Dose-Limiting Toxicity
An adverse effect severe enough to prevent further dose increases in a dose escalation study. Dose-limiting toxicities define the maximum tolerated dose and determine the upper boundary of the therapeutic dose range. They are a key outcome of Phase I clinical trials.
Technical Context
DLTs are pre-defined in the trial protocol and typically include: Grade 3-4 non-haematological toxicity, Grade 4 haematological toxicity lasting >7 days, febrile neutropenia, any toxicity resulting in dose delay >2 weeks, or any toxicity considered dose-limiting by the investigator. DLT assessment periods are defined (typically the first cycle or first 28 days). The MTD is often defined as the highest dose at which <33% of participants experience a DLT (the 3+3 dose escalation design) or using more sophisticated model-based methods (Bayesian continual reassessment method, BOIN design). For peptide drugs, common DLTs include gastrointestinal intolerance (GLP-1 RAs), injection site reactions, immunological reactions, and target-related pharmacological effects that become excessive.