Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial
Abstract In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-02116-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594402289123328 |
|---|---|
| author | Marion Thibaudin Nicolas Roussot Chloé Burlot Antonin Schmitt Julie Vincent Zoé Tharin Leila Bengrine Hélène Bellio Aurélie Bertaut Léa Hampe Susy Daumoine Emilie Rederstorff Morgane Peroz Titouan Huppe Valentin Derangère David Rageot John Simard Caroline Truntzer Jean David Fumet Francois Ghiringhelli |
| author_facet | Marion Thibaudin Nicolas Roussot Chloé Burlot Antonin Schmitt Julie Vincent Zoé Tharin Leila Bengrine Hélène Bellio Aurélie Bertaut Léa Hampe Susy Daumoine Emilie Rederstorff Morgane Peroz Titouan Huppe Valentin Derangère David Rageot John Simard Caroline Truntzer Jean David Fumet Francois Ghiringhelli |
| author_sort | Marion Thibaudin |
| collection | DOAJ |
| description | Abstract In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1–5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC. |
| format | Article |
| id | doaj-art-46b83cfaaced4e0fa5439cd6a2b2aba1 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-46b83cfaaced4e0fa5439cd6a2b2aba12025-01-19T12:40:27ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-01-0110111310.1038/s41392-024-02116-4Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trialMarion Thibaudin0Nicolas Roussot1Chloé Burlot2Antonin Schmitt3Julie Vincent4Zoé Tharin5Leila Bengrine6Hélène Bellio7Aurélie Bertaut8Léa Hampe9Susy Daumoine10Emilie Rederstorff11Morgane Peroz12Titouan Huppe13Valentin Derangère14David Rageot15John Simard16Caroline Truntzer17Jean David Fumet18Francois Ghiringhelli19Centre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicinePharmacy Department, Centre Georges-François Leclerc, 1 rue Pr MarionPharmacy Department, Centre Georges-François Leclerc, 1 rue Pr MarionDepartment of Medical Oncology, Centre Georges-François Leclerc, 1 rue du Professeur MarionDepartment of Medical Oncology, Centre Georges-François Leclerc, 1 rue du Professeur MarionDepartment of Medical Oncology, Centre Georges-François Leclerc, 1 rue du Professeur MarionDepartment of Medical Oncology, Centre Georges-François Leclerc, 1 rue du Professeur MarionMethodolgy and biostatistics unit, GF Leclerc CenterCentre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicineClinical research center, Centre Georges-François LeclercCentre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicineXBiotechCentre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicineCentre de Recherche INSERM Center for Translational and Molecular MedicineAbstract In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1–5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC.https://doi.org/10.1038/s41392-024-02116-4 |
| spellingShingle | Marion Thibaudin Nicolas Roussot Chloé Burlot Antonin Schmitt Julie Vincent Zoé Tharin Leila Bengrine Hélène Bellio Aurélie Bertaut Léa Hampe Susy Daumoine Emilie Rederstorff Morgane Peroz Titouan Huppe Valentin Derangère David Rageot John Simard Caroline Truntzer Jean David Fumet Francois Ghiringhelli Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial Signal Transduction and Targeted Therapy |
| title | Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial |
| title_full | Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial |
| title_fullStr | Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial |
| title_full_unstemmed | Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial |
| title_short | Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial |
| title_sort | safety and efficacy of trifluridine tipiracil bevacizumab plus xb2001 anti il 1α antibody a single center phase 1 trial |
| url | https://doi.org/10.1038/s41392-024-02116-4 |
| work_keys_str_mv | AT marionthibaudin safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT nicolasroussot safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT chloeburlot safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT antoninschmitt safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT julievincent safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT zoetharin safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT leilabengrine safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT helenebellio safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT aureliebertaut safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT leahampe safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT susydaumoine safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT emilierederstorff safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT morganeperoz safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT titouanhuppe safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT valentinderangere safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT davidrageot safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT johnsimard safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT carolinetruntzer safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT jeandavidfumet safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial AT francoisghiringhelli safetyandefficacyoftrifluridinetipiracilbevacizumabplusxb2001antiil1aantibodyasinglecenterphase1trial |