675P - A phase I study of safety, pharmacokinetics, and pharmacodynamics of SCR-6920, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced malignant tumors

Background

SCR-6920, a highly potent and selective PRMT5 inhibitor, demonstrates anti-tumor effect in multiple tumor models. SCR-6920 observed a better anti-tumor effect and lower target-related hematological toxicity in pre-clinical studies. Evaluation on pharmacokinetics (PK), pharmacodynamics (PD) and safety in clinic were ongoing in the phase I study.

Methods

Patients with advanced malignant tumors were enrolled in this phase I study (NCT05528055) with the guidance of the Bayesian Optimal Interval (BOIN) design for dose escalation. Patients received oral SCR-6920 once daily (QD) on a 21-day cycle. Safety, PK, PD, and preliminary efficacy were evaluated to identify the recommended phase II doses (RP2D).

Results

As of 25 February 2023, twenty-one patients were enrolled and dosed from 10 to 160 mg QD. The most common tumor types were non-small cell lung cancer (NSCLC) (28.6%), ovarian cancer (OC) (23.8%), cervical cancer (23.8%). Seventeen patients (81%) experienced treatment-related adverse events (TRAEs). Most common (≥10%) TRAEs included anaemia (47.6%), white blood cell count decreased (23.8%), hypoalbuminaemia (23.8%), and neutrophil count decreased (23.8%). Grade 3 TRAEs included anaemia (9.5%), alanine transaminas increased (4.8%), aspartate aminotransferase increased (4.8%), lymphocyte count decreased (4.8%), and chronic colitis (4.8%). No dose-limiting toxicity (DLT) and grade 4 or 5 TRAE were reported. Six patients had serious adverse events (SAEs), and only chronic colitis was treatment related. Available PK indicated fast absorption with median T_max less than 1 hour. Concentration-dependent blood-to-plasma partition was observed in clinical led to a non-linear blood and plasma PK from 10 to 160 mg QD. The terminal half-life was <1 day and > 3 days in plasma and blood respectively. The major metabolite SCR-6959 accounted for 30∼80% from SCR-6920. Plasma symmetric dimethyl arginine (SDMA), the enzymatic product of PRMT5 was significantly reduced (inhibitory rate: 52.8%∼77.4%) at steady state.

Conclusions

SCR-6920 had a manageable safety profile and further assessments are ongoing to determine the RP2Ds.

Clinical trial identification

NCT05528055.

Editorial acknowledgement

Legal entity responsible for the study

Shanghai Xianxiang Medical Technology Co., Ltd.

Funding

Has not received any funding.

Disclosure

J. Wu, X. Jiang, J. Chen, G. Yang, W. Song: Financial Interests, Personal and Institutional, Full or part-time Employment: Shanghai Xianxiang Medical Technology Co., Ltd. All other authors have declared no conflicts of interest.