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.
Lin et al. (Mon,) studied this question.