title: A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.
abstract: OBJECTIVE
  To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody-drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).
  
  
  METHODS
  Patients with R/R CD19(+) B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an "optimized" administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.
  
  
  RESULTS
  Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m(2). SAR3419 recommended dose was determined as 55 mg/m(2) qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m(2), which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.
  
  
  CONCLUSIONS
  While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies.
authors.affiliation: Authors' Affiliations: Institut Gustave Roussy, Villejuif; Centre Hospitalier Universitaire Henri Mondor-Chenevier, Creteil; Centre Henri Becquerel, Rouen; Centre Hospitalier Universitaire de Lille, Lille; Centre Hospitalier Universitaire Pontchaillou, Rennes; Sanofi, Paris; Hospices Civils de Lyon and Université Lyon-1, Lyon, France; and ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.forename: Jehan
authors.initials: J
authors.lastname: Dupuis
authors.forename: Herve
authors.initials: H
authors.lastname: Tilly
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.forename: Fabrice
authors.initials: F
authors.lastname: Laine
authors.forename: Roch
authors.initials: R
authors.lastname: Houot
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.forename: Christiane
authors.initials: C
authors.lastname: Copie
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: John
authors.initials: J
authors.lastname: Lambert
authors.forename: Laurence
authors.initials: L
authors.lastname: Hatteville
authors.forename: Samira
authors.initials: S
authors.lastname: Ziti-Ljajic
authors.forename: Anne
authors.initials: A
authors.lastname: Caron
authors.forename: Sandrine
authors.initials: S
authors.lastname: Payrard
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D001247:Asthenia / Q000139:chemically induced; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; C569646:coltuximab ravtansine