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.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Identification and characterization of murine alternatively spliced tissue factor.

Tissue factor (TF) is a transmembrane glycoprotein that initiates coagulation and plays a critical role in regulating hemostasis and thrombosis. We have recently reported a naturally occurring, soluble form of human tissue factor (asTF) generated by alternative splicing. This splice variant has a novel C-terminus with no homology to that of the full-length TF (flTF), lacks a transmembrane domain, and is active in the presence of phospholipids. Mouse models offer unique opportunities to examine the relative importance of flTF and asTF in mediating thrombosis, the response to arterial injury, and ischemic damage. To that end, we have identified and characterized murine asTF (masTF). Like the human splice variant, masTF lacks a transmembrane domain and has a unique C-terminus. We have generated antibodies specific to masTF and murine flTF (mflTF) to examine the expression of both forms of TF. masTF antigen is widely and abundantly expressed, with a pattern similar to that of mflTF, in adult tissues, in experimentally induced thrombi, and during development. These studies demonstrate that masTF contributes to the pool of total TF and may thus play an important role in mediating TF-dependent processes.