Safety, pharmacokinetic and pharmacodynamic assessments
Tumors, melanoma, Cancer
MELANOMA, ADVERSE EVENTS, ADVERSE EVENT, TUMORS, CANCER
Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 19.0 and were graded according to the National Cancer Institute (NCI) Common Terminology Criteria (CTC) for adverse events (CTCAE) (Version 4.03). The assessment period for treatment emergent adverse events (TEAEs) was from the first dose of study treatment to 30 days after the last dose of study medication, or until the start of subsequent antineoplastic therapy, whichever occurred first. Following baseline evaluation, response was assessed by investigators every two cycles by computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumors (version 1.1) [Serial blood samples were collected before and after tovorafenib dosing on days 1 and 21 (Q2D dosing) or days 1 and 22 (QW dosing) of cycle 1 for plasma PK analysis. In addition, for patients on Q2D schedules, predose or trough samples were collected on days 9 and 15 (Q2D dosing) or days 8 and 15 (QW dosing) to evaluate time to steady state. A validated liquid chromatography coupled to tandem mass spectroscopy (LC–MS/MS) method was used to quantify plasma concentrations of tovorafenib [Based on tissue availability, pharmacodynamic assays included assessment of pERK expression levels in paired biopsy samples (baseline and day 21) from patients in the melanoma dose expansion cohorts. The level of staining was assessed both by a pathologist (semi-quantitative measurements according to H-score assessment) and by quantitated image analysis (Aperio, Leica Biosystems Nussloch, Germany).