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• W2590933486 endingPage "3072" @default.
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• W2590933486 abstract "3072 Background: Temsirolimus (T) is a first in class mTOR inhibitor FDA approved for advanced renal cell cancer. It is a water soluble rapamycin ester given IV weekly, rapidly metabolized to sirolimus, and extensive metabolism by CYP3A. We conducted a phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T in patients (pts) with hepatic dysfunction (HD). Methods: Pts with advanced solid tumors or lymphoma, ECOG ≤2, adequate renal and bone marrow function, received IV T over 30 minutes weekly. Cycles q28 days. Pts stratified into 5 HD cohorts: normal, mild, moderate, severe, transplant, using NCI ODWG Criteria. Data also collected for Child-Pugh classification (CPC). T dose was escalated in sequential cohorts of pts within each HD category. Whole blood analysis for T and sirolimus concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 110 pts received 333 cycles of T at doses starting at 25 mg in mild HD (5-175 mg). Median age 60, male 58%, ECOG 1 62%. CRC 44% Cohorts: normal-25, mild-39, moderate-20, severe-24, liver transplant 2 pts. Related AEs include thrombocytopenia 40%, fatigue 29%, nausea 28%, anemia 27%, stomatitis 27%, hypophosphotemia 27%, rash 24%. Thrombocytopenia was the most common dose limiting toxicity (DLT) (n=7). Nonlinear PK disposition, and no accumulation. Sirolimus formed rapidly. Apparent increased Cmax and AUC, decreased CL with worsening HD. Cycle 1 Day 1 T 25mg Normal Cohort: Cmax 613 ng/mL, AUC 2230 ng·h/mL, T1/2 19.8 h, CL 11.6 L/h. Severe Cohort 10 mg: Cmax 455 ng/mL, AUC 3200 ng·h/mL, T1/2 28.1 h, CL 3.3 L/h. Correlates of PK exposure to the CPC were fairly consistent with the NCI ODWG categorization and support dose adjustment only in patients with severe HD. Disease stabilization was noted in 33 pts, 1 CR (NHL), and 1 PR (breast cancer). Conclusions: Recommended dose for temsirolimus for pts with mild, moderate, or severe HD are 25 mg, 25 mg, 10 mg respectively, given IV weekly for pts with baseline platelets ≥ 100 109/L" @default.
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• W2590933486 date "2011-05-20" @default.
• W2590933486 modified "2023-09-25" @default.
• W2590933486 title "Phase I pharmacokinetic study of temsirolimus (CCI-779) in patients with advanced malignancies and normal and impaired liver function: An NCI Organ Dysfunction Working Group (ODWG) study." @default.
• W2590933486 doi "https://doi.org/10.1200/jco.2011.29.15_suppl.3072" @default.
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