Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer

Article Article scientifique Article Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer eng 2022-07-15 2022-07-15 author Corro Claudia 948048 author Buchs Nicolas 516487 author Tihy Matthieu 914217 author Durham Faivre André-Dante 976635 author Bichard Philippe 0000-0001-5075-5856 813631 author Frossard Jean-Louis 35038 author Puppa Giacomo 795799 author Mckee Thomas Alexander 549937 author Roth Arnaud 134504 author Zilli Thomas 791833 author Trembleau Christelle 134027 author Di Marco Mariagrazia 768956 author Dutoit Vallotton Valérie 0000-0002-3469-4237 668630 author Dietrich Pierre-Yves 96532 author Ris Frédéric 53083 author Kossler Thibaud 500516 772 10.1186/s12885-022-09820-w 35840912 1471-2407 PMC9288067 https://bmccancer.biomedcentral.com/articles/10.1186/s12885-022-09820-w Background: Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve cancer treatment. Nevertheless, responsiveness to these treatments is often correlated with the extent of T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor T cell infiltration and, therefore, does not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy has profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immune checkpoint inhibition was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immune checkpoint inhibition have never been tested in these tumors. Methods: Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5 Gy × 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed three weeks after the last pembrolizumab injection. Our clinical trial includes an extensive translational research program involving the transcriptomic and proteomic analysis of tumor and blood samples throughout the course of the treatment. Discussion: Our study is the first clinical trial to combine short-course radiotherapy and immune checkpoint inhibition in rectal cancer, which could potentially result in a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer insights into immunological changes within the tumor and blood and their correlation with patient outcome. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients. Trial registration: This study was registered with www. Clinicaltrial: <a href="https://clinicaltrials.gov/ct2/show/NCT04109755" rel="noopener noreferrer" target="_blank">NCT04109755 </a>. Registration date: June, 2020. Pembrolizumab Radiotherapy Rectal cancer T cell infiltration Antibodies, Monoclonal, Humanized Clinical Trials, Phase II as Topic Humans Immune Checkpoint Inhibitors Neoadjuvant Therapy / adverse effects Proteomics Rectal Neoplasms / drug therapy Rectal Neoplasms / radiotherapy Tumor Microenvironment Dewey 616.0757 Dewey 616 Dewey 616.07 Dewey 617 Swiss National Science Foundation A feasibility study on salvage radiotherapy with adjuvant hyperthermia delivered by MR-guided Transperineal Ultrasound (MRgTUS) for recurrent prostate cancer after radical prostatectomy 182366 CH Projects 57 Département de chirurgie 222 56 Département de médecine 221 137 Département de pathologie et immunologie 21F 62 Département de radiologie et informatique médicale 227 false 562 Transplantation et hépatologie 905 335 Pancréatite aiguë 601 476 Lymphomes MALT et réplication virale 807 223 Groupe Roth Arnaud (oncologie) 285 27 Immunothérapie des cancers 42 BMC cancer 22 1 1a9c14d6-9005-4e43-bb19-7272e711f3e6 Article (Published version) Public Article-scientifique-from-europePmc.pdf 1372243 application/pdf CC BY-4.0 openAccess Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de radiologie et informatique médicale

Title	Published in	Year	Views	Downloads

Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer	BMC cancer	2022	261	269
Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study	Annals of oncology	2005	696	417

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