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 drug-drug 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 drug-related 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 co-administration 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.
Trial registration: ClinicalTrials.gov NCT00424164.
Keywords: Breast cancer; Lapatinib; Pharmacokinetics; Phase 1 clinical trials; Tamoxifen.
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