Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: learnings from a survey
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REVIEW ARTICLE
Starting dose selection and dose escalation for oncology small molecule first‑in‑patient trials: learnings from a survey of FDA‑approved drugs Rajendar K. Mittapalli1 · Donghua Yin1 · Darrin Beaupre2 · Rameshraja Palaparthy1 Received: 13 October 2020 / Accepted: 10 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 10 and
number of escalations ≤ 4;
• Q3: MTD or RP2D to starting dose ratio of > 10 and
number of escalations > 4;
• Q4: MTD or RP2D to starting dose ratio of ≤ 10 and
number of escalations > 4.
Additionally, reference lines were also added to the observed data that assume either two fold increase in dose for each dose escalation step or a modified Fibonacci scheme for dose increments. Exploratory graphical analyses and linear regression were performed. To gain insights on trial efficiency with respect to whether a molecule is first-in-class or not, the molecules in each target category were classified as first-in-class or not first-in-class and compared the MTD or RP2D to starting dose ratio and number of escalations to MTD or RP2D between the two classes.
Cancer Chemotherapy and Pharmacology
First‑in‑patient trial characteristics of reviewed molecules A total of 59 SMODs approved between first quarter of 2011 to last quarter of 2019 were included in the current analyses (Fig. 1). A major portion (~ 66%) of the SMODs were kinase inhibitors and approximately 69% evaluated in solid tumor indications in the dose escalation of FIP study (Supplemental Figure S1). All of the evaluated SMODs were MTAs and no cytotoxic agents were developed between 2011 and 2019 as compared to 32% of cytotoxic drugs evaluated in the prior decade between 1999 to 2010 [8], indicating a significant therapeutic shift in the field of oncology drug development with continued emergence of MTAs. The newer methodologies such as next-generation sequencing, developments in molecular modeling, and f
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