This research combines three approaches - genetic analysis of tumor cells, pharmacokinetic studies and phase I, II and II-III pilot trials - to improve the curability of childhood sarcomas that have proved resistant to conventional therapy. Project 7A will seek to identify consistent molecular and genetic abnormalities in each of the three sarcomas under study (rhabdomyosarcoma, Ewing sarcoma and osteosarcoma) and determine their clinical significance through careful correlation with clinicopathologic staging and therapeutic response. Project 7B will concentrate on (i) the pharmacokinetics of antineoplastic drugs in children and the clinical factors that influence such parameters, (ii) drug concentration-effect relationships in children (pharmacodynamics), and (iii) correlations between pharmacokinetic/pharmacodynamic findings in mouse xenograft systems and cancer patients, to improve the """"""""scale-up"""""""" from experimental models to clinical evaluation. Finally, the series of clinical trials described in this section will serve as the primary means of testing agents and concepts emerging from Projects 1-6, 7A and 7B, and from other sources such as the NCI. Phase I and II trials (Project 7C) will be conducted in a conventional manner except that maximum use will be made of pharmacokinetic data to refine drug scheduling and dose modification. In Project 7D, we will use an innovative strategy to circumvent a persistent problem in drug development: missing the potential activity of a compound because of its poor performance in phase II trials with heavily pretreated patients. Hence, agents and concepts that appear worthy of continued testing will be investigated in previously untreated patients with a poor prognosis prior to the start of more established therapy (phase II-III pilot studies). We anticipate that the interactive nature of these efforts will result in a more productive developmental therapeutics program in the solid tumors of childhood, one that should generate provocative leads for analysis in randomized clinical trials within the national cooperative groups.
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