ACO/ARO/AIO-21 - Capecitabine-based chemoradiotherapy in combination with the IL-1 receptor antagonist anakinra for rectal cancer Patients: A phase I trial of the German rectal cancer study group.
(i)CAFs, (inflammatory) cancer-associated fibroblasts
APR, abdominoperineal resection
Anakinra
CAPS, cryopyrin-associated periodic syndrome
CEA, carcinoembryonic antigen
CMS, consensus classification of molecular subtypes
CRT, chemoradiotherapy
CT, computed tomography
Chemoradiotherapy
DFS, disease-free survival
DLT, dose-limiting toxicity
DRE, digital rectal examination
ECM, extracellular matrix
EMVI, extramural vascular invasion
Fibroblast
GTV, gross tumor volume
Gy, Gray
ICH, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
IL-1, interleukin-1
IMRT, intensity modulated radiotherapy
Interleukin-1
LARC, locally advanced rectal cancer
MRI, magnetic resonance imaging
MTD, maximum tolerated dose
NOM, non-operative management
PDO, patient-derived organoids
RA, receptor antagonist
Rectal cancer
TME, total mesorectal excision
TNT, total-neoadjuvant therapy
TRG, tumor regression grading
VEGF-A, vascular endothelial growth factor A
VMAT, volumetric modulated arc therapy
W&W, watch & wait
bid, bis in die (twice a day)
c/pCR, clinical/pathological complete response
mrCRM, MRI-assessed circumferential resection margin
phase I
Journal
Clinical and translational radiation oncology
ISSN: 2405-6308
Titre abrégé: Clin Transl Radiat Oncol
Pays: Ireland
ID NLM: 101713416
Informations de publication
Date de publication:
May 2022
May 2022
Historique:
received:
21
03
2022
accepted:
04
04
2022
entrez:
22
4
2022
pubmed:
23
4
2022
medline:
23
4
2022
Statut:
epublish
Résumé
Recent advances in the treatment algorithm of locally advanced rectal cancer (LARC) have significantly improved complete response (CR) rates and disease-free survival (DFS), but therapy resistance, with its substantial impact on outcomes and survival, remains a major challenge. Our group has recently unraveled a critical role of interleukin-1α (IL-1α) signaling in activating inflammatory cancer-associated fibroblasts (iCAFs) and mediating radiation-induced senescence, extracellular matrix (ECM) accumulation, and ultimately therapy resistance. We here summarize the recently initiated ACO/ARO/AIO-21 phase I trial, testing the IL-1 receptor antagonist (IL-1 RA) anakinra in combination with fluoropyrimidine-based chemoradiotherapy (CRT) for advanced rectal cancer. The ACO/ARO/AIO-21 is an investigator-driven, prospective, open-labeled phase I drug-repurposing trial assessing the maximum tolerated dose (MTD) of capecitabine administered concurrently to standard preoperative radiotherapy (45 Gy in 25 fractions followed by 9 Gy boost in 5 fractions) in combination with fixed doses of the IL1-RA anakinra (100 mg, days -10 to 30). Capecitabine will be administered using a 3 + 3 dose-escalation design (500 mg/m Based on extensive preclinical research, the ACO/ARO/AIO-21 phase I trial will assess whether the IL-1RA anakinra can be safely combined with fluoropyrimidine-based CRT in rectal cancer. It will further explore the potential of IL-1 inhibition to overcome therapy resistance and improve response rates. A comprehensive translational research program will expand our understanding from a clinical perspective and may help translate the results into a randomized phase II trial.
Identifiants
pubmed: 35449546
doi: 10.1016/j.ctro.2022.04.003
pii: S2405-6308(22)00026-X
pmc: PMC9018120
doi:
Types de publication
Journal Article
Langues
eng
Pagination
99-106Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The trial is sponsored by the LOEWE-Zentrum Frankfurt Cancer Institute (FCI) [III L 5 - 519/03/03.001 – (0015), PI: Emmanouil Fokas]. The authors have no further conflicts of interest to declare.
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