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The past 40 years have seen significant improvements in both event-free and overall survival for children with acute lymphoblastic and acute myeloid leukemia (ALL and AML, respectively). Serial national and international clinical trials have optimized the use of conventional chemotherapeutic drugs and, along with improvements in supportive care that have enabled the delivery of more intensive regimens, have been responsible for the major improvements in patient outcome seen over the past few decades. However, the benefits of dose intensification have likely now been maximized, and over the same period, the identification of new cytotoxic drugs has been limited. Therefore, challenges remain if survival is to be improved further. In pediatric ALL, 5-year-survival rates of over 85% have been achieved with risk-stratified therapy, but a notable minority of patients will still not be cured. In pediatric AML, different challenges remain. A slower improvement in overall survival has taken place in this patient population. Despite the obvious morphological heterogeneity of AML blasts, biological stratification is comparatively limited, and translation into risk-stratified therapeutic approaches has only best characterized by the use of retinoic acid for  t (15;17)-positive AML. Even where prognostic markers have been identified, limited therapeutic options or multi-drug resistance of AML blasts has limited the impact on patient benefit. For both, the acute morbidities of current treatment remain significant and may be life-threatening alone. In addition, the Childhood Cancer Survivor Study (CCSS) highlighted many leukemia survivors develop one or more chronic medical conditions attributable to treatment ( 1 ,  2 ). As the biology of leukemogenesis has become better understood, key molecules and intracellular pathways have been identified that offer the possibility of targeting directly the leukemia cells while sparing normal cells. Consequently, there is now a drive to develop novel leukemia-specific or “targeted” therapies. These new classes of drugs will have mechanisms of action, toxicities, and therapeutic indices quite different from conventional cytotoxic drugs previously encountered, thus rendering current clinical trial methodologies inappropriate. Clinical trial methods will need to be adapted to accommodate these features of these new classes of drugs. This review will address the challenges and some of the techniques for developing clinical trials for targeted therapies.

Challenges of Clinical Trial Design for Targeted Agents Against Pediatric Leukemias