title: A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in metastatic breast cancer (MBC).
  
  
  METHODS
  Patients with measurable, progressive, or recurrent MBC whose primary tumor expressed > or =1 ErbB receptor were randomized to the following CI-1033 regimens: 50 mg (arm A) or 150 mg (arm B) daily without rest period, or 450 mg/day x 14 days every 21 days (arm C). The primary endpoint was 1-year progression-free survival (PFS).
  
  
  RESULTS
  Overall, 194 patients were treated. One-year PFS estimates were 3.8, 2.0, and 4.6%; median PFS was 61, 56, and 58 days; and investigator-assessed overall response rates were 1.5, 1.5, and 7.3%, in arms A, B, and C, respectively. Response duration was 110-419 days. In arm C, response (18.8 vs. 2.6%) and 1-year overall survival rates (86.7 vs. 47.5%) were greater in patients with HER2-positive versus HER2-negative tumors. The incidence of grade 3/4 adverse events (AEs) was dose-dependent, affecting 10.3, 48.6, and 80.4% of patients in arms A, B and C, respectively. The most common grade 3/4, treatment-related AEs were diarrhea, asthenia, and stomatitis. Arm C enrollment was prematurely discontinued due to a high frequency of grade 3/4 AEs.
  
  
  CONCLUSIONS
  Single-agent CI-1033 did not show clinically meaningful activity in heavily pretreated patients with MBC expressing > or =1 ErbB receptor. Antitumor activity was observed in arm C patients with HER2-positive tumors. However, only the 50 mg dose was well tolerated, and the highest dose reached unacceptable levels of toxicity.
authors.affiliation: Hopital de la Pitié Salpêtrière, APHP, Paris, France. rixeo@mail.nih.gov
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.forename: Sandra X
authors.initials: SX
authors.lastname: Franco
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnston
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Banu K
authors.initials: BK
authors.lastname: Arun
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Letrent
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D009362:Neoplasm Metastasis / Q000188:drug therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D066246:ErbB Receptors; D009025:Morpholines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen; C420268:Canertinib; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human