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 microbiom...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-19401-3 |
| _version_ | 1798004465193713664 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jun Gong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T12:24:11Z |
| format | Article |
| id | doaj.art-e263745a6ab941d78e370e228fec8e54 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T12:24:11Z |
| publishDate | 2022-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e263745a6ab941d78e370e228fec8e542022-12-22T04:24:01ZengNature PortfolioScientific Reports2045-23222022-09-0112111110.1038/s41598-022-19401-3Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinomaJun Gong0Shant Thomassian1Sungjin Kim2Gillian Gresham3Natalie Moshayedi4Jason Y. Ye5Julianne C. Yang6Jonathan P. Jacobs7Simon Lo8Nick Nissen9Srinivas Gaddam10Mourad Tighiouart11Arsen Osipov12Andrew Hendifar13Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterThe Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of CaliforniaThe Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of CaliforniaThe Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterAbstract 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.https://doi.org/10.1038/s41598-022-19401-3 |
| spellingShingle | 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 Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma Scientific Reports |
| title | Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma |
| title_full | Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma |
| title_fullStr | Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma |
| title_short | Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma |
| title_sort | phase i trial of bermekimab with nanoliposomal irinotecan and 5 fluorouracil folinic acid in advanced pancreatic ductal adenocarcinoma |
| url | https://doi.org/10.1038/s41598-022-19401-3 |
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