title: Phase I clinical study of atacicept in patients with relapsed and refractory B-cell non-Hodgkin's lymphoma.
abstract: OBJECTIVE
  B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies.
  
  
  METHODS
  A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done. Atacicept was given s.c. weekly for 5 weeks to sequential patient cohorts at doses of 2, 4, 7, or 10 mg/kg. Patients responding or with stable disease were eligible for treatment on an extension study for up to 24 weeks or until disease progression.
  
  
  RESULTS
  All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received a stem cell transplant. Four patients were treated at the 2, 4, or 7 mg/kg dose levels, and three patients received 10 mg/kg of atacicept. Atacicept was well tolerated at all doses. Three adverse events with grade 3 severity were reported for one patient, including jaw pain, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Pharmacokinetic results were nonlinear, and treatment with atacicept resulted in dose-dependent decreases in immunoglobulin concentrations. Two patients had stable disease at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns.
  
  
  CONCLUSIONS
  Atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin concentrations, although tumor responses were not observed.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota 55905, USA. ansell.stephen@mayo.edu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: David J
authors.initials: DJ
authors.lastname: Inwards
authors.forename: Luis F
authors.initials: LF
authors.lastname: Porrata
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ythier
authors.forename: Lee
authors.initials: L
authors.lastname: Ferrande
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.forename: Todd
authors.initials: T
authors.lastname: Devries
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.forename: Diana
authors.initials: D
authors.lastname: Hausman
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000097:blood / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D007136:Immunoglobulins; D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein