Phase i dose-escalation study and population pharmacokinetic analysis of fixed dose rate gemcitabine plus carboplatin as second-line therapy in patients with ovarian cancer

Objective This phase I study of fixed dose rate (FDR) gemcitabine and carboplatin assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profile and preliminary anti-tumor activity in patients with recurrent ovarian cancer (OC). Methods Patients with recurrent OC after first line treatment were treated with carboplatin and FDR gemcitabine (infusion speed 10 mg/m²/min) on days 1, 8 and 15, every 28 days. Pharmacokinetics included measurement of platinum concentrations in plasma ultrafiltrate (pUF) and plasma concentrations of gemcitabine (dFdC) and metabolite dFdU. Intracellular levels of dFdC triphosphate (dFdC-TP), the most active metabolite of gemcitabine, were determined in peripheral blood mononuclear cells (PBMCs). Population pharmacokinetic modeling and simulation were performed to further investigate the optimal schedule. Results Twenty three patients were enrolled. Initial dose escalation was performed using FDR gemcitabine 300 mg/m² (administered at infusion speed of 10 mg/m²/min) combined with carboplatin AUC 2.5 and 3. Excessive bone marrow toxicity led to a modified dose escalation schedule: carboplatin AUC 2 and dose escalation of FDR gemcitabine (300 mg/m², 450 mg/m², 600 mg/m² and 800 mg/m²). DLT criteria as defined per protocol prior to the study were not met with carboplatin AUC 2 in combination with FDR gemcitabine 300-800 mg/m² because of myelosuppressive dose-holds (especially thrombocytopenia and neutropenia). Conclusions FDR gemcitabine in combination with carboplatin administered in this 28 days schedule resulted in increased grade 3/4 toxicity compared to conventional 30-minute infused gemcitabine. A two weekly schedule (chemotherapy on days 1 and 8) would be more appropriate.