cemsidomide (CFT7455)

P1/2, N=158, Recruiting, C4 Therapeutics, Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes of non-Hodgkin's lymphoma (NHL)...Clinically, immunomodulatory drugs have shown activity as single agents and when used in combination with several classes of targeted therapies, such as rituximab, in both first line and relapsed/refractory NHL subtypes.We previously described the preclinical characterization of CFT7455 as a novel IKZF1/3 degrader with 800-1600-fold increased potency over pomalidomide in CRBN binding and cellular IKZF1 degradation assays...Combination studies were conducted, dosing CFT7455 in combination with rituximab, ibrutinib, or the HDAC inhibitor romidepsin in several models of NHL...Synergistic activity was also observed with the combination of CFT7455 and romidepsin in two models of anaplastic large cell lymphoma (ALCL). In conclusion, CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent and combination antitumor activity in DLBCL, ALCL, and MCL models, supporting clinical investigation of CFT7455 for NHL.

Early observations from the FIH clinical trial (NCT04756726) along with supporting translational studies are presented here. Pre-clinical studies comparing CFT7455 and CC-92480 in both in vitro and xenograft models were performed. While CFT7455 showed clinical benefit at 50 ug with deep target degradation, neutropenia was dose limiting. PK/PD modeling suggests alternative dosing regimens may result in increased tolerability with preserved efficacy, and evaluation of them is underway. Updated results will be presented at the meeting.

Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned...Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody...Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726 , enrollment is ongoing.

P1/2, N=158, Recruiting, C4 Therapeutics, Inc. | Not yet recruiting --> Recruiting

IMiDs (e.g. pomalidomide (pom)) degrade IKZF1/3 via interaction with the cereblon (CRBN) E3 ligase and have shown promise in NHL. CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent antitumor activity in DLBCL, ALCL, and MCL models including those insensitive to pom. These results support clinical investigation of CFT7455 for NHL.

IMiDs (lenalidomide[len], pomalidomide[pom]) are effective therapies for treatment of MM and promote degradation of IKZF1/3 via their interaction with CRL4-CRBN E3 ligase. Importantly, CFT7455 retains activity in models resistant or insensitive to IMiDs. These results warrant investigation of CFT7455 as a therapeutic approach for MM and a clinical study is planned.

P1/2, N=158, Not yet recruiting, C4 Therapeutics, Inc.