title: A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma.
  
  
  METHODS
  Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients.
  
  
  RESULTS
  Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n=1), and non-dose limiting G3 neutropenia (n=3). Of the 11 patients who received >or=1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib.
  
  
  CONCLUSIONS
  This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.
authors.affiliation: Division of Gynecologic Oncologic, University of Alabama at Birmingham, Birmingham, AL 35249-7333, USA. kimballk@uab.edu
authors.forename: Kristopher J
authors.initials: KJ
authors.lastname: Kimball
authors.forename: T Michael
authors.initials: TM
authors.lastname: Numnum
authors.forename: Tyler O
authors.initials: TO
authors.lastname: Kirby
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Estes
authors.forename: Mack N
authors.initials: MN
authors.lastname: Barnes
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Matei
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D016190:Carboplatin