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Clinical Trials

Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic colorectal cancer (mCRC)

Andrés Cervantes, Ben Markman, Salvatore Siena, Carles Pericay, Giuseppe Aprile, John Bridgewater, Antonio Cubillo, Ashita Waterston, Luis Paz Ares, Jean-Charles Soria, Stephane Temam, David Oppenheim, Jon Chick, David Carlile, Sophie Golding, Maria Longauer Banholzer, Alexandre Passioukov, Chrstian Gerdes, Sophia Soehrman, Christoph Mancao, Luigi Manenti and Josep Tabernero
Andrés Cervantes
1Department of Hematology and Medical Oncology INCLIVA, University of Valencia, Valencia, Spain
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Ben Markman
2Monash University, Southern Health, Melbourne, Australia
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Salvatore Siena
3Department of Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy
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Carles Pericay
4Corporació Sanitaria Parc Taulí, Sabadell, Spain
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Giuseppe Aprile
5D5Azienda Ospedaliero-Universitaria di Udine, Udine, Italy
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John Bridgewater
6UCL Cancer Institute, London, United Kingdom
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Antonio Cubillo
7Centro Integral Oncológico Clara Campal, Madrid, Spain
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Ashita Waterston
8Beatson Oncology Centre, Glasgow, United Kingdom
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Luis Paz Ares
99Instituto de Biomedicina de Sevilla (IBIS) and Hospital Universitario Virgen del Rocio, Seville, Spain
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Jean-Charles Soria
10Institut Gustave Roussy and University Paris South, Villejuif, France
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Stephane Temam
11Institut Gustave Roussy, Villejuif, France
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David Oppenheim
12Department of Haematological Medicine, King's College London, London, United Kingdom
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Jon Chick
13Roche Products Ltd, Welwyn Garden City, United Kingdom
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David Carlile
13Roche Products Ltd, Welwyn Garden City, United Kingdom
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Sophie Golding
14Hoffmann-La Roche Ltd, Basel, Switzerland
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Maria Longauer Banholzer
14Hoffmann-La Roche Ltd, Basel, Switzerland
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Alexandre Passioukov
15Roche Glycart AG, Schlieren, Switzerland
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Chrstian Gerdes
15Roche Glycart AG, Schlieren, Switzerland
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Sophia Soehrman
14Hoffmann-La Roche Ltd, Basel, Switzerland
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Christoph Mancao
14Hoffmann-La Roche Ltd, Basel, Switzerland
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Luigi Manenti
15Roche Glycart AG, Schlieren, Switzerland
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Josep Tabernero
16Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
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DOI: 10.1158/1538-7445.AM2012-LB-220 Published April 2012
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Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Abstract

GA201 is a novel dual-acting humanized, engineered IgG1 anti-EGFR mAb designed to enhance ADCC in combination with signaling inhibition. Superior efficacy was demonstrated versus cetuximab in orthotopic CRC xenograft models. Preclinical data indicated an increase in macrophages (4-5 fold) and NK cells (2-3 fold) infiltration in tumors treated with GA201 compared to cetuximab. In a phase I clinical study objective responses and long lasting disease stabilizations were observed. A marked reduction in circulating NK cells and an increased infiltration of immune cells into skin rash was seen. Preliminary evidence of the enhanced ADCC capacity of GA201 was investigated in 25 third line patients with KRAS-mutant mCRC. Best overall response was SD in 40% of patients and median OS was 9.4 months. Reduction in peripheral NK cells and regulatory T-cells was observed. Comparison of pre- and post-treatment tumour biopsies revealed that tumour-infiltrating immune cells, in particular CD68+ and CD3+ cells increased overall. EGFR-membrane staining in baseline tumour biopsies was markedly higher than in the corresponding archival tumour specimens (median H-score 52 vs 3, respectively), which might reflect technical, but most importantly, biological variability. Based on these results and the commitment to investigate the tumor immune infiltration profile as a potential predictive biomarker, a fresh tumor biopsy at baseline was mandated in the ongoing randomized phase II trial (GAIN-C). This compares GA201 plus irinotecan, infusional fluorouracil and leucovorin (FOLFIRI) with FOLFIRI alone in KRAS-mutant 2nd line mCRC patients and with cetuximab plus FOLFIRI in KRAS-wild type patients (n=160). Primary objective is PFS. The fresh tumor biopsy will be centrally analyzed for EGFR and KRAS. A comprehensive biomarker program was implemented to investigate potential predictive biomarkers, with an emphasis on the real time tumor immune-infiltration status. The safety run-in phase with 36 patients was completed. Most common treatment related AEs on GA201 arms vs cetuximab vs. chemotherapy included (≥ grade 3): rash (33 vs. 17 vs. 0%), IRR (10 vs. 0 vs. 0%), diarrhea (17 vs. 0 vs. 11%), fatigue/asthenia (0 vs. 17 vs. 0%), hypomagnesaemia (17 vs. 0 vs. 0%), stomatitis (17 vs. 0 vs. 0%) and vomiting/nausea (6 vs. 0 vs. 0%). So far, no patient discontinued due to EGFR-related skin toxicity. Immunological profiling is ongoing. Extensive research efforts, including a fresh tumor biopsy in second line mCRC patients, are taken to understand the immunological mechanism of action of GA201 and to select and test (ph. II) and validate (ph. III) potential predictive biomarkers. To guide personalized cancer immunotherapies there is a clear need for reliable biomarkers which would necessitate a tumor assessment directly prior to the therapy and immune monitoring throughout treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-220. doi:1538-7445.AM2012-LB-220

  • ©2012 American Association for Cancer Research
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Cancer Research: 72 (8 Supplement)
April 2012
Volume 72, Issue 8 Supplement
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Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic colorectal cancer (mCRC)
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Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic colorectal cancer (mCRC)
Andrés Cervantes, Ben Markman, Salvatore Siena, Carles Pericay, Giuseppe Aprile, John Bridgewater, Antonio Cubillo, Ashita Waterston, Luis Paz Ares, Jean-Charles Soria, Stephane Temam, David Oppenheim, Jon Chick, David Carlile, Sophie Golding, Maria Longauer Banholzer, Alexandre Passioukov, Chrstian Gerdes, Sophia Soehrman, Christoph Mancao, Luigi Manenti and Josep Tabernero
Cancer Res April 15 2012 (72) (8 Supplement) LB-220; DOI: 10.1158/1538-7445.AM2012-LB-220

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Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic colorectal cancer (mCRC)
Andrés Cervantes, Ben Markman, Salvatore Siena, Carles Pericay, Giuseppe Aprile, John Bridgewater, Antonio Cubillo, Ashita Waterston, Luis Paz Ares, Jean-Charles Soria, Stephane Temam, David Oppenheim, Jon Chick, David Carlile, Sophie Golding, Maria Longauer Banholzer, Alexandre Passioukov, Chrstian Gerdes, Sophia Soehrman, Christoph Mancao, Luigi Manenti and Josep Tabernero
Cancer Res April 15 2012 (72) (8 Supplement) LB-220; DOI: 10.1158/1538-7445.AM2012-LB-220
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