Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma.

Abstract

In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (-3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (-0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome.Clinical trials registration: NCT03207724 05/07/2017.

• Authors: Jun Gong, Shant Thomassian, Sungjin Kim, Gillian Gresham, Natalie Moshayedi, Jason Y Ye, Julianne C Yang, Jonathan P Jacobs, Simon Lo, Nick Nissen, Srinivas Gaddam, Mourad Tighiouart, Arsen Osipov, Andrew Hendifar
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 15013 (Sep 02 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 36056179 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• Vascular Endothelial Growth Factor A
• Irinotecan
• bermekimab
• Leucovorin
• Fluorouracil

Topics

• Adenocarcinoma (drug therapy)
• Antibodies, Monoclonal, Humanized (adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Bayes Theorem
• Fluorouracil (therapeutic use)
• Humans
• Irinotecan
• Leucovorin (therapeutic use)
• Pancreatic Neoplasms (drug therapy, pathology)
• Vascular Endothelial Growth Factor A