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

This study has been completed.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: October 18, 2006
Last updated: July 16, 2014
Last verified: July 2014

This randomized phase III trial is studying fulvestrant and lapatinib to see how well they work compared to fulvestrant and a placebo in treating postmenopausal women with stage III or stage IV breast cancer that is hormone receptor-positive. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. Lapatinib may stop the growth of breast cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether fulvestrant is more effective with or without lapatinib in treating breast cancer.

Condition Intervention Phase
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: lapatinib ditosylate
Drug: fulvestrant
Other: placebo
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Endocrine Therapy With or Without Inhibition of EGF and HER2 Growth Factor Receptors: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib (GW572016) for Postmenopausal Women With Hormone Receptor Positive Advanced Breast Cancer

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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).

Secondary Outcome Measures:
  • 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 ]

Enrollment: 295
Study Start Date: September 2006
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (enzyme inhibitor therapy, hormone therapy)
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.
Drug: lapatinib ditosylate
Given orally
Other Names:
  • GSK572016
  • GW-572016
  • GW2016
  • Lapatinib
  • Tykerb
Drug: fulvestrant
Given IM
Other Names:
  • Faslodex
  • ICI 182,780
Other: laboratory biomarker analysis
Correlative studies
Placebo Comparator: Arm II (hormone therapy)
Patients receive oral placebo once daily on days 1-28 and fulvestrant as in arm I.
Drug: fulvestrant
Given IM
Other Names:
  • Faslodex
  • ICI 182,780
Other: placebo
Given orally
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:


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.


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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically* or cytologically confirmed breast cancer, meeting 1 of the following stage criteria:

    • Stage III (locally advanced) disease not considered amenable to curative therapy
    • Stage IV (primary or metastatic) disease
  • Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 2.0 cm by conventional techniques or ≥ 1.0 cm by spiral CT scan

    • Lytic or blastic bone metastases as only site of disease allowed
    • The following are not considered measurable disease:

      • Bone lesions (except as above)
      • Leptomeningeal disease
      • Ascites
      • Pleural/pericardial effusion
      • Inflammatory breast cancer
      • Lymphangitis cutis/pulmonitis
      • Abdominal masses that are not confirmed and followed by imaging techniques
      • Cystic lesions
  • Must have received prior therapy with 1 or 2 endocrine treatments for breast cancer in either the adjuvant or metastatic setting (not including treatment for ovarian suppression or amenorrhea)

    • Tumor must be potentially sensitive to endocrine therapy, defined as ≥ 3 months of prior endocrine therapy without disease progression in the adjuvant or metastatic setting
    • Treatments must have been commercially-available third-generation aromatase inhibitors (e.g., anastrozole, exemestane, or letrozole)*
  • No symptomatic brain or other CNS metastases

    • Previously treated brain metastases allowed provided patient is free of symptoms AND > 3 months since prior treatment for brain metastases
  • Hormone receptor status:

    • Estrogen receptor- and/or progesterone receptor-positive tumor by IHC methods (≥ 1% cells considered positive)
  • Female
  • Postmenopausal, meeting 1 of the following criteria:

    • Age ≥ 60 years
    • Age ≥ 45 years with an intact uterus and amenorrhea for ≥ 12 months
    • History of bilateral oophorectomy
    • Follicle-stimulating hormone levels within postmenopausal range
    • Undergoing treatment with a gonadotropin-releasing hormone agonist for ovarian suppression for ≥ 3 consecutive months prior to study entry, and remains on such therapy throughout study treatment
  • Life expectancy > 3 months
  • ECOG performance status 0-2
  • Granulocyte count ≥ 1,000/mm³
  • Platelet count ≥ 100,000/mm³
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to Gilbert's syndrome)
  • Creatinine ≤ 2.0 mg/dL
  • AST and ALT ≤ 2.5 times ULN (5 times ULN for patients with liver metastases)
  • INR ≤ 1.6
  • LVEF normal
  • Not pregnant or nursing
  • Negative pregnancy test
  • No pending visceral crisis
  • No acquired or inherited bleeding disorder
  • No other concurrent endocrine therapy, including systemic hormone-replacement therapy or intravaginal estrogen
  • Prior initiation of and concurrent bisphosphonate therapy allowed
  • At least 2 weeks since prior chemotherapy and recovered

    • Prior chemotherapy in the adjuvant and/or neoadjuvant setting allowed
    • No more than 1 prior chemotherapy regimen for stage IV breast cancer
  • At least 3 weeks since prior trastuzumab (Herceptin®) and recovered

    • Prior trastuzumab in the adjuvant and/or neoadjuvant setting allowed
    • No prior trastuzumab for stage IV breast cancer
  • No prior fulvestrant
  • No prior epidermal growth factor receptor (EGFR) inhibitors (e.g., gefitinib, erlotinib hydrochloride, lapatinib ditosylate, or cetuximab)
  • No other prior or concurrent experimental EGFR inhibitors
  • No other concurrent chemotherapy
  • No concurrent radiotherapy, including palliative radiotherapy
  • No other concurrent hormonal therapy* except for the following:

    • Steroids for adrenal failure
    • Hormones for nondisease-related conditions (e.g., insulin for diabetes or synthroid for hypothyroidism)
    • Intermittent dexamethasone as an antiemetic
  • No concurrent therapeutic systemic anticoagulation (defined as maintaining INR > 1.6)

    • Low-dose warfarin or acetylsalicylic acid (or equivalent) for maintenance of central venous catheter patency allowed
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00390455

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Sponsors and Collaborators
Principal Investigator: Harold Burstein Cancer and Leukemia Group B
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI) Identifier: NCT00390455     History of Changes
Other Study ID Numbers: NCI-2009-00475, NCI-2009-00475, CDR0000510452, CALGB-40302, CALGB 40302, CALGB-40302, P30CA014236, U10CA031946
Study First Received: October 18, 2006
Last Updated: July 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms by Site
Skin Diseases
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Enzyme Inhibitors
Estrogen Antagonists
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses processed this record on March 03, 2015