Initial Results of a Phase 1 First-in-Human Study of Cemsidomide (CFT7455), a Novel MonoDACTM Degrader, in Patients with Non-Hodgkin's Lymphoma

Background: Cemsidomide (formerly CFT7455) is a novel, rationally designed, highly potent Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) MonoDACTM cereblon-based degrader. Cemsidomide is highly active in a variety of preclinical models of non-Hodgkin's lymphoma (NHL) and has demonstrated additive or synergistic activity with other agents. Methods: CFT7455-1101 (NCT04756726) is an open-label, phase 1/2, multi-center, first-in-human study evaluating safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of cemsidomide in patients (pts) with multiple myeloma and NHL who have relapsed from or are refractory to standard of care. Eligible B-cell lymphoma pts must have received at least two prior lines of therapy, including an anti-CD20 antibody, and eligible peripheral T-cell lymphoma (PTCL) pts must have received at least one line of therapy with an alkylating agent. The primary objective of the NHL phase 1 portion of the study is to characterize the safety and tolerability of cemsidomide monotherapy and to determine the maximum tolerated dose (MTD) and/or recommended doses for phase 2. Secondary objectives include assessments of antitumor activity according to the Lugano 2014 classification, PK, and PD. Dose escalation is guided by a Bayesian logistic regression model with an initial cohort size of 3-6 pts and a provision for additional pts to be enrolled in expansion cohorts at doses deemed safe. We report initial results from our ongoing cemsidomide study in NHL. Results: As of July 3rd, 2024, 20 pts with NHL (6 B-Cell lymphoma (BCL); 14 with PTCL) were treated with cemsidomide at various doses in the ongoing dose escalation portion of the study. The median age was 66 (range 28-79) and pts had received a median of 3 prior lines of therapy (range 1-14). Pts with PTCL included 5 with PTCL-not otherwise specified (PTCL-NOS), 5 with adult T-cell leukemia/lymphoma (ATLL), 3 with anaplastic large-cell lymphoma (ALCL), and 1 with angioimmunoblastic T-cell lymphoma (AITL). Cemsidomide doses explored in dose-escalation and expansion cohorts included 25 µg MWF (n=3), 50 µg MWF (n=3), 37.5 µg QD (n=9), 62.5 µg QD (n=4), and 100 µg QD (n=1), all on a 14 day on/14 day off dosing schedule. At all dose levels, cemsidomide has resulted in expected degradation of IKZF1 and IKZF3. As of the data cut-off, cemsidomide has been well-tolerated, with no dose-limiting toxicities (DLTs). 60% of pts experienced a grade ≥3 TEAE. Grade 3-4 TEAEs occurring in ≥10% of pts included neutropenia (50%), anemia (10%), maculo-papular rash (10%), and febrile neutropenia (10%). 4 pts had treatment-related SAEs and 1 pt had an AE of maculo-papular rash resulting in treatment discontinuation. The overall response rate among the 20 pts treated in dose escalation and expansion cohorts is 25% (2 CRs and 3 PRs). Among the 14 PTCL pts, 29% (4/14) have responded with 2 CRs (one each in AITL and ALCL) and 2 PRs (one each in PTCL-NOS and ATLL). Conclusions: Initial results from this ongoing phase 1 trial of cemsidomide in pts with NHL demonstrate that cemsidomide produces responses in BCL and PTCL with favorable tolerability as a single agent, with a 29% response rate in a difficult-to-treat relapsed/refractory PTCL population. As anticipated, grade 3-4 toxicities consist largely of myelosuppression, which has been manageable. Cemsidomide may have utility in the management of PTCL, a lymphoma with limited treatment options. Dose escalation will continue until an MTD and/or the recommended phase 2 doses are identified. Updated data will be presented at the conference.