Fulvestrant With or Without Lapatinib in Treating Postmenopausal Women With Stage III or Stage IV Breast Cancer That is Hormone Receptor-Positive

• Progression-free survival (PFS) [ Time Frame: Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years ] [ Designated as safety issue: No ]
  One-sided O'Brien-Fleming boundaries will be used to stop for superiority. Futility boundaries will be based on testing the alternative hypothesis at a one-sided 0.005 alpha level, as recommended by Freidlin and Korn. Specifically, Z-score futility boundaries will be calculated as 2.576 + log(1.5)*sqrt (n/4), where n is the total number of observed events. The final analysis will use the stratified log-rank test to test for a difference between the treatment arms in PFS (one-sided alpha of 0.025) where the stratification factors are prior tamoxifen (yes/no) and bone-only disease (yes/no).
  
  

• Treatment-related toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Day 1 of each course ] [ Designated as safety issue: Yes ]
  At each interim analysis the Fisher exact test or chi-square test, as appropriate, will be used with a one-sided Type I error rate of 5% to test arm differences in toxicity. We will also tabulate the frequency of treatment related toxicity by type, grade, and arm.
  
  
• Objective tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) for patients with measurable disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm.
  
  
• Duration of tumor response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  A Kaplan-Meier analysis will be used to compare the arms on response duration.
  
  
• Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  The proportional hazards model to do a stratified analysis to compare the arms on overall survival will be used.
  
  
• Quality of life (QOL) as measured by the symptom assessment score using the Memorial Symptom Assessment Scale (C-991) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  

PRIMARY OBJECTIVE:

I. Compare the progression-free survival of postmenopausal women with stage III or IV hormone receptor-positive breast cancer treated with fulvestrant with or without lapatinib ditosylate.

SECONDARY OBJECTIVES:

I. Compare the response rate in patients treated with these regimens. II. Compare response and stable disease rate (i.e., complete response, partial response, and stable disease > 6 months) in patients treated with these regimens.

III. Compare the duration of response in patients treated with these regimens. IV. Compare the overall survival of patients treated with these regimens. V. Compare the quality of life of patients treated with these regimens. VI. Compare the toxicity of these regimens in these patients.

OUTLINE: This is a multicenter, open-label, randomized, double-blind, placebo-controlled study. Patients are stratified according to prior tamoxifen citrate therapy (yes vs no) and bone disease only (yes vs no). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral lapatinib ditosylate once daily on days 1-28 and fulvestrant intramuscularly (IM) on days 1 and 15 of course 1 and on day 1 of each subsequent course.

ARM II: Patients receive oral placebo once daily on days 1-28 and fulvestrant as in arm I.

In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and then on day 1 of every 2 courses of treatment (i.e., day 1 of courses 3, 5, 7, etc.).

After completion of study treatment, patients are followed every 6 months for 2 years and then annually for 3 years.