A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations

• Published in: ESMO open Vol. 9; no. 4; p. 102961
• Main Authors: Rodon, J., Rodriguez, E., Maitland, M.L., Tsai, F.Y.-C., Socinski, M.A., Berlin, J.D., Thomas, J.S., Al Baghdadi, T., Wang, I.-M., Guo, C., Golmakani, M., Clark, L.N., Gazdoiu, M., Li, M., Tolcher, A.W.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2024
• Subjects: Adult; Aged; dose escalation; dose expansion; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; PF-06939999; phase I; PRMT5 inhibitor; Protein-Arginine N-Methyltransferases - genetics; RNA Splicing Factors; solid tumors; dose escalation; PRMT5 inhibitor; phase I; dose expansion; PF-06939999; solid tumors
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2024.102961

Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities. In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified. PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection. •This is a first-in-human dose-escalation/expansion study of PF-06939999, a selective small-molecule inhibitor of PRMT5.•Patients with selected solid tumors were treated with PF-06939999 0.5-12 mg daily (q.d. or b.i.d.).•PF-06939999 had a tolerable safety profile. Most common ≥G3 treatment-related AEs: hematological toxicities. RP2D: 6 mg q.d.•Response was seen in a subset of patients with metastatic NSCLC and HNSCC, suggesting PRMT5 is a cancer therapeutic target.•No predictive biomarker was identified. Additional mechanism studies of PRMT5 are needed for patient selection.