A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma☆,☆☆,★
Introduction
Annually more than 200,000 women worldwide are diagnosed with epithelial ovarian carcinoma (EOC) [1]. Despite being a highly chemotherapy sensitive disease at initial presentation, most patients relapse and ultimately develop resistance to platinum agents with a median survival of less than one year [2]. Effective novel agents with different mechanisms of action are needed.
The Lewis-Y (Ley) antigen is a blood group-related antigen expressed in over 70% of epithelial cancers [3]. It is expressed in 75% of ovarian cancers with strong or moderate expression observed in 56% of the samples [4], making ovarian cancer attractive for anti-Ley monoclonal antibody-directed therapy. Hu3S193 is a complementarity determining region (CDR)-grafted IgG1 humanized version of the murine anti-Ley monoclonal antibody 3S193 [5]. It has potent immune effector function with higher antibody-dependent cell-mediated cytotoxicity than its murine counterpart, as well as potent complement-dependent cytotoxicity [6]. The safety profile and the phase II dosing schedule of hu3S193 were established in previous phase I dose-escalation trials which evaluated toxicity, biodistribution, and pharmacokinetics when given weekly for 4 doses [7], [8].
Given the limited benefit of chemotherapeutic agents in this platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma and the high expression of the Ley antigen in ovarian cancer, a phase II trial was conducted to determine the clinical efficacy of hu3S193 in this patient population.
Section snippets
Methods
This study was registered at ClinicalTrials.gov (identifier: NCT00617773). The trial was conducted according to the Brazilian clinical research legislation and in compliance with the Declaration of Helsinki. It was approved by the Ethics Committee of all participating centers. Written informed consent was obtained from each patient before study entry.
Patients and treatment
Thirty-one patients were accrued to the study over a period of 4 years. Five of these patients were not considered for the primary objective (clinical benefit) analysis because either they did not get four doses of the hu3S193 (4 patients) or because of platinum sensitive disease (one patient) but they were considered eligible for safety evaluation. Demographics and baseline characteristics for the 31 enrolled patients are presented in Table 1.
The median age of the cohort was 55 years (range, 24
Discussion
This phase II trial of hu3S193 given as a single agent in the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma did not reach its primary clinical efficacy endpoint. Although no objective responses were seen in this heavily pretreated population, clinical benefit from disease stabilization for more than 24 weeks, was present in 25% of the patients.
The median PFS of 8.4 weeks is similar to the PFS reported for platinum resistant patients treated
Disclosure of potential conflicts of interest
Dr. Smaletz reports personal fees from Recepta Biopharma, non-financial support from Roche, during the conduct of the study; and personal fees from Recepta Biopharma, outside the submitted work.
Dr. Barrios reports grants from Amgem, grants from Astra Zeneca, grants from Boehringer, grants and personal fees from GSK, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from Roche, personal fees from Eisai, grants from Celgene, grants from Sanofi,
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Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2011.
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This work was supported in part by a grant from Fundo de Financiamento de Estudos de Projetos e Programas, Brazil (FINEP) 01.06.0759.00 and 01.07.0096.00.
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The authors would like to acknowledge the important contribution of Lloyd J. Old, MD (in memoriam) to this project.
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Present address: Centro Oncológico Antonio Ermírio de Moraes-Beneficência Portuguesa de São Paulo, Rua Martiniano de Carvalho, 965, São Paulo, SP 01321-001, Brazil.