Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference

Abstract

One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials.

Figure 1

(A) Probability of rejecting all doses of a new agent X when agent X is added to a backbone chemotherapy regimen but adds negligible toxicity to the combination, as a function of background toxicity rate. (B) Probability of selecting a dose of agent X which adds no toxicity over a background rate of 20%. Computations are based on standard 3+3 cohort design with 6 dose levels. With the high background rates of DLT in the backbone regimen, there is a high probability that no dose of X will be found acceptable in combination with standard chemotherapy.