This application proposes to provide a research base of investigators who will participate in the timely evaluation of novel therapeutic agents for pediatric cancer in a Phase I setting coordinated through the Childrens Cancer Study Group (CCSG). Although current anti-cancer therapies have cured the majority of children with cancer, a substantial portion of such patents fail to achieve remission or demonstrate progression of disease once initially controlled. Therefore, the identification and testing of new cytotoxic, biologic, and immunotherapeutic agents will provide novel treatments which will result in continued improvements in the long term outcome of children with cancer. Patients entered on such trials frequently represent a heterogeneous group with respect to clinical characteristics and diagnoses. A large data base of study entrants will be available to identify specific factors which, if measured prior to entry, may predispose to inevaluability; the recognition of such factors will result in the design of more efficient Phase I trials. The centralized nature of this clinical trials group proposes to provide a central resource for monitoring patient entry and requesting follow-up data at specified intervals, to provide a central resource for computerization of clinical and biologic data and to provide statistical expertise in the design and analysis of data arising from such efforts. In addition, the provision of centralized pharmacology laboratory facilities as well as specific reference laboratories, not related to clinical care issues, and not available at all institutions will provide pharmacokinetic and pharmacodynamic support for the identification of appropriate treatment plans for individual patients. We propose to conduct pharmacologically-guided, dose escalation phase I clinical trials when pre-clinical pharmacologic data are available and when such studies are warranted in the pediatric population. Precise pharmacological profiles will aid in efficiently identifying the appropriate dose to evaluate in Phase II and Phase III settings. Appropriate correlative biologic studies to determine optimum biologic effect in the case of bio- and immunotherapeutic agents will be undertaken. Selected institutions of the CCSG will participate in these Phase I clinical trials and correlative studies if review of projected accrual and performance at such institutions is considered appropriate for the safe and efficient conduct of such studies. Rigorous quality control and performance monitoring and sound scientific rationale in the design of studies will assure the efficient identification of tolerable and biologically effective doses for timely incorporation into wider scale pediatric clinical trials.
