UAB 0282 GEMCITABINE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。该方案的主要目的是确定吉西他滨的推荐剂量，即先静脉滴注24小时，然后每2周静脉滴注24小时伊立替康(4周=1个周期)。吉西他滨具有广泛的抗肿瘤活性，可用于治疗白血病和实体瘤，包括胰腺癌、肺癌、卵巢癌、肝胆癌、乳腺癌和结肠癌。此外，高药物浓度可能不是导致临床上显著的DNA损伤的必要因素。相反，维持长期稳定的SN-38内酯水平高于一个低但关键的阈值浓度可能是最终细胞死亡的一个更关键的决定因素。伊立替康的起始量为70毫克/平方米，是推荐的II期剂量的50%，每两周口服一次24小时。吉西他滨的起始量为75毫克/平方米，是环磷酰胺24小时输注时推荐的II期剂量的50%。最初，伊立替康的剂量将随着固定剂量的吉西他滨以大约25%的增量递增。每个剂量水平将进入3-6名患者的队列，直到出现剂量限制性毒性。吉西他滨的剂量将与伊立替康联合使用，剂量将比MTD低一个剂量水平。将按伊立替康和吉西他滨的推荐剂量扩大应计范围，以实现统一剂量下的药代动力学和药效相关性。

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. The primary purpose of this protocol is to determine the recommended doses of gemcitabine given as a 24-hr IV infusion followed by a 24-hr infusion of irinotecan every 2 weeks (4 weeks =1 cycle). Gemcitabine has a broad spectrum of antitumor activity against leukemias and solid tumors including pancreatic, lung, ovarian, hepatobiliary, breast, and colon cancers. Furthermore, high drug concentrations may not be necessary to cause a clinically significant amount of DNA damage. Rather, maintaining prolonged steady-state SN-38 lactone levels above a low but critical threshold concentration may be a more crucial determinant for eventual cell lethality. The starting dose for irinotecan is 70 mg/m2, 50% of the recommended phase II dose when given as a 24-hr infusion every 2 weeks with oral UFT. The starting dose of Gemcitabine is 75 mg/m2, 50% of the recommended phase II dose when given as a 24-hr infusion with cyclophosphamide. Initially, the dose of irinotecan will be escalated in approximately 25% increments with a fixed dose of gemcitabine. Cohorts of 3-6 patients will be entered at each dose level until dose-limiting toxicity is seen. The dose of gemcitabine will then be escalated in combination with irinotecan at one dose level below the MTD. Accrual will be expanded at the recommended doses of both irinotecan and gemcitabine to allow pharmacokinetic and pharmacodynamic correlations at uniform doses.