THERAPEUTIC STUDIES OF PEDIATRIC SOLID TUMORS--PHARMACOKINETICS

这项研究结合了三种方法-遗传分析 肿瘤细胞、药代动力学研究和I、II-III期先导试验 -提高儿童肉瘤的治愈率 证明对常规疗法有抵抗力。项目7A将寻求 识别每个患者一致的分子和遗传异常 正在研究的三种肉瘤(横纹肌肉瘤、尤因 肉瘤和骨肉瘤)，并确定其临床 与临床病理密切相关的意义 分期和治疗反应。项目7B将专注于 (I)抗肿瘤药物在儿童中的药代动力学 影响这些参数的临床因素：(二)药物 儿童的浓度-效应关系 (药效学)，以及(Iii) 小鼠异种移植瘤的药代动力学/药效学研究 系统和癌症患者，以改善从 对实验模型进行临床评价。最后，这一系列 本节中描述的临床试验将作为主要的 项目1-6中出现的试剂和概念的测试手段， 7A和7B，以及其他来源，如NCI。第一阶段和第二阶段 试验(项目7C)将以常规方式进行 除了最大限度地利用药代动力学数据 改进药物调度和剂量调整。在项目7D中， 我们将使用创新战略来规避持续的 药物开发中的问题：错过了一种潜在的活性 化合物，因为它在第二阶段试验中表现不佳 经过大量预治疗的病人。因此，代理和概念 是否值得继续测试将在 以前未接受治疗的患者，在治疗前预后较差 开始更成熟的治疗(II-III阶段试点研究)。我们 预期这些努力的互动性将导致 在一个更有成效的发展疗法项目中 童年的实体瘤，一种应该产生挑衅性的 在全国随机临床试验中用于分析的铅 合作小组。

This research combines three approaches - genetic analysis of tumor cells, pharmacokinetic studies and phase I, 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 (Projects 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.