Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs

Abstract

Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012. The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting AE 20% of the RP2D for targeted vs. other classes; P ¼ 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n ¼ 374) were described in phase I. A significant relationship (P ¼ 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.

Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval

“…The toxicitymortality rate described herein is similar to that in a previous report of phase I trials that evaluated anticancer drugs studied by the National Cancer Institute (mortality that was possibly drug related = 0.49%) (22,23). Other studies have also shown that safety and dose in early trials is highly predictive for later trials, possibly accounting in part for the low drug-related death rates in our registration trials (24).…”

Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example

“…Figure 1 shows that roughly two-thirds of oncolytic monotherapies have approved doses less than MTD. These findings are consistent with a previous review, which found that, for about 30% of compounds, MTD is not within 20% of the approved dose (23). More details are available in Supplementary Data S2 and Supplementary Fig.…”

Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?

“…Focus is on the fact that most common side effects described in registration trials were previously accurately described in phase I trials. Moreover, they also concluded that the final approved dose was within 20% of the RP2D in the majority of trials assessed (7). However, this analysis combined MTAs and…”

“…Researchers using an exhaustive retrospective analysis have shown that a substantial proportion of clinically relevant toxicities found in registration trials were previously described in early trials. This review included data studying MTAs and conventional cytotoxics which have very different therapeutic indices and crucially did not comment on the tolerability of targeted agents in phase III clinical trials (7).…”