Abstract PS4-06-13: Pharmacokinetic Evaluation of MBQ-167 a Dual Rac/Cdc42 Inhibitor in Advanced Breast Cancer Patients

Abstract MBQ-167 is a first-in-class dual inhibitor of Rac and Cdc42 GTPases with potent preclinical anti-metastatic activity and is currently under evaluation in a Phase 1 clinical trial (NCT06075810) in patients with advanced breast cancer. This study aimed to characterize the pharmacokinetic (PK) profile of MBQ-167 and its active metabolite M6 in patients treated with 20 mg, 40 mg and 80 mg BID doses (cohorts 0, 1 and 2, respectively). Plasma concentration-time data were analyzed from eight patients using non-compartmental analysis. MBQ-167 was rapidly absorbed with a median Tmax of 1–4 hours and a Cmax ranging from 139 to 573 ng/mL (20 mg BID), 520 to 843 ng/mL (40 mg BID) and 578 to 688 ng/mL (80 mg BID). The elimination half-life (t½) of MBQ-167 was approximately 3–4.5 hours, and the mean residence time (MRT) was <7 hours. Dose-normalized systemic exposure (AUC/D) did not increase proportionally with dose, suggesting a possible reduction in bioavailability at higher doses, potentially due to enterohepatic recycling or saturation of absorption. Importantly, there was no evidence of systemic overexposure or meaningful accumulation (Rac < 2.0) of MBQ-167 or M6, indicating a favorable safety margin. Volume of distribution (Vdss) exceeded 30L for both compounds, reflecting extensive tissue distribution consistent with their lipophilicity. M6 demonstrated rapid formation and elimination with t½ values ranging from 3.1 to 4.4 hours, further supporting efficient metabolic conversion. These findings confirm that MBQ-167 exhibits linear PK at clinically relevant doses with manageable exposure and clearance. The observed pharmacokinetics support continued clinical development and provided essential dosing guidance for Phase 2 trials. Further analyses with additional cohorts will be presented up to 400 mg BID. Citation Format: J. F. Rodriguez-Orengo, J. Duconge, M. Acosta, J. Wang, D. Yardley, S. Dharmawardhane, N. Sankar. Pharmacokinetic Evaluation of MBQ-167 a Dual Rac/Cdc42 Inhibitor in Advanced Breast Cancer Patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-13.