Dose escalation schedule.

The first cohort was treated at a starting dose of 105 mg/m2 (daily dose of 35 mg/m2) that was considered to be safe based on extrapolation from toxicological data in dogs [21]. In the three following dose levels, a 20%- increase dose level was used. Due to the good tolerance at the dose levels n°1, 2, 3 and 4 but a minimal therapeutic effect observed, it was decided to treat dogs with a 25% and then a 33%-increase dose level in cohort n°5 and 6 respectively in order to reach the daily dose of 100 mg/m2 reported in humans [28]. In the cohort n°7, dogs were treated with the initial 20%-increase dose level.