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

Biol Blood Marrow Transplant. 2007 Nov;13(11):1324-37. doi: 10.1016/j.bbmt.2007.07.008. Epub 2007 Sep 7.

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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / administration & dosage
  • Child
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Disease-Free Survival
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Female
  • Gemcitabine
  • Hematopoietic Stem Cell Transplantation / methods*
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Melphalan / administration & dosage
  • Middle Aged
  • Neoplasms / drug therapy
  • Taxoids / administration & dosage
  • Transplantation, Autologous / methods*

Substances

  • Taxoids
  • Deoxycytidine
  • Docetaxel
  • Carboplatin
  • Melphalan
  • Gemcitabine