PK/PD model-informed dose selection for oncology phase I expansion: Case study based on PF-06939999, a PRMT5 inhibitor.

The optimal dose for targeted oncology therapeutics is often not the maximum tolerated dose. Pharmacokinetic/pharmacodynamic (PK/PD) modeling can be an effective tool to integrate clinical data to help identify the optimal dose. This case study shows the utility of population PK/PD modeling in selecting the recommended dose for expansion (RDE) for the first-in-patient (FIP) study of PF-06939999, a small-molecule inhibitor of protein arginine methyltransferase 5. In the dose escalation part of the FIP trial (NCT03854227), 28 patients with solid tumors were administered PF-06939999 at 0.5 mg, 4 mg, 6 mg, or 8 mg once daily (q.d.) or 0.5 mg, 1 mg, 2 mg, 4 mg, or 6 mg twice daily (b.i.d.). Tolerability, safety, PK, PD biomarkers (plasma symmetrical dimethyl-arginine [SDMA]), and antitumor response were assessed. Semimechanistic population PK/PD modeling analyses were performed to characterize the time-courses of plasma PF-06939999 concentrations, plasma SDMA, and platelet counts collected from 28 patients. Platelet counts were evaluated because thrombocytopenia was the treatment-related adverse event with clinical safety concern. The models adequately described the PK, SDMA, and platelet count profiles both at individual and population levels. Simulations suggested that among a range of dose levels, 6 mg q.d. would yield the optimal balance between achieving the PD target (i.e., 78% reduction in plasma SDMA) and staying below an acceptable probability of developing grade ≥3 thrombocytopenia. As a result, 6 mg q.d. was selected as the RDE. The model-informed drug development approach informed the rational dose selection for the early clinical development of PF-06939999.