title: Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab.
abstract: OBJECTIVE
  Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20(+)/CD22(+) B-cell non-Hodgkin lymphoma (NHL).
  
  
  METHODS
  A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles.
  
  
  RESULTS
  In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m(2)) was confirmed to be the same as that for single-agent INO (1.8 mg/m(2)). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL.
  
  
  CONCLUSIONS
  R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20(+)/CD22(+) B-cell NHL.
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 429, Houston, TX 77030, USA. lefayad@mdanderson.org
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.forename: Peter
authors.initials: P
authors.lastname: Johnson
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Kaufman
authors.forename: Ama
authors.initials: A
authors.lastname: Rohatiner
authors.forename: Anjali
authors.initials: A
authors.lastname: Advani
authors.forename: James
authors.initials: J
authors.lastname: Foran
authors.forename: Georg
authors.initials: G
authors.lastname: Hess
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.forename: Myron
authors.initials: M
authors.lastname: Czuczman
authors.forename: Eva
authors.initials: E
authors.lastname: Giné
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.forename: Michelle
authors.initials: M
authors.lastname: Kneissl
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Luu
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Hua
authors.forename: Joseph
authors.initials: J
authors.lastname: Boni
authors.forename: Erik
authors.initials: E
authors.lastname: Vandendries
authors.forename: Nam H
authors.initials: NH
authors.lastname: Dang
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D000080045:Inotuzumab Ozogamicin; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000139:chemically induced; D017093:Liver Failure / Q000139:chemically induced; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009503:Neutropenia / Q000139:chemically induced; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors; D000069283:Rituximab; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D000080045:Inotuzumab Ozogamicin