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

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

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oxaliplatin
Stomach Neoplasms
Adenocarcinoma
Safety
Drug Therapy
Disease-Free Survival
Vomiting
Appointments and Schedules
Neoplasms
Neoadjuvant Therapy
Capecitabine
AZD 8931
Exanthema
Epidermal Growth Factor Receptor
Fatigue

Keywords

  • AZD8931
  • Dual erbB inhibitor
  • Oesophagogastric cancer

Cite this

Thomas, Anne ; Virdee, Pradeep S. ; Eatock, Martin ; Lord, Simon R. ; Falk, Stephen ; Anthoney, D. Alan ; Turkington, Richard C. ; Goff, Matthew ; Elhussein, Leena ; Collins, Linda ; Love, Sharon ; Moschandreas, Joanna ; Middleton, Mark R. / 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. In: European Journal of Cancer. 2020 ; Vol. 124. pp. 131-141.
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title = "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",
abstract = "BackgroundAZD8931 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).MethodsAZD8931 (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.ResultsDuring 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).ConclusionXelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC.",
keywords = "AZD8931, Dual erbB inhibitor, Oesophagogastric cancer",
author = "Anne Thomas and Virdee, {Pradeep S.} and Martin Eatock and Lord, {Simon R.} and Stephen Falk and Anthoney, {D. Alan} and Turkington, {Richard C.} and Matthew Goff and Leena Elhussein and Linda Collins and Sharon Love and Joanna Moschandreas and Middleton, {Mark R.}",
year = "2020",
month = "1",
doi = "10.1016/j.ejca.2019.10.010",
language = "English",
volume = "124",
pages = "131--141",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier",

}

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

In: European Journal of Cancer, Vol. 124, 01.2020, p. 131-141.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Thomas, Anne

AU - Virdee, Pradeep S.

AU - Eatock, Martin

AU - Lord, Simon R.

AU - Falk, Stephen

AU - Anthoney, D. Alan

AU - Turkington, Richard C.

AU - Goff, Matthew

AU - Elhussein, Leena

AU - Collins, Linda

AU - Love, Sharon

AU - Moschandreas, Joanna

AU - Middleton, Mark R.

PY - 2020/1

Y1 - 2020/1

N2 - BackgroundAZD8931 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).MethodsAZD8931 (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.ResultsDuring 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).ConclusionXelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC.

AB - BackgroundAZD8931 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).MethodsAZD8931 (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.ResultsDuring 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).ConclusionXelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC.

KW - AZD8931

KW - Dual erbB inhibitor

KW - Oesophagogastric cancer

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U2 - 10.1016/j.ejca.2019.10.010

DO - 10.1016/j.ejca.2019.10.010

M3 - Article

C2 - 31765988

AN - SCOPUS:85075286756

VL - 124

SP - 131

EP - 141

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

ER -