title: Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
abstract: BACKGROUND
  Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma.
  
  
  METHODS
  In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov, number NCT01649024.
  
  
  RESULTS
  Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3-11·1) and a median overall survival of 10·7 months (0·0-21·9). 27 patients (93%) had at least one grade 1-2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3-4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic).
  
  
  CONCLUSIONS
  Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma.
  
  
  BACKGROUND
  Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Calabrò
authors.affiliation: Department of Radiology, Euganea Medica Diagnostic Center, Padua, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Morra
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Fonsatti
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cutaia
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Amato
authors.affiliation: Statistics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giacomo
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Danielli
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Maresa
authors.initials: M
authors.lastname: Altomonte
authors.affiliation: Department of Medicine, Laboratory of Clinical Oncology, Hospital of Vercelli, Vercelli, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. Electronic address: mmaio@cro.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C520704:tremelimumab