Early 3+3 trial dose-escalation phase I clinical trial design and suitability for immune checkpoint inhibitors

Background: Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose-escalation. Methods: We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3-5 adverse events (G3-5AEs), immune-related adverse events (irAEs), and response were correlated with doses within each ICI using marginal exact generalized linear models. Results: A total of 74 trials (7469 patients) published between 1/2010 - 1/2017 were included. For ipilimumab, the incidence of G3-5AEs was 34% with a significant 27% reduced risk in lower doses (p=0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3-5AEs was 20.1% which was lower in NSCLC compared to RCC or melanoma (p≤0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose-response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3-5 AEs was 13.3%, which was lower in melanoma compared to NSCLC (p=0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (p=0.01), a relationship that was not observed in NSCLC. Conclusion: Our analysis shows a lack of consistent dose-toxicity or dose-response correlation with ICIs. Therefore, dose-escalation is not an appropriate design to conduct ICIs studies. Here we present an innovative trial design for immune modulating agents.