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.
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