DEBIOC: A Combinations Alliance Study of AZD8931 in combination with Oxaliplatin and Capecitabine chemotherapy in patients with Oesophago-gastric adenocarcinoma
1University of Leicester, Leicester, UK
Treatment options for patients with oesophago-gastric cancer remain poor. AZD8931 is a novel small-molecule inhibitor which has equipotent activity against signalling by three members of the erbB family; EGFR, erbB2(HER-2), and erbB3. Our hypothesis is that combining AZD8931 with chemotherapy will be effective not just in patients who overexpress high levels of HER-2, but those with low HER-2 expression as well. This study seeks to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of AZD8931 with oxaliplatin and capecitabine (XELOX) in patients with oesophagogastric cancer (OGC).
In protocol design, special attention was paid to potential overlapping toxicity from AZD8931 and XELOX. Moreover, in line with Combination Alliance studies a two phase approach was required: escalation and a randomised expansion including a control arm. To maximise recruitment rates the dose-escalation phase was planned in chemonaive all-comers with OGC although we wished to expand the study in patients receiving neoadjuvant chemotherapy; this would facilitate a translational substudy. We recognised the importance of planned dose delivery in the neoadjuvant setting and therefore in addition to classical Dose Limiting Toxicity (DLT) definitions, another DLT definition was utilised: failure to deliver 100% of the planned dose of XELOX due to toxicity attributable to AZD8931 or the AZD8931/XELOX combination.
For the dose escalation a rolling 6 method was used and patients received oxaliplatin (130 mg/m2 day(d) 1 every 21 days (q21) and capecitabine (X) (1250mg/m2/d) d1-21, for a maximum of 8 cycles. AZD8931 dosing was planned for 3 cohorts (20mg bd, 40 mg bd, 60 mg bd continuously). In the expansion phase, 20 operable patients were planned to receive 2 cycles of the RP2D combination and 10 patients XELOX alone pre oesophagectomy.
In this talk, demographic, safety, PK and early results from the expansion phase will be presented.