title: Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin's lymphoma.
abstract: OBJECTIVE
  PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab.
  
  
  METHODS
  Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks.
  
  
  RESULTS
  Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease.
  
  
  CONCLUSIONS
  Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.
authors.affiliation: Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Brian K
authors.initials: BK
authors.lastname: Link
authors.forename: Christos
authors.initials: C
authors.lastname: Emmanouilides
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Gregory
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Andrey
authors.forename: John
authors.initials: J
authors.lastname: Hainsworth
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: Donald E
authors.initials: DE
authors.lastname: Tsai
authors.forename: Sandra
authors.initials: S
authors.lastname: Horning
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
authors.forename: George J
authors.initials: GJ
authors.lastname: Weiner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015331:Cohort Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D012008:Recurrence; D000069283:Rituximab; D051193:Toll-Like Receptors / Q000819:agonists*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D051193:Toll-Like Receptors; D000069283:Rituximab