title: Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125.
abstract: BACKGROUND
  The primary objective of this study was to determine the safety and maximum tolerated dose (MTD) of the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) (a recombinant antimesothelin immunotoxin consisting of a murine antimesothelin variable antibody fragment [Fv] linked to PE38, a truncated portion of Pseudomonas exotoxin A) in combination with pemetrexed and cisplatin in chemotherapy-naive patients with advanced malignant pleural mesothelioma (MPM). Secondary objectives included tumor response, SS1P pharmacokinetics, and serum biomarkers of response.
  
  
  METHODS
  Chemotherapy-naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m(2) on day 1) and cisplatin (75 mg/m(2) on day 1) were administered every 3 weeks for up to 6 cycles with escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2. Tumor response was evaluated every 6 weeks.
  
  
  RESULTS
  Twenty-four patients received SS1P at 4 dose levels from 25 to 55 mcg/kg. Grade 3 fatigue was dose-limiting in 1 patient at 55 mcg/kg. The MTD of SS1P was established as 45 mcg/kg. Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%). Of 20 evaluable patients, 12 (60%) had a partial response, 3 had stable disease, and 5 had progressive disease. Of 13 patients who received the MTD, 10 (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin (P=.0030), megakaryocyte potentiating factor (P=.0005), and cancer antigen 125 (P < .0001).
  
  
  CONCLUSIONS
  SS1P given with pemetrexed and cisplatin is safe and well tolerated and exhibits significant antitumor activity in patients with unresectable, advanced pleural mesothelioma. Serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125 levels correlated with objective tumor responses.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.forename: Elad
authors.initials: E
authors.lastname: Sharon
authors.forename: Anish
authors.initials: A
authors.lastname: Thomas
authors.forename: Jingli
authors.initials: J
authors.lastname: Zhang
authors.forename: Alexander
authors.initials: A
authors.lastname: Ling
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Kevin
authors.initials: K
authors.lastname: Hollevoet
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D036002:ADP Ribose Transferases; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001427:Bacterial Toxins; D018394:CA-125 Antigen / Q000097:blood; D002945:Cisplatin / Q000008:administration & dosage; D005098:Exotoxins; D005260:Female; D058851:GPI-Linked Proteins / Q000008:administration & dosage / Q000097:blood; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D000090204:Mesothelin; D008654:Mesothelioma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D018394:CA-125 Antigen; D002945:Cisplatin; D005098:Exotoxins; D058851:GPI-Linked Proteins; D005971:Glutamates; D006147:Guanine; D000090204:Mesothelin; D000068437:Pemetrexed; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C000715527:MSLN protein, human; C474515:SS1(dsFv)PE38
keywords: SS1P; immunotoxin; mesothelin; pleural mesothelioma