A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study)

Objective: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC). Methods: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T -> T+L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L -> T+L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drugedrug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day. Results: Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS <= 1. Eleven (91.7%) pts in the T -> T+L group and 10 (76.9%) in L -> T+L group received at least 2 cycles of treatment. The most frequently reported drugrelated adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of coadministration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months. Conclusions: The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index. (C) 2014 Elsevier Ltd. All rights reserved.