Background Immune checkpoint inhibitors (ICI), such as ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4; CTLA-4) or nivolumab (anti-programmed cell death protein 1; PD-1) have been proven to be an effective strategy in solid cancers. Nevertheless, ICI seem not to be effective in microsatellite stable (MSS) tumors, as those potentially lack an immunogenic priming. Radiotherapy is capable to induce an immunogenic cell death (ICD) and subsequently an immunogenic tumor immune microenvironment (TIME). Thus, the pro-inflammatory effect of radiotherapy might restore the susceptibility of MSS tumors to ICI, leading to more pronounced tumor shrinkage, as well as to an effective anti-tumor immune response.
Material and Methods In total 80 patients with a locally advanced rectal cancer (LARC) will be randomly assigned in a 30:50 ratio, to receive either standard of care (SOC) neoadjuvant chemoradiotherapy alone (CRT; 50 Gy in 2 Gy fractions with capecitabine 1650 mg/m2/d over 25 working days) or concomitant with a single dose of ipilimumab 1 mg/kg on day 7 following sequentially 3 cycles of nivolumab 3 mg/kg Q2W starting on day 14. Patients will undergo surgery within 10 to 12 weeks post CRT. The primary endpoint is safety, tolerability and feasibility assessed by the latest Clavien-Dindo classification of surgical complications and the common terminology criteria of adverse events (CTCAE).
Results ClinicalTrials. gov identifier: NCT04124601. Serial liquid (plasma, serum, peripheral blood mononuclear cells) and tissue biopsies will be taken sequentially before, during and after neoadjuvant therapy. Secondary objectives are radiographic (mrTRG) and pathological (TRG) therapy response. Immune cell infiltrate of resected specimen, as well as genomic, transcriptomic, epigenomic and proteomic pattern of sequential liquid and tissue biopsies will be correlated with therapy response and clinical outcome.
Conclusion This is the first in human study, which uses neoadjuvant CRT in LARC patients with concomitant ipilimumab and nivolumab, applied in a sequential approach. A detailed understanding of therapy induced changes during neoadjuvant CRT with concomitant ICI in a human translation setting will allow the application of radiotherapy as a part of novel immunotherapeutic concept. This is an investigator-initiated trial (IIT), which received a research grant and the study medications from Bristol-Myers Squibb (BMS).
Disclosure Information J. Laengle: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; IIT, Research Grant & Study Medication from BMS. I. Kuehrer: None. D. Pils: None. J. Kabiljo: None. K. Wöran: None. J. Stift: None. F. Herbst: None. B. Dauser: None. M. Monschein: None. P. Razek: None. S. Haegele: None. M. Herac: None. W. Hulla: None. C. Bitterman: None. F. Laengle: None. D. Tamandl: None. J. Widder: None. R. Schmid: None. M. Bergmann: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; IIT, Research Grant & Study Medication from BMS.
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