Phase i pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors

Matteo Simonelli, Paolo A. Zucali, Elena Lorenzi, Luca Rubino, Fabio De Vincenzo, Rita De Sanctis, Matteo Perrino, Luca Mancini, Luca Di Tommaso, Lorenza Rimassa, Giovanna Masci, Monica Zuradelli, Matteo B. Suter, Monica Bertossi, Giuseppe Fattuzzo, Laura Giordano, Massimo G. Roncalli, Armando Santoro

Research output: Contribution to journalArticle


Background: The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. Methods: Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3 + 3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with, number NCT00984425. Findings: Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250 mg/day and sorafenib 400 mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. Interpretation: Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.

Original languageEnglish
Pages (from-to)989-998
Number of pages10
JournalEuropean Journal of Cancer
Issue number5
Publication statusPublished - Mar 2013


  • Advanced refractory solid tumours
  • Lapatinib
  • Phase I
  • Sorafenib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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