Preliminary results of a first-in-human, Phase 1 study of GLB-002, a novel molecular glue degrader of IKZF1/3, in patients with relapsed or refractory non-Hodgkin lymphoma

Abstract Introduction GLB-002 is a novel cereblon E3 ubiquitin ligase modulator selectively targeting Ikaros (IKZF1) and Aiolos (IKZF3) for degradation. Compared to classical immunomodulatory drugs (IMiDs) and other next-generation IKZF1/3 degraders, GLB-002 possesses improved IKZF1/3 degradation potency, efficacy and selectivity, and therefore is capable of triggering the near-complete degradation of IKZF1/3 in the picomolar concentration range with minimal effect on the protein levels of other common cereblon neosubstrates. In addition, GLB-002 exhibits strong in vitro and in vivo antitumor activities in all preclinical models of non-Hodgkin lymphoma (NHL) that are sensitive or resistant to treatment with IMiDs. Thus, GLB-002 is currently being evaluated as a potential therapy for NHL in an ongoing phase 1 study, GLB-002-01 (NCT06219356). Methods GLB-002-01 is a phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of GLB-002 in patients with relapsed or refractory (R/R) NHL. The study comprises two parts: a phase 1a dose escalation following the 3+3 rule and a phase 1b dose expansion with 3 cohorts: 1) follicular lymphoma (FL)1-3a; 2) large B cell lymphoma (LBCL) or FL3b; 3) other NHL subtypes. Results As of June 13, 2025, a total of 36 patients were enrolled, including 17 patients with FL1-3a, 10 patients with LBCL or FL3b, and 9 patients with other NHL subtypes. In each 28-day treatment cycle, 9 patients were treated with GLB-002 0.5 mg for 14 days on/14 days off (0.5 mg, 14/28), 3 patients with 1.0 mg for 14 days on/14 days off (1.0 mg, 14/28), and 24 patients with 1.0 mg for 10 days on/18 days off (1.0 mg, 10/28). The median age of patients was 60.5 (range 37-79). The median number of prior anticancer therapies was 3 (range 2-8); 17 (47.2%) patients had prior treatment with IMiDs, 4 (11.1%) patients with cell therapy, and 2 (5.6%) patients with hematopoietic stem cell transplantation. Treatment-emergent adverse events (TEAEs) of ≥ grade 3 related to GLB-002 occurred in 20 (55.6%) patients, the most common being neutrophil count decreased (14 [38.9%] patients), white blood cell count decreased (10 [27.8%] patients), lymphocyte count decreased (6 [16.7%] patients), and platelet count decreased (4 [11.1%] patients). Only 1 dose-limiting toxicity (DLT) event (grade 4 platelet count decreased) occurred throughout the whole study as of date. In line with the clinical management of this class of drugs, the hematologic toxicities of GLB-002 were well-controlled through dose reductions and/or interruptions, prophylaxis, and/or treatment with colony-stimulating factors. At the date of data cutoff for analysis, at least 1 cycle of tumor response assessment has been completed in 13 IMiDs-naive and 13 IMiDs-pretreated patients. GLB-002 monotherapy achieved an overall response rate (ORR) of 61.5% (16/26), and durable responses with a maximum duration of response (DOR) of 495 days were observed. In all 13 enrolled patients with prior treatment of lenalidomide or thalidomide, the ORR was 61.5% (8/13, including 5 FL1-3a, 2 LBCL, and 1 marginal zone lymphoma [MZL]). At the potential recommended phase 2 dose (RP2D) of 1.0 mg, 10/28, the ORR was 73.3% (11/15), of which 20.0% (3/15) was complete response (CR) (including 1 LBCL and 2 MZL) and 53.3% (8/15) was partial response (PR) (including 4 FL1-3a, 2 LBCL, 1 MZL, and 1 T-NHL); in patients with indolent NHL (4 FL1-3a and 3 MZL), the ORR was 100.0% (2 CRs and 5 PRs). Human PK analysis revealed rapid absorption (median Tmax= 2 hours) and slow elimination (t1/2 = 24-48 hours) of GLB-002, associated with a dose-dependent increase in plasma concentration across the evaluated dose range. The extent and duration of IKZF1/3 degradation correlated with the dose level and exposure of GLB-002; at 1.0 mg, the maximum degradation of IKZF1/3 was nearly complete. Conclusion GLB-002 monotherapy demonstrated a manageable safety profile and promising antitumor activities in R/R NHL patients, with similar response rate observed in patients who had prior treatment with versus without IMiDs, supporting our therapeutic hypothesis that GLB-002, as a next-generation IKZF1/3 degrader, can overcome resistance to IMiDs. Enrollment for all NHL subtypes in the expansion cohort is still ongoing, and further updated data will be presented.