title: Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors.
abstract: 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 ClinicalTrials.gov, number NCT00984425.
  
  
  RESULTS
  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 1250mg/day and sorafenib 400mg 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%.
  
  
  CONCLUSIONS
  Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.
authors.affiliation: Oncology and Hematology Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy. matteo.simonelli@cancercenter.humanitas.it
authors.forename: Matteo
authors.initials: M
authors.lastname: Simonelli
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Zucali
authors.forename: Elena
authors.initials: E
authors.lastname: Lorenzi
authors.forename: Luca
authors.initials: L
authors.lastname: Rubino
authors.forename: Fabio
authors.initials: F
authors.lastname: De Vincenzo
authors.forename: Rita
authors.initials: R
authors.lastname: De Sanctis
authors.forename: Matteo
authors.initials: M
authors.lastname: Perrino
authors.forename: Luca
authors.initials: L
authors.lastname: Mancini
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.forename: Lorenza
authors.initials: L
authors.lastname: Rimassa
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masci
authors.forename: Monica
authors.initials: M
authors.lastname: Zuradelli
authors.forename: Matteo B
authors.initials: MB
authors.lastname: Suter
authors.forename: Monica
authors.initials: M
authors.lastname: Bertossi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fattuzzo
authors.forename: Laura
authors.initials: L
authors.lastname: Giordano
authors.forename: Massimo G
authors.initials: MG
authors.lastname: Roncalli
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000453:epidemiology / Q000209:etiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D011799:Quinazolines; D000077341:Lapatinib; D009536:Niacinamide; D000077157:Sorafenib