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.

Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: a methodological review

“… 54 t-tests Change in PRO score between baseline and another timepoint or difference in PRO score between dose cohorts. 25 , 34 , 35 , 58 29 , 38 , 41 , 46 , 48 Fisher's exact test Association between MCID and each dose cohort 45 Survival Analysis Fit model predicting time from inclusion in study until deterioration or grade 3/4 toxicity using a Cox proportional hazards model. 33 PRO: patient-reported outcome; MCID: minimal clinically important difference; HRQoL: health related quality of life.…”

PEGylated Lipid Nanoparticle Formulations: Immunological Safety and Efficiency Perspective

“… 227 , 228 In contrast, Onivyde, a nanoliposomal irinotecan formulation used to treat various solid tumors, failed to show immune-induced side effects in numerous clinical trials (NCT01770353, NCT03524508, and NCT03207724). 224 − 226 2B3-201, a glutathione-PEGylated liposome containing methylprednisolone for the treatment of multiple sclerosis, also did not show immune-induced side effects in a phase I trial with healthy subjects. 238 …”

“…Clinical trials (NCT01485874/NCT02163720) , researching the treatment of ovarian cancer with liposomal doxorubicin formulations, Doxil and Caelyx, respectively, both revealed instances of hypersensitivity. , Another clinical trial (NCT00826085) researching the safety of ThermoDox for the treatment of breast cancer also revealed hypersensitivity as a side effect . Small inhibitory RNA-based nanoparticle formulation, Patisiran, displayed hypersensitivity as well in clinical trials (NCT01961921/NCT03862807) , for the treatment of transthyretin-mediated amyloidosis. , In contrast, Onivyde, a nanoliposomal irinotecan formulation used to treat various solid tumors, failed to show immune-induced side effects in numerous clinical trials (NCT01770353, NCT03524508, and NCT03207724). − 2B3-201, a glutathione-PEGylated liposome containing methylprednisolone for the treatment of multiple sclerosis, also did not show immune-induced side effects in a phase I trial with healthy subjects …”

A Review of Gut Microbiota‐Derived Metabolites in Tumor Progression and Cancer Therapy

“…[112,113] The prodrug irinotecan exerts critical functions in the treatment of various types of cancer, including pancreatic ductal adenocarcinoma and colorectal cancer. [114,115] Its anti-cancer mechanism in humans comprises inhibition of topoisomerase I activity. [116] Topoisomerase I relaxes the DNA supercoil structure accumulated during replication and transcription, ensuring the smooth progress of these biological processes.…”