DoseLimiting

Doselimiting toxicity (DLT) is an adverse effect of a drug that limits the tolerated dose in a dose-escalation study. In early-phase clinical trials, investigators gradually increase the drug dose across cohorts of patients until a predefined proportion experience DLTs. The highest dose at which toxicities are deemed acceptable is used to establish the maximum tolerated dose (MTD), a key parameter guiding further development.

DLTs are typically defined during the first treatment cycle and are assessed using standardized toxicity criteria, such as the National Cancer Institute's CTCAE. DLTs are usually grade 3 or higher adverse events or grade 4 laboratory abnormalities that are considered treatment-related and clinically meaningful. Common DLTs in oncology include cytopenias, hepatotoxicity, nephrotoxicity, and severe non-hematologic toxicities.

Trial designs for determining the MTD include traditional 3+3 designs, accelerated titration, and model-based approaches such as continual reassessment method. Once the MTD or a recommended phase II dose (RP2D) is identified, it may become the basis for later trial dosing. Immunotherapies and targeted agents may require modified criteria due to delayed or non-conventional toxicities, influencing dose selection.

Limitations of the DLT concept include that MTD may not align with the optimal biological dose or efficacy. Toxicity profiles vary among patients, and some adverse effects occur after the first cycle or accumulate over time. Consequently, dose selection often integrates pharmacokinetics, pharmacodynamics, and real-world safety data, not solely DLT incidence.