TY - JOUR
T1 - First-In-Human, First-In-Class, Phase I Trial of the Fucosylation Inhibitor SGN-2FF in Patients with Advanced Solid Tumors
AU - Do, Khanh T.
AU - Chow, Laura Quan Man
AU - Reckamp, Karen
AU - Sanborn, Rachel E.
AU - Burris, Howard
AU - Robert, Francisco
AU - Camidge, D. Ross
AU - Steuer, Conor E.
AU - Strickler, John H.
AU - Weise, Amy
AU - Specht, Jennifer M.
AU - Gutierrez, Martin
AU - Haughney, Peter
AU - Hengel, Shawna
AU - Derleth, Christina Louise
AU - Yap, Timothy A.
N1 - Publisher Copyright:
© AlphaMed Press; the data published online to support this summary is the property of the authors.
PY - 2021/11
Y1 - 2021/11
N2 - Lessons Learned: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination. Background: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors. Methods: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab. Results: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1–15 g once daily (QD) and 2–5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1–2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2–5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation. Conclusion: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination.
AB - Lessons Learned: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination. Background: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors. Methods: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab. Results: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1–15 g once daily (QD) and 2–5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1–2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2–5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation. Conclusion: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination.
KW - Clinical trials
KW - Fucosylation inhibitor
KW - Immunotherapy
KW - SGN-2FF
KW - Small molecule agents
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U2 - 10.1002/onco.13911
DO - 10.1002/onco.13911
M3 - Article
C2 - 34288257
AN - SCOPUS:85115318198
SN - 1083-7159
VL - 26
SP - 925-e1918
JO - Oncologist
JF - Oncologist
IS - 11
ER -