Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III
Methods: Dose escalation was performed to explore the maximum tolerated dose (MTD) of BR105 monotherapy at 7 dose levels (0.2, 1, 3, 10, 20, 30, 40mg/kg), using a traditional 3+3 design with accelerated titration for the first 2 dose levels. Patients with R/R lymphoid malignancies or advanced solid tumors without standard treatments were enrolled.
Results: As of Jun 15th, 2024, dose-escalation part has completed, and a total of 19 patients were enrolled. The pharmacokinetic analysis of BR105 showed dose dependent decrease of clearance. At dose levels of 10 mg/kg and higher, saturation of Target-Mediated Drug Disposition (TMDD) was achieved, and the half-life remained at 8~10 days. PK-PD modeling of clearance versus dose and monocyte receptor occupancy (RO) versus BR105 concentration were performed to characterize RO in whole body as well as RO in peripheral blood, respectively. Results showed that at doses of 10 mg/kg QW or above, peripheral blood RO reached >97% and whole-body RO reached >86%.
In 7 patients with lymphoid malignancies (DLBCL[n=2], FL, FDCS, AITL, PTCL, cHL[n=1]), 2 partial responses (ORR 28.6%) were achieved at dose levels with ~ 98% peripheral blood RO (AITL-30mg/kg and cHL-40mg/kg), 5 disease controls (DCR 71.4%) were achieved at dose levels with > 85% peripheral blood RO.
Up to 40mg/kg (4 times of the saturated dose), BR105 was well tolerated with no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) has not reached. The frequency of treatment emergent adverse event (TEAE) in patients with lymphoid malignancies were 100%, with 2 (28.57%) ≥Grade 3 (dyspnea, pain), and 1 (14.29%) SAE (pain). The most common TEAEs were interleukin increase in 4 (57.14%), hypokalemia in 3 (42.86%), neutrophil decrease in 3 (42.86%), prothrombin activity increase in 3 (42.86%), leucocyte decrease in 3 (42.86%), anemia in 2 (28.57%), thrombocyte decrease in 2 (28.57%), hyperlipidemia in 2 (28.57%), hyperuricemia in 2 (28.57%), and upper respiratory tract infection in 2 (28.57%) patients. No treatment related adverse events (TRAEs) led to drug discontinuation. No treatment relevant death was reported. One case with upper respiratory tract infection (Grade 2) and one with pain (Grade 3) resulted in delayed drug administration.
Conclusions: These results showed that BR105 exhibited satisfactory receptor occupancy in both peripheral blood and whole-body tissues, leading to promising efficacy and safety profiles in lymphoid malignancies. Further investigation as monotherapy or in combination with other agents are ongoing.
Disclosures: No relevant conflicts of interest to declare.
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