CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours
Abstract Background Dual programmed cell death protein (ligand)-1 (PD-[L]1) and lymphocyte-activation gene-3 (LAG-3) blockade has demonstrated improved anti-tumour response in some advanced solid tumours. CITRINO, a two-part, Phase 1 dose-escalation study, evaluated encelimab (TSR-033; novel anti-LA...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s44276-024-00118-x |
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| author | J. Randolph Hecht Jean-Marie Michot David Bajor Amita Patnaik Ki Y. Chung Judy Wang Gerald Falchook James M. Cleary Richard Kim Anuradha Krishnamurthy Omkar Marathe Hagop Youssoufian Catherine Ellis Angela Waszak Srimoyee Ghosh Hailei Zhang Kaitlin Yablonski Shruti D. Shah Ivan Diaz-Padilla Susanna Ulahannan |
| author_facet | J. Randolph Hecht Jean-Marie Michot David Bajor Amita Patnaik Ki Y. Chung Judy Wang Gerald Falchook James M. Cleary Richard Kim Anuradha Krishnamurthy Omkar Marathe Hagop Youssoufian Catherine Ellis Angela Waszak Srimoyee Ghosh Hailei Zhang Kaitlin Yablonski Shruti D. Shah Ivan Diaz-Padilla Susanna Ulahannan |
| author_sort | J. Randolph Hecht |
| collection | DOAJ |
| description | Abstract Background Dual programmed cell death protein (ligand)-1 (PD-[L]1) and lymphocyte-activation gene-3 (LAG-3) blockade has demonstrated improved anti-tumour response in some advanced solid tumours. CITRINO, a two-part, Phase 1 dose-escalation study, evaluated encelimab (TSR-033; novel anti-LAG-3) monotherapy and in combination in patients with advanced/metastatic solid tumours. Methods Part 1 (P1) involved dose escalation (20–720 mg Q2W) of encelimab as monotherapy (P1A/B) and with dostarlimab (500 mg Q3W) in patients with previously treated advanced/metastatic solid tumours (P1C). P2 involved cohort expansion in patients with anti-PD-(L)1-naïve microsatellite stable advanced/metastatic colorectal cancer with recommended phase 2 dose (RP2D) of encelimab with dostarlimab as third/fourth-line therapy (P2A), or with dostarlimab, bevacizumab and mFOLFOX6/FOLFIRI as second-line therapy (P2B). Objectives included RP2D, safety/tolerability, efficacy, pharmacokinetics/pharmacodynamics, and exploratory biomarkers. Results Maximum tolerated encelimab dose was not reached; 720 mg Q2W was used for P2 plus dostarlimab 1000 mg Q6W. One dose-limiting toxicity occurred (Grade 2 myasthenia gravis; P1A). No clinical responses were observed in P1; 1 (3%) and 4 (17%) patients achieved partial response in P2A and 2B, respectively. Conclusions Encelimab has a manageable safety profile as a monotherapy and in tested combinations; however, anti-tumour activity was limited. Clinical trial registration NCT03250832. |
| format | Article |
| id | doaj-art-6c0b259adc2d4f718bb230fe2fa55d61 |
| institution | DOAJ |
| issn | 2731-9377 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | BJC Reports |
| spelling | doaj-art-6c0b259adc2d4f718bb230fe2fa55d612025-08-20T03:04:11ZengNature PortfolioBJC Reports2731-93772025-02-013111110.1038/s44276-024-00118-xCITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumoursJ. Randolph Hecht0Jean-Marie Michot1David Bajor2Amita Patnaik3Ki Y. Chung4Judy Wang5Gerald Falchook6James M. Cleary7Richard Kim8Anuradha Krishnamurthy9Omkar Marathe10Hagop Youssoufian11Catherine Ellis12Angela Waszak13Srimoyee Ghosh14Hailei Zhang15Kaitlin Yablonski16Shruti D. Shah17Ivan Diaz-Padilla18Susanna Ulahannan19David Geffen School of Medicine, University of California Los Angeles (UCLA)Département d’Innovation Thérapeutique et d’Essais Précoces, Institut de Cancérologie Gustave RoussyDepartment of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical CenterSTART San AntonioDepartment of Medicine, Prisma Health Cancer InstituteDrug Development Unit, Florida Cancer Specialists/Sarah Cannon Research InstituteDrug Development Unit, Sarah Cannon Research Institute at HealthONEDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, H. Lee Moffitt Cancer CenterDepartment of Medicine, Roswell Park Comprehensive Cancer CenterThe Oncology Institute of Hope and InnovationOncology Clinical Development, GSKOncology Clinical Development, GSKOncology Clinical Development, GSKOncology Clinical Development, GSKOncology Clinical Development, GSKOncology Clinical Development, GSKOncology Clinical Development, GSKOncology Clinical Development, GSKStephenson Cancer Center, University of OklahomaAbstract Background Dual programmed cell death protein (ligand)-1 (PD-[L]1) and lymphocyte-activation gene-3 (LAG-3) blockade has demonstrated improved anti-tumour response in some advanced solid tumours. CITRINO, a two-part, Phase 1 dose-escalation study, evaluated encelimab (TSR-033; novel anti-LAG-3) monotherapy and in combination in patients with advanced/metastatic solid tumours. Methods Part 1 (P1) involved dose escalation (20–720 mg Q2W) of encelimab as monotherapy (P1A/B) and with dostarlimab (500 mg Q3W) in patients with previously treated advanced/metastatic solid tumours (P1C). P2 involved cohort expansion in patients with anti-PD-(L)1-naïve microsatellite stable advanced/metastatic colorectal cancer with recommended phase 2 dose (RP2D) of encelimab with dostarlimab as third/fourth-line therapy (P2A), or with dostarlimab, bevacizumab and mFOLFOX6/FOLFIRI as second-line therapy (P2B). Objectives included RP2D, safety/tolerability, efficacy, pharmacokinetics/pharmacodynamics, and exploratory biomarkers. Results Maximum tolerated encelimab dose was not reached; 720 mg Q2W was used for P2 plus dostarlimab 1000 mg Q6W. One dose-limiting toxicity occurred (Grade 2 myasthenia gravis; P1A). No clinical responses were observed in P1; 1 (3%) and 4 (17%) patients achieved partial response in P2A and 2B, respectively. Conclusions Encelimab has a manageable safety profile as a monotherapy and in tested combinations; however, anti-tumour activity was limited. Clinical trial registration NCT03250832.https://doi.org/10.1038/s44276-024-00118-x |
| spellingShingle | J. Randolph Hecht Jean-Marie Michot David Bajor Amita Patnaik Ki Y. Chung Judy Wang Gerald Falchook James M. Cleary Richard Kim Anuradha Krishnamurthy Omkar Marathe Hagop Youssoufian Catherine Ellis Angela Waszak Srimoyee Ghosh Hailei Zhang Kaitlin Yablonski Shruti D. Shah Ivan Diaz-Padilla Susanna Ulahannan CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours BJC Reports |
| title | CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours |
| title_full | CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours |
| title_fullStr | CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours |
| title_full_unstemmed | CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours |
| title_short | CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours |
| title_sort | citrino phase 1 dose escalation study of anti lag 3 antibody encelimab alone or in combination with anti pd 1 dostarlimab in patients with advanced metastatic solid tumours |
| url | https://doi.org/10.1038/s44276-024-00118-x |
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