Phase I pharmacokinetic and pharmacodynamic dose-escalation study of RG7160 (GA201), the first glycoengineered monoclonal antibody against the epidermal growth factor receptor, in patients with advanced solid tumors

Luis Paz-Ares, Carlos Gomez-Roca, Jean-Pierre Delord, Andres Cervantes, Benjamin Markman, Jesus Corral, Jean-Charles Soria, Yann Berge, Desamparados Roda, Fiona Russell-Yarde, Simon Hollingsworth, Jose Baselga, Pablo Umana, Luigi Manenti, Josep Tabernero

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Abstract

We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G(1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. PATIENTS AND METHODS: Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. RESULTS: No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80 of patients), infusion-related reactions (77 ), and hypomagnesemia (56 ). Grades 3 and 4 AEs were rash (grade 3, 25 ), infusion-related reaction (grade 3, 7 ; grade 4, 1 ), paronychia (grade 3, 3 ), and hypomagnesemia (grade 3, 1 ; grade 4, 1 ). RG7160 exposure increased greater than proportionally over the 50- to 400-mg dose range (with greater than proportional decline in clearance) and approximately dose proportionally above 400 mg (where clearance plateaued). A marked reduction in circulating natural killer cells and increased infiltration of immune effector cells into skin rash were seen. Clinical efficacy included one complete response and two partial responses in patients with colorectal cancer (including one with KRAS mutation) and disease stabilization in 27 patients. CONCLUSION: RG7160 had an acceptable safety profile with manageable AEs and demonstrated promising efficacy in this heavily pretreated patient cohort. On the basis of modeling of available PK parameters, the RG7160 dose selected for part two of this study is 1,400 mg on days 1 and 8 followed by 1,400 mg every 2 weeks.
Original languageEnglish
Pages (from-to)3783 - 3790
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number28
DOIs
Publication statusPublished - 2011

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