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: Kensei Tobinai, Michinori Ogura, Yukio Kobayashi, Toshiki Uchida, Takashi Watanabe, Takashi Oyama, Dai Maruyama, Tatsuya Suzuki, Masakazu Mori, Masanobu Kasai, Damien Cronier, James E Wooldridge, Minori Koshiji
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 2 Pg. 432-8 (Feb 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21205069 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigens, CD20
• Antineoplastic Agents
• FCGR3A protein, human
• Receptors, IgG
• ocaratuzumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, pharmacokinetics)
• Antibodies, Monoclonal, Humanized
• Antigens, CD20 (drug effects, immunology)
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Heterozygote
• Humans
• Lymphoma, Follicular (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• Neoplasm Staging
• Receptors, IgG (genetics)