title: Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer.
abstract: BACKGROUND
  Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined.
  
  
  METHODS
  Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals.
  
  
  RESULTS
  In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73%), nausea (70%), diarrhea (58%), increases in ALAT and ASAT (55 and 52%, respectively) and rash (46%). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m(2). Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4%) showing complete response and six (23%) partial response.
  
  
  CONCLUSIONS
  Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van der Noll
authors.affiliation: Department of Internal Medicine, Medisch Spectrum Twente, P.O. Box 50 000, 7500 KA, Enschede, The Netherlands.
authors.forename: W M
authors.initials: WM
authors.lastname: Smit
authors.affiliation: Department of Internal Medicine, Medisch Spectrum Twente, P.O. Box 50 000, 7500 KA, Enschede, The Netherlands.
authors.forename: A N M
authors.initials: AN
authors.lastname: Wymenga
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Boss
authors.affiliation: Department of Internal Medicine, Medisch Spectrum Twente, P.O. Box 50 000, 7500 KA, Enschede, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Grob
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Tibben
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Keessen
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rehorst
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Utrecht Institute of Pharmaceutical Sciences (UIPS), David de Wied building Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. j.schellens@nki.nl.|Utrecht Institute of Pharmaceutical Sciences (UIPS), David de Wied building Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. j.schellens@nki.nl.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000093542:Gemcitabine
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Advanced breast cancer; Gemcitabine; Lapatinib; Phase I trial