NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis

OBJECTIVES: This study was an open-label phase I study to confirm the safety and tolerability of NC-6004 in combination with gemcitabine in Japanese patients with advanced solid tumors and to assess the PK effects of NC-6004 monotherapy. METHODS: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended dose of NC-6004 combined with gemcitabine. Safety and pharmacokinetics were assessed. The administration of NC-6004 alone was started at 60 mg/m(2) every treatment cycle (21 days per cycle). From the second through eighth cycles, patients received NC-6004 in combination with 1000 mg/m(2) of gemcitabine that was administered on day 1 and day 8 of each cycle, except for the first treatment cycle. RESULTS: Twelve patients with advanced solid tumors received 60 or 90 mg/m(2) NC-6004. Both MTD and RD were determined to be 90 mg/m(2). The most common drug-related adverse events were neutrophil decrease (66.7%) and white blood cell count decrease (41.7%). Population pharmacokinetic (PK) analysis revealed that NC-6004 PK profile in Japanese study was not significantly different from that in a previous Caucasian study. CONCLUSIONS: Both MTD and RD of NC-6004 were determined to be 90 mg/m(2). The pharmacodynamic (PD) model well explained the time course of estimated glomerular filtration rate (eGFR) and amplitude of decrease in eGFR. The decrease in eGFR appeared to reach saturation at >100 mg/m(2) with NC-6004. Estimated probability of acute kidney injury on this PK/PD simulation was 30% with NC-6004 and 70% with cisplatin, which may better explain the renal toxicity profile.