title: Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer.
abstract: OBJECTIVE
  Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with selective binding to activatory Fcgamma type I/III receptors, resulting in the formation of a tri-cell complex between tumor cells, T cells, and accessory cells. Patients with metastatic breast cancer were enrolled into a multicenter phase I dose-escalating trial.
  
  
  METHODS
  Three ascending doses of ertumaxomab (10-200 microg) were administered i.v. on day 1, 7 +/- 1, and 13 +/- 1. Safety and tolerability were the primary objectives. Secondary objectives were antitumor activity and different immunologic variables.
  
  
  RESULTS
  Fifteen out of 17 enrolled patients completed the study. One hundred micrograms was identified as the maximal tolerable single dose. Most drug-related adverse events were mild and transient including fever (94%), rigors (47%), headache (35%), nausea (29%), vomiting (29%). Grades 3 and 4 (Common Toxicity Criteria) were lymphocytopenia (76%) and elevation of liver enzymes (47%). One patient (200 mug dose) developed severe hypotension and respiratory distress syndrome, another patient (150 mug dose) developed a systemic inflammatory response syndrome and acute renal failure. Aggravation of congestive heart failure was seen in one patient with preexisting ventricular dysfunction after administration of the third dose (200 microg). All adverse events were fully reversible. Antitumor response was seen in 5 out of 15 evaluable patients (one with a complete response, two with partial responses, two with stable disease) at dose levels of > or = 100 microg. Measurements of cytokines (interleukin-6, interleukin-2, tumor necrosis factor-alpha, and IFN-gamma) suggest a strong T helper cell type 1-associated immune response. The induction of human anti-mouse/anti-rat antibodies was detected in 5 out of 16 (31%) patients.
  
  
  CONCLUSIONS
  Treatment with triple infusions of ertumaxomab yields a strong immunologic response. Doses up to 100 microg can be safely infused with close monitoring of patients. The observed clinical responses are encouraging and indicate antitumor efficacy.
authors.affiliation: Department of Haematology, Oncology, and Transfusion Medicine, Charité Campus Benjamin Franklin, Berlin, Germany. philipp.kiewe@charite.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Kiewe
authors.forename: Stephan
authors.initials: S
authors.lastname: Hasmüller
authors.forename: Steffen
authors.initials: S
authors.lastname: Kahlert
authors.forename: Maja
authors.initials: M
authors.lastname: Heinrigs
authors.forename: Brigitte
authors.initials: B
authors.lastname: Rack
authors.forename: Alexander
authors.initials: A
authors.lastname: Marmé
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Korfel
authors.forename: Michael
authors.initials: M
authors.lastname: Jäger
authors.forename: Horst
authors.initials: H
authors.lastname: Lindhofer
authors.forename: Harald
authors.initials: H
authors.lastname: Sommer
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017252:CD3 Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; C511895:ertumaxomab