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， 对传统疗法有抵抗力 7A项目将寻求 在每一个人身上发现一致的分子和遗传异常， 研究中的三种肉瘤（横纹肌肉瘤，Ewing 肉瘤和骨肉瘤），并确定其临床 通过与临床病理学密切相关， 分期和治疗反应。 7 B项目将专注于 (i)在儿童中的药物代谢动力学， 影响这些参数的临床因素，（ii）药物 儿童浓度-效应关系 （药效学），和（iii）之间的相关性 小鼠异种移植物中的药代动力学/药效学结果 系统和癌症患者，以改善“规模扩大”， 实验模型到临床评价。 最后，系列 本节中描述的临床试验将作为主要的 测试项目1-6中出现的代理和概念的方法， 7A和7 B，以及其他来源，如NCI。 I期和II期 试验（项目7 C）将以传统方式进行 除了最大限度地利用药代动力学数据 来完善药物治疗和剂量调整。 在7 D项目中， 我们将使用创新的策略来规避持续的 药物开发中的问题：缺少药物的潜在活性 由于其在II期试验中表现不佳， 重度预治疗患者。 因此，代理和概念， 值得继续进行测试，将在 既往未经治疗的患者，在治疗前预后不良， 开始更成熟的治疗（II-III期先导性研究）。 我们 预计这些努力的互动性质将导致 在一个更有成效的发展治疗项目中， 儿童实体瘤，一个应该引起挑衅性 在全国范围内的随机临床试验中进行分析的线索 合作团体。

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.