title: A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.
abstract: BACKGROUND
  Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM).
  
  
  METHODS
  Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry.
  
  
  RESULTS
  Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation.
  
  
  CONCLUSIONS
  CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival.
  ACTRN12609000294257.
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth anna.nowak@uwa.edu.au.
authors.forename: A K
authors.initials: AK
authors.lastname: Nowak
authors.affiliation: School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth.
authors.forename: A M
authors.initials: AM
authors.lastname: Cook
authors.affiliation: School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth.
authors.forename: A M
authors.initials: AM
authors.lastname: McDonnell
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth School of Medicine and Pharmacology.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millward
authors.affiliation: School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth.
authors.forename: J
authors.initials: J
authors.lastname: Creaney
authors.affiliation: School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth Department of Nuclear Medicine.
authors.forename: R J
authors.initials: RJ
authors.lastname: Francis
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth.
authors.forename: A
authors.initials: A
authors.lastname: Hasani
authors.affiliation: PathWest and.
authors.forename: A
authors.initials: A
authors.lastname: Segal
authors.affiliation: School of Medicine and Pharmacology Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth School of Population Health.
authors.forename: A W
authors.initials: AW
authors.lastname: Musk
authors.affiliation: Centre for Applied Statistics, University of Western Australia, Perth.
authors.forename: B A
authors.initials: BA
authors.lastname: Turlach
authors.affiliation: School of Medicine and Pharmacology St John of God Hospital, Perth, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: McCoy
authors.affiliation: School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth.
authors.forename: B W S
authors.initials: BW
authors.lastname: Robinson
authors.affiliation: School of Medicine and Pharmacology National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth.
authors.forename: R A
authors.initials: RA
authors.lastname: Lake
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000819:agonists / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage*; D010997:Pleural Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; D000068437:Pemetrexed; C518149:selicrelumab; D002945:Cisplatin
keywords: CD40; clinical trial; immunotherapy; malignant mesothelioma; phase I