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

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.