“Classical 3 + 3 design” versus “accelerated titration designs”: analysis of 270 phase 1 trials investigating anti-cancer agents

Abstract

The number of patients treated at each dose-level in dose seeking phase I trials is arbitrarily established. The most frequently used design is the “classical 3 + 3 design (3 + 3D)”. Recently, Simon et al. had introduced several “accelerated titration designs (ATD)”. In the present analysis, we compared the performance of these two types of designs in 270 recently (1997–2008) published phase I trials. ATD had been used in only 10% of the recent studies. ATD had permitted to explore significantly more dose levels (seven versus five, p = 0.0001) and reduced the rate of patients treated at doses below phase-2 recommended dose (46% versus 56%, p = 0.0001). Nevertheless, ATD did not allow a reduction in the number of enrolled patients, shorten the accrual time nor increase the efficacy of phase I trials. These data support that ATD as an effective clinical trial design over a standard 3 + 3 dose escalation design.