Nieto Y, Aldaz A [SP], Rifón J, Pérez-Calvo J, Zafra A, Zufia L, Viúdez A, Viteri S, Aramendía JM [SP], Aristu J [SP], Centeno C [SP], Moreno M [SP], Sayar O, Hernández M.
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Magazine: Biology of Blood and Marrow Transplantation
Date: Nov 1, 2007Haematology and Hameotherapy Cell Therapy Area [SP] Pharmacy [SP] Medical Oncology Radiation Oncology
The purpose of this trial was to define the maximum tolerated duration (MTD), dose-limiting toxicity (DLT), regimen-related toxicities (RRT), and pharmacokinetics of gemcitabine infused at a fixed dose rate (FDR) of 10 mg/m2/min, combined with docetaxel/melphalan/carboplatin, using autologous stem cell transplantation (ASCT).
The duration of gemcitabine infusion was incrementally escalated as a single treatment on day -6 or as 4 daily infusions on days -5 to -2. Gemcitabine was followed by docetaxel (300 or 350 mg/m2) on day -5, and then melphalan (50 mg/m2/day) and carboplatin (333 mg/m2/day) on days -4 to -2. Fifty-two patients with refractory tumors were accrued with a median age of 40 (range: 6-66), a median of 3 (1-6) prior chemotherapy regimens, and 3 (1-7) organs involved. The gemcitabine MTD was defined at 20 hours (total dose 12,000 mg/m2) on both schedules. The DLT was enteritis. Three patients died from aspiration, catheter-related sepsis, and enteritis, respectively.
The tumor response rate was 91%, with 50% complete responses. At current 2-year median follow-up, the event-free and overall survival (EFS, OS) rates are 54% (median 26 months) and 79% (median not reached), respectively. Gemcitabine area under the curve (AUC), but not clearance, increased linearly with infusion duration, and correlated with grade 3 RRT. Docetaxel showed a linear increase of its AUC and similar clearance compared with prior reports at lower doses. In conclusion, ASCT-supported infusions of gemcitabine at FDR could be prolonged up to 20 hours.
The resulting gemcitabine/docetaxel/melphalan/carboplatin combination was highly active in refractory cancers and should be further tested in disease-specific trials.
CITATION Biol Blood Marrow Transplant. 2007 Nov;13(11):1324-37
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