title: Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma.
abstract: Patients with follicular lymphoma (FL), where position 158 of FcγR-IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F-carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F-carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody-dependent cell-mediated cytotoxicity. This dose-escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20-positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m(2) weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F-carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose-limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F-carriers. Further investigation of FL is warranted.
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Oyama
authors.forename: Dai
authors.initials: D
authors.lastname: Maruyama
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Mori
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kasai
authors.forename: Damien
authors.initials: D
authors.lastname: Cronier
authors.forename: James E
authors.initials: JE
authors.lastname: Wooldridge
authors.forename: Minori
authors.initials: M
authors.lastname: Koshiji
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20 / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006579:Heterozygote; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009367:Neoplasm Staging; D017452:Receptors, IgG / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D000970:Antineoplastic Agents; C496124:FCGR3A protein, human; D017452:Receptors, IgG; C550337:ocaratuzumab