treated at the Royal Marsden Hospital (RPS). The RPS is an objective tool used in patient selection for phase I trials based on albumin, number of disease sites and LDH. Patients with mesothelioma are often selected for phase I trials as the disease remains localised for long periods of time. We have now reviewed the clinical outcomes of patients with relapsed malignant mesothelioma (MM) and propose a specific mesothelioma prognostic score (m-RPS) that can help identify patients who are most likely to benefit from early referral.
  
  
  
  Patients who participated in 38 phase I trials between September 2003 and November 2015 were included in the analysis. Efficacy was assessed by response rate, median overall survival (OS) and progression-free survival (PFS). Univariate (UVA) and multivariate analyses (MVA) were carried out to develop the m-RPS.
  
  
  
  A total of 65 patients with advanced MM were included in this retrospective study. The PFS was 2.5 months (95% confidence interval [CI] 2.0-3.1 months) and OS was 8 months (95% CI 5.6-9.8 months). A total of four (6%) patients had RECIST partial responses, whereas 26 (40%) patients had RECIST stable disease >3 months. The m-RPS was developed comprising of three different prognostic factors: a neutrophil: lymphocyte ratio greater than 3, the presence of more than two disease sites (including lymph nodes as a single site of disease) and albumin levels less than 35 from the MVA. Patients each received a score of 1 for the presence of each factor. Patients in group A (m-RPS 0-1; n = 35) had a median OS of 13.4 months (95% CI 8.5-21.6), whereas those in group B (m-RPS 2-3; n = 30) had a median OS of 4.0 months (95% CI 2.9-7.1, P < 0.0001). A total of 56 (86%) patients experienced G1-2 toxicities, whereas reversible G3-4 toxicities were observed in 18 (28%) patients. Only 10 (15%) patients discontinued phase I trials due to toxicity.
  
  
  
  Phase I clinical trial therapies were well tolerated with early signals of antitumour activity in advanced MM patients. The m-RPS is a useful tool to assess MM patient suitability for phase I trials and should now be prospectively validated.
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Dionysis
authors.initials: D
authors.lastname: Papadatos-Pastos
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Desam
authors.initials: D
authors.lastname: Roda
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: De Miguel Luken
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ann
authors.initials: A
authors.lastname: Petruckevitch
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Awais
authors.initials: A
authors.lastname: Jalil
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Capelan
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Michalarea
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Joao
authors.initials: J
authors.lastname: Lima
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Diamantis
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Jaishree
authors.initials: J
authors.lastname: Bhosle
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Mary E R
authors.initials: MER
authors.lastname: O'Brien
authors.affiliation: Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, United Kingdom. Electronic address: timothy.yap@icr.ac.uk.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: Drug development; Mesothelioma; PI3K; Phase 1; Targeted therapies