TY - JOUR
T1 - A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors
AU - Harding, James J.
AU - Garrido-Laguna, Ignacio
AU - Chen, Xiaoying
AU - Basu, Cynthia
AU - Dowlati, Afshin
AU - Forgie, Alison
AU - Hooper, Andrea T.
AU - Kamperschroer, Cris
AU - Max, Steven I.
AU - Moreau, Allison
AU - Shannon, Megan
AU - Wong, Gilbert Y.
AU - Hong, David S.
N1 - Publisher Copyright:
Copyright © 2022 Harding, Garrido-Laguna, Chen, Basu, Dowlati, Forgie, Hooper, Kamperschroer, Max, Moreau, Shannon, Wong and Hong.
PY - 2022/4/14
Y1 - 2022/4/14
N2 - 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 Registration: URL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631.
AB - 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 Registration: URL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631.
KW - cytokine release syndrome (CRS)
KW - immunotherapy
KW - P-cadherin
KW - phase 1
KW - solid tumor
KW - T-cell–redirecting bispecific antibody
UR - http://www.scopus.com/inward/record.url?scp=85128990569&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128990569&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2022.845417
DO - 10.3389/fimmu.2022.845417
M3 - Article
C2 - 35493516
AN - SCOPUS:85128990569
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 845417
ER -