Phase I Dose-Escalation Study and Population Pharmacokinetic Analysis of Fixed Dose Rate Gemcitabine+Carboplatin as 2nd-Line Therapy Ovarian Cancer

abstract

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Highlights

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Study with weekly fixed dose rate gemcitabine plus carboplatin in ovarian carcinoma after first line therapy (28 day schedule).

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Population pharmacokinetic modeling shows that increase of carboplatin dose requires decrease of fixed dose rate gemcitabine dose and vice versa.

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Carboplatin plus fixed dose rate gemcitabine as a weekly schedule in ovarian carcinoma results in increased myelosuppression.

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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. ....... Population pharmacokinetic modeling and simulation was performed for the 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 day 1 and 8) would be more appropriate.