PHASE I TRIAL OF DOCETAXEL AND OXALIPLATIN IN ADVANCED SOLID TUMORS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。引言虽然随着新的化疗和靶向治疗的发展，晚期实体瘤的治疗取得了适度的进展，但绝大多数转移性恶性肿瘤仍然无法治愈。 在进一步治疗这种肿瘤的尝试中，一种探索方法是将抗肿瘤剂与潜在的协同或至少非重叠的活性机制组合，以试图阻止肿瘤对化疗的抗性的发展。方案和剂量的依据由于多西他赛已被证明每周给药时具有改善的治疗指数，我们建议评估多西他赛每周给药持续两周，每三周一次，奥沙利铂每三周一次的联合给药。由于多西他赛的这种方案通常耐受性良好，我们建议将奥沙利铂的剂量递增至奥沙利铂通常作为单药使用的剂量。 我们假设我们可以维持并可能增加多西他赛与奥沙利铂联合治疗的剂量强度，而不需要添加G-CSF。本研究中的起始剂量将是Agelaki推荐用于II期评价的剂量。但是，每个周期的多西他赛总剂量将分为两周给药，而不是单次给药。目的主要终点：奥沙利铂和多西他赛每周一次联合治疗的II期研究（RP 2D）的最大耐受剂量（MTD）和推荐剂量的确定次要终点：奥沙利铂和多西他赛每周一次联合治疗的毒性评价次要终点：奥沙利铂和多西他赛每周一次联合治疗的抗肿瘤活性评估次要终点：奥沙利铂和多西他赛的药代动力学评估次要目的。毒性将使用描述性统计量报告各剂量内发生任何毒性的患者数量（按级别）。此外，将对剂量从其原始队列剂量分配改变的患者中的毒性进行特殊描述。重点将是确定一旦毒性相关症状消退，DLT患者是否能够耐受较低剂量。肿瘤缓解。将连续报告联合用药的抗肿瘤疗效，并连续报告药代动力学结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction Although modest advances have been made in the treatment of advanced solid tumors with the development of new chemotherapies, and targeted therapies, the vast majority of metastatic malignancies remain incurable. In the attempts to further the treatment of such neoplasms, one method of exploration is the combination of anti-tumor agents with potential synergistic, or at least non-overlapping mechanisms of activity in an attempt to forestall the development of tumor resistance to chemotherapy. Rationale for schema and doses As docetaxel has been demonstrated to have an improved therapeutic index when administered weekly, we propose to evaluate the combination of docetaxel administered weekly for two weeks in cycles every three weeks, with oxaliplatin given once every three weeks. Since this regimen of docetaxel is generally well tolerated, we propose to escalate the dose of oxaliplatin towards the dose which is typically used for oxaliplatin as a single agent. We hypothesize that we could potentially maintain, and possibly increase the dose intensity of the docetaxel in combination with oxaliplatin, without requiring the addition of G-CSF. The starting doses in this study will be those recommended for phase II evaluation by Agelaki. However, the total dose of docetaxel per cycle will be divided into doses administered over two weeks, rather than as a single dose. Objectives Primary endpoint: Determination of Maximum Tolerated Dose (MTD) and Recommended Dose for Phase II Study (RP2D) of the combination of oxaliplatin and weekly docetaxel Secondary endpoint: Evaluation of the toxicity of the combination of oxaliplatin and weekly docetaxel Secondary endpoint: Assessment of the anti-tumor activity of the combination of oxaliplatin and weekly docetaxel Secondary endpoint: Assessment of the pharmacokinetics of oxaliplatin and docetaxel Secondary objectives. Toxicity. Descriptive statistics will be used to report the numbers of patients experiencing any toxicity by grade, within each dose. Additionally, special descriptions will be made of toxicities among patients whose dose changed from their original cohort dose assignment. The focus will be on determining whether patients with DLTs are able to tolerate a lower dose once toxicity-related symptoms resolve. Tumor Response. Anti-tumor efficacy of the combination will be reported descriptively.Pharmocokinetic results will be reported descriptiv