PMID- 31765988 OWN - NLM STAT- MEDLINE DCOM- 20200629 LR - 20240210 IS - 1879-0852 (Electronic) IS - 0959-8049 (Print) IS - 0959-8049 (Linking) VI - 124 DP - 2020 Jan TI - Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma. PG - 131-141 LID - S0959-8049(19)30773-7 [pii] LID - 10.1016/j.ejca.2019.10.010 [doi] AB - BACKGROUND: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). METHODS: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. RESULTS: During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III-IV AEs. Six-month PFS was 85% (90% CI: 66%-94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). CONCLUSION: Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791). CI - Copyright (c) 2019 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Thomas, Anne AU - Thomas A AD - University of Leicester, Leicester, UK. Electronic address: at107@le.ac.uk. FAU - Virdee, Pradeep S AU - Virdee PS AD - Centre for Statistics in Medicine, University of Oxford, Oxford, UK. FAU - Eatock, Martin AU - Eatock M AD - Belfast City Hospital, Belfast, UK. FAU - Lord, Simon R AU - Lord SR AD - University of Oxford, Oxford, UK. FAU - Falk, Stephen AU - Falk S AD - Bristol Haematology & Oncology Centre, Bristol, UK. FAU - Anthoney, D Alan AU - Anthoney DA AD - St. James University Hospital, Leeds, UK. FAU - Turkington, Richard C AU - Turkington RC AD - Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK. FAU - Goff, Matthew AU - Goff M AD - Oncology Clinical Trials Office, University of Oxford, Oxford, UK. FAU - Elhussein, Leena AU - Elhussein L AD - Centre for Statistics in Medicine, University of Oxford, Oxford, UK. FAU - Collins, Linda AU - Collins L AD - Oncology Clinical Trials Office, University of Oxford, Oxford, UK. FAU - Love, Sharon AU - Love S AD - Centre for Statistics in Medicine, University of Oxford, Oxford, UK. FAU - Moschandreas, Joanna AU - Moschandreas J AD - Centre for Statistics in Medicine, University of Oxford, Oxford, UK. FAU - Middleton, Mark R AU - Middleton MR AD - University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, UK. LA - eng SI - EudraCT/2011-003169-13 SI - ISRCTN/ISRCTN68093791 GR - 14112/CRUK_/Cancer Research UK/United Kingdom GR - 16895/CRUK_/Cancer Research UK/United Kingdom GR - C5529/A16895/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191122 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (AZD 8931) RN - 0 (Oxaloacetates) RN - 0 (Quinazolines) RN - 04ZR38536J (Oxaliplatin) RN - 6804DJ8Z9U (Capecitabine) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - XELOX SB - IM MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects MH - Capecitabine/*administration & dosage/adverse effects MH - Diarrhea/chemically induced/epidemiology MH - Esophageal Neoplasms/mortality/pathology/*therapy MH - Esophagogastric Junction/pathology/surgery MH - Exanthema/chemically induced/epidemiology MH - Fatigue/chemically induced/epidemiology MH - Female MH - Humans MH - Male MH - Margins of Excision MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoadjuvant Therapy/adverse effects/methods MH - Oxaliplatin/administration & dosage/adverse effects MH - Oxaloacetates/*administration & dosage/adverse effects MH - Progression-Free Survival MH - Quinazolines/*administration & dosage/adverse effects MH - Receptor, ErbB-2/*antagonists & inhibitors MH - Receptor, ErbB-3/*antagonists & inhibitors MH - Stomach Neoplasms/mortality/pathology/*therapy MH - Vomiting/chemically induced/epidemiology PMC - PMC6947485 OTO - NOTNLM OT - AZD8931 OT - Dual erbB inhibitor OT - Oesophagogastric cancer COIS- A.T., M.E., S.R.L., S.F., D.A.A., R.C.T., M.G., L.E., and S.L. declare no conflict of interest. During the conduct of the study, P.S.V. and L.C. report receiving grants from AstraZeneca. J.M. reports grants from AstraZeneca and Cancer Research UK. M.R.M. reports grants from Roche, AstraZeneca and GSK; received personal fees from Amgen, Roche, GSK, Novartis, Immunocore, BMS, Eisai, Merck, Rigontec, BiolineRx and Array Biopharma; received non-financial support from Immunocore and Merck; has been a member of the Advisory Board/and has also received study fees (institution only) from Novartis, Millennium, Immunocore, BMS, Vertex, Eisai, Pfizer, Merck, Rigontec, Regeneron, TCBiopharma, Array Biopharma and Replimune; and also having IDSMC membership with Eisai. EDAT- 2019/11/26 06:00 MHDA- 2020/07/01 06:00 PMCR- 2020/01/01 CRDT- 2019/11/26 06:00 PHST- 2019/08/22 00:00 [received] PHST- 2019/10/07 00:00 [revised] PHST- 2019/10/13 00:00 [accepted] PHST- 2019/11/26 06:00 [pubmed] PHST- 2020/07/01 06:00 [medline] PHST- 2019/11/26 06:00 [entrez] PHST- 2020/01/01 00:00 [pmc-release] AID - S0959-8049(19)30773-7 [pii] AID - 10.1016/j.ejca.2019.10.010 [doi] PST - ppublish SO - Eur J Cancer. 2020 Jan;124:131-141. doi: 10.1016/j.ejca.2019.10.010. Epub 2019 Nov 22.