title: Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4.
  
  
  METHODS
  Patients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti-SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study).
  
  
  RESULTS
  Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 microg/kg (NSCLC and PC) and 15 microg/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 microg/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56.
  
  
  CONCLUSIONS
  ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.
authors.affiliation: DO, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA. hossein.borghaei@fccc.edu
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
authors.forename: Katherine
authors.initials: K
authors.lastname: Alpaugh
authors.forename: Gunnar
authors.initials: G
authors.lastname: Hedlund
authors.forename: Göran
authors.initials: G
authors.lastname: Forsberg
authors.forename: Corey
authors.initials: C
authors.lastname: Langer
authors.forename: Andre
authors.initials: A
authors.lastname: Rogatko
authors.forename: Robert
authors.initials: R
authors.lastname: Hawkins
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lassen
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000097:blood; D000077143:Docetaxel; D004768:Enterotoxins / Q000008:administration & dosage; D005060:Europe; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D004768:Enterotoxins; D018796:Immunoconjugates; D011993:Recombinant Fusion Proteins; D043823:Taxoids; D000077143:Docetaxel; C543500:naptumomab estafenatox