First-In-Human, First-In-Class, Phase I Trial of the Fucosylation Inhibitor SGN-2FF in Patients with Advanced Solid Tumors.
oregon; portland; chiles
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 QD and 2-5 g BID, 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 5/32 patients (16%). Safety measures implemented included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In Part C, despite the safety measures implemented, a thromboembolic event occurred in 1/7 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 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.
Earle A. Chiles Research Institute
Do, Khanh T; Chow, Laura Quan Man; Reckamp, Karen; Sanborn, Rachel E; Burris, Howard; Robert, Francisco; Camidge, D Ross; Steuer, Conor E; Strickler, John H; Weise, Amy; Specht, Jennifer M; Gutierrez, Martin; Haughney, Peter; Hengel, Shawna; Derleth, Christina Louise; and Yap, Timothy A, "First-In-Human, First-In-Class, Phase I Trial of the Fucosylation Inhibitor SGN-2FF in Patients with Advanced Solid Tumors." (2021). Articles, Abstracts, and Reports. 5088.