TY - JOUR

T1 - Evaluating the efficacy and safety of neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer

T2 - a national, multicentre, prospective, single-arm, phase II study protocol

AU - Justesen, Tobias Freyberg

AU - Gögenur, Ismail

AU - Tarpgaard, Line Schmidt

AU - Pfeiffer, Per

AU - Qvortrup, Camilla

N1 - Funding Information: In accordance with good academic practice, the study data (health data and genomic data) is planned to be transferred in anonymised form to the secure database European Genome-Phenome Archive (EGA). This will happen after the study has been completed. The purpose is to enable sharing of the data with other research groups for future research, inside and outside of Denmark. In all cases, data access decisions will be made by the study protocol committee. Data sharing will be conducted in accordance with the European data protection regulations, including The Danish Data Protection Act and the General Data Protection Regulation. The EGA is part of the European life-sciences Infrastructure for biological Information (ELIXIR) research infrastructure, which is partly funded by the European Commission. Funding Information: The study was supported with grants by the Danish Comprehensive Cancer Center (grant number 16), the Medical Doctor Sofus Carl Emil Friis and Wife Olga Doris Friis' Foundation (grant number not provided), the Danish Cancer Society (grant number R343-A19803), the Axel Muusfeldt’s Foundation (grant number 2022-0016), the Frimodt-Heineke Foundation (grant number not provided) and the Dagmar Marshalls Foundation (grant number not provided). The grants were unrestricted, the funding parties were not involved in the design of the study and will not be involved in the execution of the study or the analyses and interpretation of study results. There is no financial gain for the departments involved. Further unrestricted funding will be applied on an ongoing basis from private and public funds. Funding Information: The authors are grateful for the grants provided by the funding parties including the Danish Comprehensive Cancer Center, the Medical Doctor Sofus Carl Emil Friis and Wife Olga Doris Friis' Foundation, the Danish Cancer Society, the Axel Muusfeldt’s Foundation, the Frimodt-Heineke Foundation and the Dagmar Marshalls Foundation. Further, we would like to thank all the participating study investigators including Hans Raskov, Mustafa Bulut, Anne-Marie Kanstrup Fiehn, Paulo Urbano, Peter Clausager Petersen, Lars Simon Reiter, Søren Salomon, Claus Lindbjerg Andersen, Anders Kindberg Boysen, Anne Ramlov, Lene Hjerrild Iversen, Katrine Emmertsen, Helle Attermann Abildgaard, Michael Bødker Lauritzen, Laurids Østergaard Poulsen, Ole Thorlacius-Ussing, Peter-Martin Krarup, Laura Buskov, Jakob Lykke, Jakob Schou, Torben Frøstrup Hansen, Lars Henrik Jensen and Hans Rahr who made contributions to the development of the study protocol. Publisher Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023

Y1 - 2023

N2 - Introduction Within the last two decades, major advances have been made in the surgical approach for patients with colorectal cancer. However, to this day we face considerable challenges in reducing surgery-related complications and improving long-term oncological outcomes. Unprecedented response rates have been achieved in studies investigating immunotherapy in patients with mismatch repair deficient (dMMR) colorectal cancer. This has raised the question of whether neoadjuvant immunotherapy may change the standard of care for localised dMMR colon cancer and pave the way for organ-sparing treatment. Methods and analysis This is an investigator-initiated, multicentre, prospective, single-arm, phase II study in patients with stage I-III dMMR colon cancer scheduled for intended curative surgery. Eighty-five patients will be treated with one dose of pembrolizumab (4 mg/kg) and within 5 weeks will undergo a re-evaluation with an endoscopy and a CT scan - to assess tumour response - before standard resection of the tumour. The primary endpoint is the number of patients with pathological complete response, and secondary endpoints include safety (number and severity of adverse events) and postoperative surgical complications. In addition, we aspire to identify predictive biomarkers that can point out patients that achieve pathological complete response. Ethics and dissemination The Regional Committee for Health Research and Ethics and the Danish Medicines Agency have approved this study. The study will be performed according to the Helsinki II declaration. Written informed consent will be obtained from all participants. The results of the study will be submitted to peer-reviewed journals for publication and presented at international congresses. Trial registration number NCT05662527.

AB - Introduction Within the last two decades, major advances have been made in the surgical approach for patients with colorectal cancer. However, to this day we face considerable challenges in reducing surgery-related complications and improving long-term oncological outcomes. Unprecedented response rates have been achieved in studies investigating immunotherapy in patients with mismatch repair deficient (dMMR) colorectal cancer. This has raised the question of whether neoadjuvant immunotherapy may change the standard of care for localised dMMR colon cancer and pave the way for organ-sparing treatment. Methods and analysis This is an investigator-initiated, multicentre, prospective, single-arm, phase II study in patients with stage I-III dMMR colon cancer scheduled for intended curative surgery. Eighty-five patients will be treated with one dose of pembrolizumab (4 mg/kg) and within 5 weeks will undergo a re-evaluation with an endoscopy and a CT scan - to assess tumour response - before standard resection of the tumour. The primary endpoint is the number of patients with pathological complete response, and secondary endpoints include safety (number and severity of adverse events) and postoperative surgical complications. In addition, we aspire to identify predictive biomarkers that can point out patients that achieve pathological complete response. Ethics and dissemination The Regional Committee for Health Research and Ethics and the Danish Medicines Agency have approved this study. The study will be performed according to the Helsinki II declaration. Written informed consent will be obtained from all participants. The results of the study will be submitted to peer-reviewed journals for publication and presented at international congresses. Trial registration number NCT05662527.

KW - Clinical trials

KW - Colorectal surgery

KW - Gastrointestinal tumours

KW - ONCOLOGY

U2 - 10.1136/bmjopen-2023-073372

DO - 10.1136/bmjopen-2023-073372

M3 - Journal article

C2 - 37349100

AN - SCOPUS:85162809327

VL - 13

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

IS - 6

M1 - e073372

ER -