INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

Lyn Ley Lam; Nick Pavlakis; Kohei Shitara; Katrin M. Sjoquist; Andrew J. Martin; Sonia Yip; Yoon Koo Kang; Yung Jue Bang; Li Tzong Chen; Markus Moehler; Tanios Bekaii-Saab; Thierry Alcindor; Christopher J. O’Callaghan; Niall C. Tebbutt; Wendy Hague; Howard Chan; Sun Young Rha; Keun Wook Lee; Val Gebski; Anthony Jaworski; John Zalcberg; Timothy Price; John Simes; David Goldstein

doi:10.1186/s12885-023-10642-7

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

Lyn Ley Lam, Nick Pavlakis, Kohei Shitara, Katrin M. Sjoquist, Andrew J. Martin, Sonia Yip, Yoon Koo Kang, Yung Jue Bang, Li Tzong Chen, Markus Moehler, Tanios Bekaii-Saab, Thierry Alcindor, Christopher J. O’Callaghan, Niall C. Tebbutt, Wendy Hague, Howard Chan, Sun Young Rha, Keun Wook Lee, Val Gebski, Anthony JaworskiJohn Zalcberg, Timothy Price, John Simes, David Goldstein

Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

Original language	English (US)
Article number	180
Journal	BMC cancer
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12885-023-10642-7
State	Published - Dec 2023

Keywords

Advanced gastro-oesophageal cancer
Clinical trial
Nivolumab
Regorafenib
Tyrosine kinase inhibitor

ASJC Scopus subject areas

Oncology
Genetics
Cancer Research

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Lam, L. L., Pavlakis, N., Shitara, K., Sjoquist, K. M., Martin, A. J., Yip, S., Kang, Y. K., Bang, Y. J., Chen, L. T., Moehler, M., Bekaii-Saab, T., Alcindor, T., O’Callaghan, C. J., Tebbutt, N. C., Hague, W., Chan, H., Rha, S. Y., Lee, K. W., Gebski, V., ... Goldstein, D. (2023). INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG). BMC cancer, 23(1), Article 180. https://doi.org/10.1186/s12885-023-10642-7

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG). / Lam, Lyn Ley; Pavlakis, Nick; Shitara, Kohei et al.
In: BMC cancer, Vol. 23, No. 1, 180, 12.2023.

Research output: Contribution to journal › Article › peer-review

Lam, LL, Pavlakis, N, Shitara, K, Sjoquist, KM, Martin, AJ, Yip, S, Kang, YK, Bang, YJ, Chen, LT, Moehler, M, Bekaii-Saab, T, Alcindor, T, O’Callaghan, CJ, Tebbutt, NC, Hague, W, Chan, H, Rha, SY, Lee, KW, Gebski, V, Jaworski, A, Zalcberg, J, Price, T, Simes, J & Goldstein, D 2023, 'INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)', BMC cancer, vol. 23, no. 1, 180. https://doi.org/10.1186/s12885-023-10642-7

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title = "INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)",

abstract = "Background: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator{\textquoteright}s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.",

keywords = "Advanced gastro-oesophageal cancer, Clinical trial, Nivolumab, Regorafenib, Tyrosine kinase inhibitor",

author = "Lam, {Lyn Ley} and Nick Pavlakis and Kohei Shitara and Sjoquist, {Katrin M.} and Martin, {Andrew J.} and Sonia Yip and Kang, {Yoon Koo} and Bang, {Yung Jue} and Chen, {Li Tzong} and Markus Moehler and Tanios Bekaii-Saab and Thierry Alcindor and O{\textquoteright}Callaghan, {Christopher J.} and Tebbutt, {Niall C.} and Wendy Hague and Howard Chan and Rha, {Sun Young} and Lee, {Keun Wook} and Val Gebski and Anthony Jaworski and John Zalcberg and Timothy Price and John Simes and David Goldstein",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1186/s12885-023-10642-7",

language = "English (US)",

volume = "23",

journal = "BMC cancer",

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T1 - INTEGRATE II

T2 - randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

AU - Lam, Lyn Ley

AU - Pavlakis, Nick

AU - Shitara, Kohei

AU - Sjoquist, Katrin M.

AU - Martin, Andrew J.

AU - Yip, Sonia

AU - Kang, Yoon Koo

AU - Bang, Yung Jue

AU - Chen, Li Tzong

AU - Moehler, Markus

AU - Bekaii-Saab, Tanios

AU - Alcindor, Thierry

AU - O’Callaghan, Christopher J.

AU - Tebbutt, Niall C.

AU - Hague, Wendy

AU - Chan, Howard

AU - Rha, Sun Young

AU - Lee, Keun Wook

AU - Gebski, Val

AU - Jaworski, Anthony

AU - Zalcberg, John

AU - Price, Timothy

AU - Simes, John

AU - Goldstein, David

PY - 2023/12

Y1 - 2023/12

N2 - Background: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

AB - Background: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

KW - Advanced gastro-oesophageal cancer

KW - Clinical trial

KW - Nivolumab

KW - Regorafenib

KW - Tyrosine kinase inhibitor

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INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

Abstract

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