A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors
P-cadherin is a cell-cell adhesion molecule that is overexpressed in several solid tumors. PF-06671008 is a T-cell–redirecting bispecific antibody that engages both P-cadherin on tumors and CD3ϵ on T cells and induces antitumor activity in preclinical models. We conducted a phase 1, open-label, firs...
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.845417/full |
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| author | James J. Harding Ignacio Garrido-Laguna Xiaoying Chen Cynthia Basu Afshin Dowlati Alison Forgie Andrea T. Hooper Cris Kamperschroer Steven I. Max Steven I. Max Allison Moreau Megan Shannon Gilbert Y. Wong David S. Hong |
| author_facet | James J. Harding Ignacio Garrido-Laguna Xiaoying Chen Cynthia Basu Afshin Dowlati Alison Forgie Andrea T. Hooper Cris Kamperschroer Steven I. Max Steven I. Max Allison Moreau Megan Shannon Gilbert Y. Wong David S. Hong |
| author_sort | James J. Harding |
| collection | DOAJ |
| description | P-cadherin is a cell-cell adhesion molecule that is overexpressed in several solid tumors. PF-06671008 is a T-cell–redirecting bispecific antibody that engages both P-cadherin on tumors and CD3ϵ on T cells and induces antitumor activity in preclinical models. We conducted a phase 1, open-label, first-in-human, dose-escalation study to characterize the safety and tolerability of PF-06671008, towards determining the recommended phase 2 dose. Adult patients with treatment-refractory solid tumors received PF-06671008 (1.5–400 ng/kg) as a weekly intravenous (IV) infusion on a 21-day/3-week cycle. Parallel cohorts evaluated dosing via subcutaneous injection (SC) or an IV-prime dose. Of the 27 patients enrolled in the study, 24 received PF-06671008 IV in escalating doses, two received SC, and one IV-prime. A dose-limiting toxicity of cytokine release syndrome (CRS) occurred in the 400-ng/kg IV group, prompting evaluation of SC and IV-prime schedules. In all, 25/27 patients who received PF-06671008 reported at least one treatment-related adverse event (TRAE); the most common were CRS (21/27), decreased lymphocyte count (9/27), and hypophosphatemia (8/27). Seven patients permanently discontinued treatment due to adverse events and no treatment-related deaths occurred. Cytokine peak concentrations and CRS grade appeared to positively correlate with Cmax. Although the study was terminated due to limited antitumor activity, it provides important insights into understanding and managing immune-related adverse events resulting from this class of molecules.Clinical Trial RegistrationURL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631. |
| first_indexed | 2024-12-10T13:18:32Z |
| format | Article |
| id | doaj.art-cbbc152e331a4efbaff13402339432fe |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T13:18:32Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-cbbc152e331a4efbaff13402339432fe2022-12-22T01:47:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-04-011310.3389/fimmu.2022.845417845417A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid TumorsJames J. Harding0Ignacio Garrido-Laguna1Xiaoying Chen2Cynthia Basu3Afshin Dowlati4Alison Forgie5Andrea T. Hooper6Cris Kamperschroer7Steven I. Max8Steven I. Max9Allison Moreau10Megan Shannon11Gilbert Y. Wong12David S. Hong13Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, United StatesHuntsman Cancer Institute at University of Utah, Salt Lake City, UT, United StatesEarly Oncology Development and Clinical Research, Worldwide Research and Development, Pfizer, San Diego, CA, United StatesEarly Oncology Development and Clinical Research, Worldwide Research and Development, Pfizer, San Diego, CA, United StatesUniversity Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, United StatesEarly Clinical Development and Oncology Research, Worldwide Research and Development, Pfizer, San Francisco, CA, United StatesOncology Research and Development, Pfizer, Inc., Pearl River, NY, United StatesDrug Safety Research and Development, Worldwide Research and Development, Pfizer, Groton, CT, United StatesEarly Oncology Development and Clinical Research, Worldwide Research and Development, Pfizer, San Diego, CA, United StatesJanssen Pharmaceutical Companies of Johnson & Johnson, Philadelphia, PA, United StatesEarly Oncology Development and Clinical Research, Worldwide Research and Development, Pfizer, San Diego, CA, United StatesEarly Oncology Development and Clinical Research, Worldwide Research and Development, Pfizer, San Diego, CA, United StatesEarly Clinical Development and Oncology Research, Worldwide Research and Development, Pfizer, San Francisco, CA, United StatesDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesP-cadherin is a cell-cell adhesion molecule that is overexpressed in several solid tumors. PF-06671008 is a T-cell–redirecting bispecific antibody that engages both P-cadherin on tumors and CD3ϵ on T cells and induces antitumor activity in preclinical models. We conducted a phase 1, open-label, first-in-human, dose-escalation study to characterize the safety and tolerability of PF-06671008, towards determining the recommended phase 2 dose. Adult patients with treatment-refractory solid tumors received PF-06671008 (1.5–400 ng/kg) as a weekly intravenous (IV) infusion on a 21-day/3-week cycle. Parallel cohorts evaluated dosing via subcutaneous injection (SC) or an IV-prime dose. Of the 27 patients enrolled in the study, 24 received PF-06671008 IV in escalating doses, two received SC, and one IV-prime. A dose-limiting toxicity of cytokine release syndrome (CRS) occurred in the 400-ng/kg IV group, prompting evaluation of SC and IV-prime schedules. In all, 25/27 patients who received PF-06671008 reported at least one treatment-related adverse event (TRAE); the most common were CRS (21/27), decreased lymphocyte count (9/27), and hypophosphatemia (8/27). Seven patients permanently discontinued treatment due to adverse events and no treatment-related deaths occurred. Cytokine peak concentrations and CRS grade appeared to positively correlate with Cmax. Although the study was terminated due to limited antitumor activity, it provides important insights into understanding and managing immune-related adverse events resulting from this class of molecules.Clinical Trial RegistrationURL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631.https://www.frontiersin.org/articles/10.3389/fimmu.2022.845417/fullP-cadherinsolid tumorT-cell–redirecting bispecific antibodyimmunotherapyphase 1cytokine release syndrome (CRS) |
| spellingShingle | James J. Harding Ignacio Garrido-Laguna Xiaoying Chen Cynthia Basu Afshin Dowlati Alison Forgie Andrea T. Hooper Cris Kamperschroer Steven I. Max Steven I. Max Allison Moreau Megan Shannon Gilbert Y. Wong David S. Hong A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors Frontiers in Immunology P-cadherin solid tumor T-cell–redirecting bispecific antibody immunotherapy phase 1 cytokine release syndrome (CRS) |
| title | A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors |
| title_full | A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors |
| title_fullStr | A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors |
| title_full_unstemmed | A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors |
| title_short | A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors |
| title_sort | phase 1 dose escalation study of pf 06671008 a bispecific t cell engaging therapy targeting p cadherin in patients with advanced solid tumors |
| topic | P-cadherin solid tumor T-cell–redirecting bispecific antibody immunotherapy phase 1 cytokine release syndrome (CRS) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.845417/full |
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