Untenable dosing: A common pitfall of modern DLT-targeting Phase I designs in oncology.

ABSTRACT

BACKGROUND: There is increasing use of Phase I statistical designs to find a dose that causes rapidly emerging and particularly concerning severe or life-threatening toxicities (dose-limiting toxicities, DLTs) in a specified percent of patients most commonly 25%. While a convenient statistical framework, the foundation for selecting any specified target DLT rate, and its relevance to the recommended Phase II dose is generally lacking. METHOD: We surveyed 78 medical oncologists, most (69%) with experience as a principal investigator on a Phase I study, to ascertain their opinions related to this approach to Phase I studies and the targets often chosen. RESULTS: Eighty-seven percent of respondents preferred severe toxicities in only 5%-10% of patients, consistent with 58% of respondents noting that 10% or fewer patients experience severe toxicities in the first cycle with standard outpatient treatments. The survey also documented in an example that the majority (62%) of physicians modify their patient selection during the conduct of the study based on observed toxicity and 78% note that higher toxicity is acceptable in patients where a cure is more likely. CONCLUSION: DLT-target rate designs search for a single target that is rarely well-supported in a patient population that is not stable. The most common target used is inconsistent with the toxicity of most clinically used drugs and investigator preference and can lead to the pursuit of unacceptable doses. Use of Phase I trial designs with a target DLT rate should be limited to settings with a well-justified target and should specify how the target relates to the recommended Phase II dose.