Dose escalation and tolerability
diarrhoea, DLTs, neutropenia, dose-limiting, nausea, vomiting
THROMBOCYTOPENIA, NEUTROPENIA
The study enrolled a total of 18 patients in the dose-escalation phase and followed a single-patient dose escalation strategy at SRA737 dose levels of 20, 40, 80, 160, 300, 600 and 1000 mg QD. No DLTs were seen in the 1000 mg QD dose-escalation cohort (or any lower-dose cohorts), and thus the expansion cohorts were opened. Safety data were reviewed when a total of 16 patients had been enrolled at the 1000 mg QD dose level (dose-escalation or expansion cohort); of the 10 evaluable patients, 3 patients required dose reduction to 600 mg due to GI intolerability and 7 patients tolerated the 1000 mg dose but required the support of anti-emetic medication and/or night-time dosing. A cohort evaluating the 1000 mg daily dose split into two doses (500 mg twice daily [BID]) then enrolled six patients, four of whom were evaluable for DLT. One patient in the 500 mg BID dose group had a DLT of Grade 4 thrombocytopenia, and review of all patients showed no clear differentiation in overall tolerability of 500 mg BID vs. 1000 mg QD dosing, thus there was no further enrolment in BID dosing. Three patients were enrolled into the 1300 mg QD cohort; 2 of these patients had dose-limiting GI intolerability (Grade 1–2 nausea, vomiting, and/or diarrhoea), and 1 patient had dose-limiting Grade 3 neutropenia. Therefore, the dose of 1000 mg QD was considered the MTD. Expansion cohorts were initially enrolled at 600 mg QD (5 patients), however, the expansion phase was predominantly enrolled at the 1000 mg QD and 800 mg QD dose levels (Fig. 