Phase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer

Abstract

Background: Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer.

Methods: Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug.

Results: In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib.

Conclusion: The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.

Trial registration: ClinicalTrials.gov NCT00764972.

Conflict of interest statement

The study was funded by Bayer Pharmaceutical. IS, ES, and ON are affiliated with Sede Secondaria Della Cell Therapeutics and helped provide statistical analysis for the study, without further conflict of interest, financial or other. These do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow diagram of the patients enrolled in the study.

Fig 2. Progression-free survival of the VS combination

Fig 3. Progression-free survival by the dose of the regorafenib

Fig 4

A: Plasma concentration of Sorafenib over time. B: Plasma concentration of sorafenib metabolites (M2) over time

Fig 5. Mean plasma concentrations of vinorelbine when administered as a single agent (cycle 1 day 1, blue curve) or in the presence of steady-state concentrations of sorafenib (cycle 2 day 1, red curve).