Research article

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer

Mark D Pegram¹ , Virginia F Borges² , Nuhad Ibrahim³ , Jyotsna Fuloria⁴ , Charles Shapiro⁵ , Susan Perez⁶ , Karen Wang⁶ , Franziska Schaedli Stark⁷ and Nigel Courtenay Luck⁸

¹  Division of Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Avenue; Suite 3400 (D8-4), Miami, FL 33136, USA

²  Division of Medical Oncology, University of Colorado Denver, 12801 E 17th Avenue, MS 8117, Aurora, CO, USA

³  Department of Breast Medical Oncology, UT MD Anderson Cancer Center, 1155 Pressler Street, CPB5.3540, Houston, TX, 77030, USA

⁴  Department of Hematology/Oncology, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA 70121, USA

⁵  Division of Medical Oncology, James Cancer Center, B405 Starling Loving 320 West 10th Avenue, Columbus, OH 43210, USA

⁶  Hoffmann La Roche Pharmaceuticals, 340 Kingsland Street, Nutley, NJ 07110, USA

⁷  Hoffmann La Roche Pharmaceuticals, Konzern-Hauptsitz, Grenzacherstrasse 124, CH-4070 Basel, Switzerland

⁸  Antisoma Research Ltd, Chiswick Park Building 5, 566 Chiswick High Road, London, W4 5YF, UK

author email corresponding author email

Breast Cancer Research 2009, 11:R73doi:10.1186/bcr2409

Published:	7 October 2009

Abstract

Introduction

MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy.

Methods

Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied.

Results

Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 ± 37.1 hours.

Conclusions

Repeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer.

Trial registration

ClinicalTrials.gov Identifier: NCT00096057.