Table 2. Main phase I study designs.

Design	Description
3 + 3	Cohorts of three patients received escalating doses – where one is DLT, include three more; the DRF2 is the dose corresponding to the previous stage in which 33% of patients had DLT.
Accelerated titration	Using a model for dose-toxicity monitoring providing faster initial scheduling, and the scheduling and descaling for the same patient.
Pharmacologically guided dose escalation	Model variation 3 + 3 using pharmacokinetics analysis pharmacologically guided or allowing for rapid dose escalation until achieving the established target concentration in the preclinical study DLT, then following with smaller increases.
Rotation of six	Model guided by rule where between two and six patients are allowed per stage, increasing the scaling speed and decreasing the exposure to subdoses with fewer patients in the early stages.
Continuous reassessment	Treatment of cohorts with initial dose close to MTD (based on preclinical data) and performance of DLT estimated based on data from each new patient entering each dose stage allowing scaling and descaling.
Scheduling with overdose control	Similar to the continuous reassessment, however, to evaluate probability to exceed the MTD for each step of the dose-interruption indication from a certain critical pre-specified probability value.
Time to event	Incorporates the evaluation of toxicity and efficacy for determining acceptable dose based on the odds of treatment efficacy (using standard response criteria or surrogate endpoints) and toxicity.

DLT : Dose-limiting toxicity;

DRF2: recommended dose for phase II study;

MTD: maximum tolerated dose.