title: Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma.
abstract: OBJECTIVE
  We determine the maximum-tolerated dose (MTD), pharmacokinetics, safety, and preliminary efficacy of SAR3419, an antibody-drug conjugate targeting CD19, in a first-in-man phase I clinical trial in patients with relapsed lymphoma.
  
  
  METHODS
  Patients with relapsed CD19+ B-cell lymphoma were treated with escalating doses of SAR3419 given by intravenous infusion once every 21 days.
  
  
  RESULTS
  Thirty-nine patients were treated on seven dose levels ranging from 10 to 270 mg/m(2). The median number of prior treatment regimens was four (range, 1 to 9), and 11 patients had prior autologous or allogeneic stem-cell transplantation. The dose-limiting toxicities were reversible severe blurred vision associated with microcystic epithelial corneal changes reported in six patients and neuropathy in one patient. The MTD was 160 mg/m(2) once every 21 days. Hematologic and hepatic toxicities were predominantly grade 1 or 2 in severity. A total of 35 patients have completed at least two cycles of treatment and were evaluable for tumor response. Twenty-six patients (74%) demonstrated reduction in their tumor size; six of those patients achieved partial or complete remissions. Seven (47%) of 15 patients with rituximab-refractory disease demonstrated reduction in their tumor sizes. The pharmacokinetic profile of SAR3419 is characterized by linear kinetics, low clearance from 0.2 to 0.6 L/d/m(2), and an elimination half-life in the range of 3 to 7 days.
  
  
  CONCLUSIONS
  Using an every 3-week-schedule of SAR3419 for six cycles, the MTD is 160 mg/m(2). SAR3419 can be safely administered to patients with relapsed B-cell lymphoma and demonstrates promising clinical activity, including patients who were refractory to rituximab.
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ayounes@mdanderson.org
authors: Anas
authors: A
authors: Younes
authors: Stella
authors: S
authors: Kim
authors: Jorge
authors: J
authors: Romaguera
authors: Amanda
authors: A
authors: Copeland
authors: Silvana de Castro
authors: Sde C
authors: Farial
authors: Larry W
authors: LW
authors: Kwak
authors: Luis
authors: L
authors: Fayad
authors: Frederick
authors: F
authors: Hagemeister
authors: Michelle
authors: M
authors: Fanale
authors: Sattva
authors: S
authors: Neelapu
authors: John M
authors: JM
authors: Lambert
authors: Rodica
authors: R
authors: Morariu-Zamfir
authors: Sandrine
authors: S
authors: Payrard
authors: Leo I
authors: LI
authors: Gordon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008875:Middle Aged; D012008:Recurrence
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000922:Immunotoxins; D008453:Maytansine; C569646:coltuximab ravtansine