Elsevier

Gynecologic Oncology

Volume 138, Issue 2, August 2015, Pages 272-277
Gynecologic Oncology

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,☆☆,

https://doi.org/10.1016/j.ygyno.2015.05.023Get rights and content

Highlights

  • Phase II study of hu3S193 in platinum resistant/refractory ovarian cancer patients.

  • Didn’t reach the primary endpoint whit mPFS of 8.4 weeks but safe toxicity profile.

  • mPFS was higher in patients with no ascites/no visceral disease.

Abstract

Objectives

The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics.

Methods

This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20 mg/m2 intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks).

Results

26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24 + weeks [clinical benefit rate 23% (95% CI = 9.77%–46.71%)]. Median PFS was 8.4 weeks (95% CI = 6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p = 0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3).

Conclusions

Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested.

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.

☆☆

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.

The authors would like to acknowledge the important contribution of Lloyd J. Old, MD (in memoriam) to this project.

1

Present address: Centro Oncológico Antonio Ermírio de Moraes-Beneficência Portuguesa de São Paulo, Rua Martiniano de Carvalho, 965, São Paulo, SP 01321-001, Brazil.

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