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

• Published in: Breast (Edinburgh) Vol. 23; no. 5; pp. 663 - 669
• Main Authors: Fumoleau, Pierre, Koch, Kevin M., Brain, Etienne, Lokiec, François, Rezai, Keyvan, Awada, Ahmad, Hayward, Larry, Werutsky, Gustavo, Bogaerts, Jan, Marréaud, Sandrine, Cardoso, Fatima
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.2014
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - blood; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematology, Oncology and Palliative Medicine; Humans; Lapatinib; Middle Aged; Neoplasm Metastasis; Pharmacokinetics; Phase 1 clinical trials; Quinazolines - administration & dosage; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Tamoxifen; Tamoxifen - administration & dosage; Treatment Outcome; Breast cancer; Lapatinib; Tamoxifen; Pharmacokinetics; Phase 1 clinical trials
• ISSN: 0960-9776; 1532-3080; 1532-3080
• DOI: 10.1016/j.breast.2014.07.003

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). 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. 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. The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.