Assessments and endpoints
DLTs, Tumor, Cancer
ADVERSE EVENT, TUMOR, ADVERSE EVENTS, SECONDARY, CANCER
The primary objective was to determine safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy. Associated endpoints were DLTs, adverse events (AEs), and study drug discontinuations because of AEs. The secondary objective was to evaluate PK. Exploratory objectives included preliminary evaluation of efficacy and biomarker analyses (phosphorylation of ERK [pERK], serum interleukin-8 [IL-8], The DLT window of observation was cycle 1. AEs were monitored from study treatment initiation through 30 days (90 days for serious AEs) following cessation of study treatment and graded using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Ophthalmic examinations were completed at screening, on day 1 of cycle 2, and every 8 weeks thereafter.PK concentrations of MK-8353 and selumetinib (and its metabolite, desmethyl selumetinib) were used to derive PK parameters. Serial plasma samples were collected for PK analysis on days 1 and 4 of cycle 1 before the morning dose; at 1, 2, 4, 6, and between 8−12 h after the morning dose. Additional samples were taken before the morning dose and 1 and 4 h after the morning dose on days 1 and 4 of cycle 2 and days 1 and 4 of cycle 5. PK parameters were determined using standard noncompartmental methods with Phoenix WinNonlin v8.1 (Certara, Princeton, NJ). Area under the plasma concentration−time curve (AUC) was calculated using the linear up/log down trapezoidal rule.Tumor imaging was performed at baseline, every 9 weeks in year 1, and every 12 weeks thereafter. Samples for assessment of biomarkers (including IL-8) were collected predose on days 1 and 4 of cycle 1 and on day 4 of cycles 2 and 5; additional blood samples for pERK assessment were collected on day 1 of cycles 2 and 5. FDG-PET was done at baseline and on day 4 of cycle 2 as a pharmacodynamic biomarker reflective of the study drug–induced effects.