Determination of recommended Phase 2 dose
toxicity, diarrhoea, nausea, vomiting
EVENTS
The majority of patients in this study initiated SRA737 at either the MTD of 1000 mg total daily dose (44/107 patients) or a dose of 800 mg QD (43/107 patients). The choice of 800 mg QD as the recommended Phase 2 dose for SRA737 monotherapy was based on the clinical observation that GI tolerability appeared to be improved at 800 mg QD versus the MTD of 1000 mg QD. Looking specifically at the frequency of AEs at 800 mg and 1000 mg SRA737, Grade 1–2 TEAEs of diarrhoea, nausea, and vomiting occurred in 68%, 78%, and 50% of patients at the 800 mg SRA737 dose level respectively, whilst these occurred in 72%, 65%, and 63% of patients respectively at the 1000 mg SRA737 dose level. Events of GI toxicity above Grade 2 were observed in one patient at the 800 mg dose level who experienced Grade 3 diarrhoea, whereas at the 1000 mg dose level 1 patient experienced Grade 3 diarrhoea and another single patient experienced both Grade 3 nausea and vomiting.Exposure at both 800 mg QD and 1000 mg QD exceeded the minimum effective concentration extrapolated from preclinical models.