title: Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma.
abstract: OBJECTIVE
  Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM.
  
  
  METHODS
  In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety.
  
  
  RESULTS
  Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1-6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1-62.3)], median PFS was 6.1 months (95% CI, 5.8-6.4), and median OS was 14.8 months (95% CI, 12.4-18.5) with 29 patients alive at data cut-off.
  
  
  CONCLUSIONS
  Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis.
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. hassanr@mail.nih.gov.
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.affiliation: University of Chicago, Chicago, Illinois.
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.affiliation: University of California, San Francisco, California.
authors.forename: Thierry
authors.initials: T
authors.lastname: Jahan
authors.affiliation: University of California, San Diego, California.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Bazhenova
authors.affiliation: Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Grosshansdorf, Stormarn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Anish
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: United BioSource Corp., Blue Bell, Pennsylvania.
authors.forename: Jeff
authors.initials: J
authors.lastname: Parno
authors.affiliation: Morphotek, Inc., Exton, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Shannessy
authors.affiliation: Morphotek, Inc., Exton, Pennsylvania.
authors.forename: Penny
authors.initials: P
authors.lastname: Fatato
authors.affiliation: Morphotek, Inc., Exton, Pennsylvania.
authors.forename: Julia D
authors.initials: JD
authors.lastname: Maltzman
authors.affiliation: Morphotek, Inc., Exton, Pennsylvania.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Wallin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D000090204:Mesothelin; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D058851:GPI-Linked Proteins; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; C526187:amatuximab; D000090204:Mesothelin; D002945:Cisplatin