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

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, 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

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.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Study schema.
Figure 2
Figure 2
Kaplan–Meier estimates of the probability of progression-free survival (PFS) for evaluable patients receiving intervention. Median PFS is 7.66 months (95% CI 4.34–12.70) with an estimated 12-month PFS rate of 31.25% (95% CI: 11.39–53.65) (top). Kaplan–Meier estimates of the probability of overall survival (OS) for evaluable patients receiving intervention. Median OS is 9.85 months (95% CI 7.04–16.41) with an estimated 12-month OS rate of 43.75% (95% CI 19.81–65.56) (bottom).
Figure 3
Figure 3
Plot showing Log2(fold-change) of bacterial genera abundance in samples from patients with increased IL-1α levels post-intervention compared to samples from patients with reduced IL-1α levels post-intervention. Each dot represents one bacterial genus and is colored by phylum and sized according to average relative abundance.

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