Posted: Wednesday, April 27, 2022
A first-in-human phase I/II study, performed by Sagar Lonial, MD, FACP, of Emory University Winship Cancer Institute, Atlanta, and colleagues, evaluated the efficacy of CFT7455—a novel Ikaros family zinc finger protein 1/3 (IKZF1/3) degrader—in multiple myeloma. CFT7455 showed clinical benefit with deep target degradation, and pharmacologic modeling suggests alternative dosing regimens may increase tolerability and efficacy. These results were presented during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract CT186/11).
“Early pharmacodynamic data demonstrates deep persistent degradation of IKZF3 and serum free light chain reduction (up to 72%) in response to treatment,” concluded the study authors. “Stable disease has been observed in 34 patients, suggesting clinical benefit.”
This open-label, phase I/II study enrolled patients with heavily pretreated relapsed or refractory multiple myeloma. Participants were administered a starting dose of 50 μg once daily for 21 days on and 7 days off.
Both CFT7455 and CC-92480—another Ikaros degrader— demonstrated similar cereblon binding profiles and IKZF1/3 degradation kinetics in vitro. A dose of 100 μg/kg of CFT7455 in the National Cancer Institute–H929 xenograft model demonstrated durable tumor regression, whereas 1,000 μg of CC-92480 showed tumor stasis; a systemic model of multiple myeloma yielded similar results. CFT7455 was significantly more effective than CC-92480 in maintaining IKZF3 degradation (65% vs. 6%) 48 hours post-dose.
Levels of CFT7455 were high in tumors 48 hours post-dose, whereas CC-92480 levels were undetectable in tumor and plasma. In cohort A, five patients with heavily pretreated multiple myeloma received CFT7455 monotherapy; four patients received three cycles, and two patients received five cycles. Notably, grade 4 neutropenia was reported in three patients but without infection or fever. Furthermore, a two- to four-fold accumulation in plasma CFT7455 exposure at steady state was observed.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.