title: A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors.
abstract: BACKGROUND
  Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.
  
  
  METHODS
  A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies.
  
  
  RESULTS
  Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity.
  
  
  CONCLUSIONS
  Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier NCT00435916.
authors.affiliation: David Geffen School of Medicine at UCLA, University of California Los Angeles, 650 Charles E, Young Drive 11-934 Factor Bldg, Los Angeles, CA 90095-1678, USA. deVos@mednet.ucla.edu.
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Brad
authors.initials: B
authors.lastname: Kahl
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cheson
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.forename: Henry
authors.initials: H
authors.lastname: Kaplan
authors.forename: John
authors.initials: J
authors.lastname: Timmerman
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Whiting
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Drachman
authors.forename: Ranjana
authors.initials: R
authors.lastname: Advani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023341:Chills / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; C543331:dacetuzumab