Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: learnings from a survey of FDA-approved drugs.

Abstract

The ideal starting dose for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. A low starting dose combined with small dose increments could lead to a lengthy dose escalation and could expose patients unnecessarily to sub-therapeutic dosing. In the current analyses, we reviewed 59 approved small molecule oncology drugs (SMOD) with the overarching goals to assess the current approaches of FIP starting dose selection and dose escalation, and to identify potential opportunities for improving trial efficiency and minimizing number of patients receiving sub-therapeutic dose levels. Of 59 SMODs, the majority (~ 66%) were kinase inhibitors and ~ 73% were approved for solid tumor indications. Most of the trials used a 3 + 3 design for dose escalation and had a median (range) of 4 cohorts (0-11) to reach MTD from the starting dose. The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) to starting dose ratio was highly variable with a median (range) of 8 (0.25-125). About 71% of the FIP trials had < 6 dose escalation steps to reach MTD or RP2D (with 15% ≤ 2 dose escalations), but the remaining 29% of trials had ≥ 6 dose escalation steps to reach MTD or RP2D suggesting that there is still room for increasing efficiency by reducing the number of dose escalation steps, reducing the variability in MTD to starting dose ratio, and consequently reducing significant number of patients exposed at sub-therapeutic doses in the dose escalation phase of FIP study.