TY - JOUR
T1 - Phase 1 dose-escalation study of SEA-CD40
T2 - a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas
AU - Coveler, Andrew L.
AU - Smith, David C.
AU - Phillips, Tycel
AU - Curti, Brendan D.
AU - Goel, Sanjay
AU - Mehta, Amitkumar N.
AU - Kuzel, Timothy M.
AU - Markovic, Svetomir N.
AU - Rixe, Olivier
AU - Bajor, David L.
AU - Gajewski, Thomas F.
AU - Gutierrez, Martin
AU - Lee, Hun Ju
AU - Gopal, Ajay K.
AU - Caimi, Paolo
AU - Heath, Elisabeth I.
AU - Thompson, John A.
AU - Ansari, Sahar
AU - Jacquemont, Celine
AU - Topletz-Erickson, Ariel
AU - Zhou, Peigen
AU - Schmitt, Michael W.
AU - Grilley-Olson, Juneko E.
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023/6/29
Y1 - 2023/6/29
N2 - Background SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG 1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating Fc?3RIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. Methods SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 μg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. Results A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 μg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. Conclusions SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. Trial registration number NCT02376699.
AB - Background SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG 1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating Fc?3RIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. Methods SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 μg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. Results A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 μg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. Conclusions SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. Trial registration number NCT02376699.
KW - antibodies, neoplasm
KW - head and neck neoplasms
KW - immunotherapy
KW - lung neoplasms
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U2 - 10.1136/jitc-2022-005584
DO - 10.1136/jitc-2022-005584
M3 - Article
C2 - 37385724
AN - SCOPUS:85164229410
SN - 2051-1426
VL - 11
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 6
M1 - 005584
ER -