UAB 0282 GEMCITABINE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本方案的主要目的是确定吉西他滨的推荐剂量，以24小时静脉输注，然后每2周（4周=1个周期）输注伊立替康24小时。吉西他滨对白血病和实体肿瘤具有广泛的抗肿瘤活性，包括胰腺癌、肺癌、卵巢癌、肝胆癌、乳腺癌和结肠癌。此外，高药物浓度可能不需要引起临床显著量的DNA损伤。相反，维持长时间的稳态SN-38内酯水平高于低但关键的阈值浓度可能是最终细胞致死的更关键的决定因素。伊立替康的起始剂量为70mg /m2，为推荐的II期剂量的50%，每2周输注24小时，同时口服UFT。吉西他滨的起始剂量为75mg /m2，是环磷酰胺24小时输注时推荐II期剂量的50%。最初，伊立替康的剂量将在固定剂量的吉西他滨的基础上以大约25%的增量递增。每组3-6例患者按不同剂量水平进行研究，直至发现剂量限制毒性。吉西他滨的剂量随后将与伊立替康联合增加，剂量水平低于MTD。在伊立替康和吉西他滨的推荐剂量下，应计值将扩大，以允许在统一剂量下的药代动力学和药效学相关性。

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.