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.

The Emerging Role of Gemcitabine in Conditioning Regimens for Hematopoietic Stem Cell Transplantation

“…Gemcitabine exhibited a linear PK behavior at high doses, with a linear increase of its area under the curve with the duration of infusion from 9 to 20 hours (r 2 ¼ .71, P < 10 -5 ), with no major differences observed in clearance (r 2 ¼ .005, P ¼ .60), maximum concentration (P ¼ .14), volume of distribution (P ¼ .95), half-life (P ¼ .85), or steady-state concentration (P ¼ .37). Serial measurements of intracellular dFdCTP levels throughout treatment showed an exponential increase after the last of the 4 daily treatments, consistent with the selfpotentiating mechanisms of gemcitabine activation [33].…”

“…Gemcitabine/Docetaxel/Melphalan/Carboplatin Several gemcitabine-containing conditioning regimens have been assessed in the autologous HSCT setting. In 1 of the earlier reports of gemcitabine use by Nieto et al, gemcitabine at FDR of 10 mg/m 2 /minute was combined with a previously described regimen consisting of high-dose docetaxel, melphalan, and carboplatin [33]. The length of gemcitabine infusion was escalated from 9 to 20 hours (total dose of 12,000 mg/m 2 ), which was established as its maximum tolerated dose (MTD) ( Figure 3).…”

“…At median follow-up time of 24 months (range, 13 to 33 months), 79% of patients were alive, with 54% of them remaining disease free. Median event-free survival (EFS) was 26 months, although overall survival (OS) had not yet been reached (Table 5) [33].…”

High-Dose Infusional Gemcitabine Combined with Busulfan and Melphalan with Autologous Stem-Cell Transplantation in Patients with Refractory Lymphoid Malignancies

“…[38–40] In contrast, ASCT allowed us in a prior trial to circumvent myelotoxicity and fully dose escalate gemcitabine in multiple 4-hour infusions combined with a high-dose triplet of docetaxel/melphalan/carboplatin. [26] The resulting regimen was feasible and markedly active against refractory solid tumors. We observed a dose-linear pharmacokinetic behavior of parental gemcitabine and prolonged intracellular retention times of dFdCTP, which accounted, at least in part, for the predictable side effects of that regimen.…”

“…[24,25] Autologous hematopoietic support circumvents myelotoxicity of HDC, which allows for substantial prolongation of gemcitabine infusions. [26] We hypothesized that infusional gemcitabine can be safely combined at high doses with busulfan/melphalan with ASCT. We report here the results of a dose- and schedule-finding study of gemcitabine, busulfan and melphalan (Gem/Bu/Mel) in patients with refractory or poor-risk relapsed lymphoid malignancies.…”