title: Phase I and pharmacokinetic study of gemcitabine administered at fixed-dose rate, combined with docetaxel/melphalan/carboplatin, with autologous hematopoietic progenitor-cell support, in patients with advanced refractory tumors.
abstract: 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.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ynieto@mdanderson.org
authors.forename: Yago
authors.initials: Y
authors.lastname: Nieto
authors.forename: Azucena
authors.initials: A
authors.lastname: Aldaz
authors.forename: José
authors.initials: J
authors.lastname: Rifón
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez-Calvo
authors.forename: Ana
authors.initials: A
authors.lastname: Zafra
authors.forename: Laura
authors.initials: L
authors.lastname: Zufia
authors.forename: Antonio
authors.initials: A
authors.lastname: Viúdez
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Aramendía
authors.forename: Javier
authors.initials: J
authors.lastname: Aristu
authors.forename: Carlos
authors.initials: C
authors.lastname: Centeno
authors.forename: Marta
authors.initials: M
authors.lastname: Moreno
authors.forename: Onintza
authors.initials: O
authors.lastname: Sayar
authors.forename: Milagros
authors.initials: M
authors.lastname: Hernández
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D043823:Taxoids / Q000008:administration & dosage; D014182:Transplantation, Autologous / Q000379:methods*; D000093542:Gemcitabine
chemical_list: D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D016190:Carboplatin; D008558:Melphalan; D000093542:Gemcitabine