Challenges of clinical trial design for targeted agents against XXXX .

@entity1 @entity981 @entity137 @entity5 @entity3052 @entity1778 @entity1968
The past 40   years have seen significant improvements in both event-free and overall survival for @entity1 with acute lymphoblastic and @entity3052 ( @entity981 and @entity3052 , 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 @entity1 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 @entity981 , 5-year-survival rates of over 85% have been achieved with risk-stratified therapy, but a notable minority of @entity1 will still not be cured. In @entity3052 , different challenges remain. A slower improvement in overall survival has taken place in this @entity1 population. Despite the obvious morphological heterogeneity of @entity3052 blasts, biological stratification is comparatively limited, and translation into risk-stratified therapeutic approaches has only best characterized by the use of @entity1968 for t(15;17)-positive @entity3052 . Even where prognostic markers have been identified, limited therapeutic options or multi-drug resistance of @entity3052 blasts has limited the impact on @entity1 benefit. For both, the acute morbidities of current treatment remain significant and may be life-threatening alone. In addition, the @entity5 Survivor Study (CCSS) highlighted many @entity1778 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 @entity1778 cells while sparing normal cells. Consequently, there is now a drive to develop novel @entity1778 -specific or "targeted" therapies. These new classes of drugs will have mechanisms of action, @entity137 , 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.
