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

Anne Thomas*, Pradeep S. Virdee, Martin Eatock, Simon R. Lord, Stephen Falk, D. Alan Anthoney, Richard C. Turkington, Matthew Goff, Leena Elhussein, Linda Collins, Sharon Love, Joanna Moschandreas, Mark R. Middleton

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)131-141
Number of pages11
JournalEuropean Journal of Cancer
Volume124
Early online date22 Nov 2019
DOIs
Publication statusPublished - Jan 2020

Keywords

  • AZD8931
  • Dual erbB inhibitor
  • Oesophagogastric cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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