Figure 2.

Rules for individual dose-escalation of sorafenib. Schema of sorafenib dose-titration rules. The first pShift within 7 days to the first sorafenib dose (‘day R0'). The escalation rounds were terminated and treatment phase cycle 1 day 1 started as soon as any of the depicted criteria was met, whichever occurred first: (1) reaching a ⩾90% pShift inhibition; (2) any grade 3 or any grade 2 non-tolerable, non-haematologic toxicity at least possibly related to sorafenib; (3) a maximum dose of 800 mg b.i.d of sorafenib. The following exceptions apply for the dose-titration phase: *After the first round, all the subsequent rounds lasted 14 days. **In the absence of prespecified toxicity, dose-escalation of sorafenib to 400 mg b.i.d. was mandatory after the first round regardless of the pShift.