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

Study Overview
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Brief Summary
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This randomized phase III trial studies 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.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the effect, in terms of progression free survival, of the antiestrogen fulvestrant alone with fulvestrant administered in combination with the dual-kinase inhibitor lapatinib for postmenopausal women with estrogen receptor (ER) and/or progesterone receptor (PgR) positive advanced breast cancer. SECONDARY OBJECTIVES: I. To compare the effects of fulvestrant alone with fulvestrant and lapatinib on other clinical endpoints, including response rate, response and stable disease rate (complete response [CR] + partial response [PR] + stable disease >= 6 months), duration of response, overall survival, symptom checklist scores, and toxicity. II. To define predictive markers of clinical activity among women receiving fulvestrant with or without lapatinib. III. To determine if the clinical benefits for combination of hormonal and growth factor inhibitor therapy are most pronounced in women whose tumors express higher levels of ER, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), phosphorylated protein kinase B (pAkt), and/or phosphorylated mitogen-activated protein kinase 1/2 (pERK1/2). IV. To serologically determine if HER2 extracellular domain (ECD) and EGFR ECD levels can identify patients with a greater likelihood of response and clinical benefit to fulvestrant with or without lapatinib. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive lapatinib ditosylate orally (PO) once daily (QD) 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 placebo PO QD 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. After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 3 years.

Official Title
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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

Conditions
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Estrogen Receptor Positive, HER2 Positive Breast Carcinoma, HER2/Neu Negative, Progesterone Receptor Positive, Recurrent Breast Carcinoma, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7

Intervention / Treatment
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* Drug: Fulvestrant
* Other: Laboratory Biomarker Analysis
* Drug: Lapatinib Ditosylate
* Other: Placebo Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic, pathologic or cytologic diagnosis of cancer of the female breast in either primary or metastatic setting; histological documentation of metastatic/recurrent disease is not required if there is unequivocal clinical evidence for recurrence Stage IV breast cancer (using American Joint Committee on Cancer [AJCC] criteria, 6th edition), or locally advanced (stage III) breast cancer not considered amenable to curative therapy Patients with symptomatic brain metastases or other symptomatic central nervous system (CNS) metastases are not eligible for the study; no screening studies are required among asymptomatic patients; patients with previously treated brain metastases, who are free of symptoms referable to CNS disease and who are > 3 months from treatment for brain metastases are eligible Tumors (as determined on pathology from either primary or metastatic sites) must be potentially sensitive to endocrine therapy, defined as expressing estrogen receptor (ER) and/or progesterone receptor (PgR) as determined immunohistochemical methods according to the local institution's standard protocol, >= 1% cells will be considered to be positive The protocol has been amended to permit tumors with any HER2 status, though a determination of HER2 status must have been made; patients will be considered to be eligible if HER2 expression is documented by one of the following methods: Immunohistochemistry (IHC) 0 (i.e., negative), 1+, 2+, or 3+ levels of expression, or Gene amplification (fluorescent in situ hybridization [FISH]) positive or negative Patients must have at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2.0 cm with conventional techniques or as >= 1.0 cm with spiral computed tomography (CT) scan Exception: Patients with lytic or blastic bone metastases as their only site of disease will be eligible for the study even though these patients are not considered to have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; these patients will be evaluable for time to progression, but not response Patients with all other lesions, including small lesions (longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral CT scan) and truly non-measurable lesions including those listed below are not eligible Lesions that are considered non-measurable include the following: Bone lesions (women with bone lesions will be eligible as described 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 Patients must have had one or two prior endocrine treatments for breast cancer in either the adjuvant or metastatic setting, exclusive of treatment-related amenorrhea or ovarian suppression; sequential use of two different third-generation aromatase inhibitors is considered one treatment; it is not required that tumors be resistant to such treatments; for example: A patient with de novo metastatic breast cancer who had never received endocrine therapy is not eligible; A patient who received adjuvant tamoxifen and subsequent therapy with an aromatase inhibitor (adjuvant or metastatic) is eligible; A patient who received an aromatase inhibitor in either the adjuvant or metastatic setting, and who discontinued therapy after several months because of side effects, is eligible; A patient who received an aromatase inhibitor in the adjuvant setting is eligible, regardless of whether they did or did not receive tamoxifen at some point; A patient who received adjuvant tamoxifen, and subsequently a nonsteroidal aromatase inhibitor and a steroidal aromatase inhibitor for advanced breast cancer in the adjuvant or metastatic setting is eligible; A patient who received adjuvant tamoxifen, and then a nonsteroidal aromatase inhibitor and subsequently megesterol acetate for advanced breast cancer is not eligible Tumors potentially sensitive to endocrine therapy, defined as >= 3 months of prior endocrine therapy without disease progression in the adjuvant or metastatic setting Patients must have had prior treatment in either the adjuvant or metastatic setting with a commercially available third-generation aromatase inhibitor (i.e. anastrozole, exemestane, or letrozole); it is not required that tumors be resistant to such therapies Patients may have received up to one prior chemotherapy regimen for stage IV breast cancer; prior chemotherapy in the adjuvant and/or neoadjuvant setting is permitted; patients must have finished chemotherapy at least 1 week prior to starting protocol based treatment Patients may have received prior trastuzumab therapy for stage IV breast cancer, in combination with up to one chemotherapy and/or endocrine therapy regimen, but that must have concluded at least 3 weeks prior to starting protocol-based therapy; prior trastuzumab therapy in the adjuvant and/or neoadjuvant setting is permitted, but must have concluded at least 3 weeks prior to starting protocol-based therapy Prior therapy with commercially available inhibitor of EGFR (including but not limited to gefitinib, erlotinib, lapatinib or cetuximab) or experimental inhibitors of EGFR is prohibited Patients may have initiated bisphosphonate therapy prior to study entry; such patients will have bone lesions considered evaluable for progression but not for response Prior fulvestrant therapy is prohibited Patients receiving a gonadotropin-releasing hormone (GnRH) agonist for ovarian suppression must remain on such therapy throughout the course of protocol treatment; patients must discontinue other endocrine treatments, including systemic hormone-replacement therapy and intravaginal estrogens prior to study entry; patients must have concluded radiation therapy prior to study entry; patients must be at least 1 week from prior chemotherapy or 3 weeks from prior trastuzumab therapy, with adequate recovery of bone marrow function and performance status Patients must be postmenopausal women, defined as a woman fulfilling any of the following criteria: Age >= 60 years; or Age >= 45 years with an intact uterus and amenorrhea for 12 months or more; or History of bilateral oophorectomy; or Follicle stimulating hormone (FSH) levels within postmenopausal range according to the ranges established by the testing facility; or Treatment with a GnRH agonist for ovarian suppression for at least 3 consecutive months prior to study registration, and remaining on such therapy throughout the course of protocol treatment Women who are pregnant or nursing are not eligible for the study; clinicians should advise patients that there are no data for the safety of lapatinib or fulvestrant among pregnant patients, nor data on the impact of these agents on fertility or pregnancy Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-2 Absence of pending visceral crisis, in the opinion of the treating physician Absence of acquired or inherited bleeding disorder Absence of need for therapeutic systemic anticoagulation (defined as maintaining international normalized ratio [INR] > 1.6); patients may take low-dose warfarin or aspirin (or equivalent) for maintenance of central venous catheter patency Granulocytes >= 1,000/μl Platelet count >= 100,000/μl Creatinine =< 2 mg/dl Total bilirubin =< 1.5 x upper limits of normal (ULN) unless due to Gilbert's syndrome Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN without liver metastases; =< 5 x ULN with liver metastases INR =< 1.6 Left ventricular ejection fraction (LVEF) within institutional limits of normal

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (lapatinib)<br>Patients receive lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 and 15 of course 1 and on day 1 of each subsequent course. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lapatinib Ditosylate<br>* Given PO<br>* Other names: Tykerb;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD on days 1-28 and fulvestrant as in Arm I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per RECIST criteria). | Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response Rate | Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm. | Up to 5 years | 
| Overall Survival (OS) | Overall survival was measured as the interval from study entry until death, from any cause, or last contact. | Study entry to death or last follow-up, up to 5 years |