Fulvestrant With or Without Lapatinib and/or Aromatase Inhibitor Therapy in Treating Postmenopausal Women With Metastatic Breast Cancer That Progressed After Previous Aromatase Inhibitor Therapy

Study Overview
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Brief Summary
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RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant and exemestane, anastrozole, or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells and by lowering the amount of estrogen the body makes. Lapatinib may stop the growth of tumor 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 and/or aromatase inhibitor therapy in treating breast cancer. PURPOSE: This randomized phase III trial is studying fulvestrant with or without lapatinib and/or aromatase inhibitor therapy to compare how well they work in treating postmenopausal women with metastatic breast cancer that progressed after previous aromatase inhibitor therapy.

Detailed Description
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OBJECTIVES: Primary To compare the progression-free survival of postmenopausal women with progressive metastatic breast cancer treated with fulvestrant with or without lapatinib tosylate and/or aromatase inhibitor therapy. Secondary To compare time to progression in these patients. To compare overall survival of these patients. To compare response rates in these patients. To compare clinical benefit rates in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to timing of progressive disease (during adjuvant therapy vs > 12 months after completion of adjuvant therapy vs during treatment for metastatic disease). Patients are randomized to 1 of 4 treatment arms. Arm I: Patients receive fulvestrant intramuscularly (IM) on days 0, 14, and 28 of course 1 and on day 1 of all subsequent courses. Patients also receive oral placebo once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive fulvestrant and placebo as in arm I. Patients also receive aromatase inhibitor (AI) therapy (e.g., exemestane, anastrozole, or letrozole) according to standard treatment regulations. Arm III: Patients receive fulvestrant as in arm I and oral lapatinib tosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Arm IV: Patients receive fulvestrant as in arm I and lapatinib as in arm III. Patients also receive AI therapy according to standard treatment regulations.

Official Title
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Overcoming Endocrine Resistance in Metastatic Breast Cancer: A Randomized Trial With Factorial Design Comparing Fulvestrant ± Lapatinib ± Aromatase Inhibitor in Metastatic Breast Cancer Progressing After Aromatase Inhibitor Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: anastrozole
* Drug: exemestane
* Drug: fulvestrant
* Drug: lapatinib ditosylate
* Drug: letrozole
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed breast cancer Metastatic disease Confirmed disease progression after treatment with an aromatase inhibitor (AI) administered in the adjuvant or metastatic setting Must have demonstrated a prior response to AI therapy (i.e., responded after > 2 years of treatment in the adjuvant setting OR complete or partial response or stable disease after ≥ 24 weeks of treatment in the metastatic setting) AND have subsequent disease progression after completion of AI therapy Meets 1 of the following criteria: Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral CT scan Evaluable disease, defined as bone lesions, lytic or mixed (lytic and sclerotic), evaluable by plain x-ray, CT scan, or MRI Lesions identified only by radionucleotide bone scan are not allowed No HER2/neu-overexpressing tumor (IHC 3+ or FISH+) Hormone receptor status: Estrogen receptor- and/or progesterone receptor-positive primary or metastatic tumor PATIENT CHARACTERISTICS: Female Postmenopausal, as defined by any of the following criteria: At least 60 years of age 45 to 59 years of age and meets ≥ 1 of the following criteria: Amenorrhea for ≥ 12 months and intact uterus Amenorrhea for < 12 months and follicle-stimulating hormone within the postmenopausal range (including patients with hysterectomy, prior hormone replacement therapy, or chemotherapy-induced amenorrhea) Patients who received prior luteinizing hormone-releasing hormone (LHRH) analogues must not have restarted their menses after cessation of therapy Over 18 years of age and bilateral oophorectomy WHO performance status 0-2 Life expectancy ≥ 8 months Leukocytes ≥ 3,000/μL Absolute neutrophil count ≥ 1,500/μL Platelet count ≥ 100,000/μL Total bilirubin normal AST/ALT ≤ 2.5 times upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min LVEF normal as measured by ECHO or MUGA Able to swallow and retain oral medication No ulcerative colitis No malabsorption syndrome or disease significantly affecting gastrointestinal function No known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to fulvestrant, aromatase inhibitors, lapatinib tosylate, or excipients No unresolved or unstable serious toxicity from prior therapy No active or uncontrolled infection No dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent No other malignancy within the past 5 years except for adequately treated cervical carcinoma in situ, melanoma in situ, or basal cell or squamous cell carcinoma of the skin No other concurrent disease or condition that would make the patient inappropriate for study participation No serious medical disorder that would interfere with patient safety PRIOR CONCURRENT THERAPY: See Disease Characteristics Prior radiotherapy for the primary or metastatic tumor allowed More than 4 months since prior LHRH analogues More than 30 days (or 5 half-lives, whichever is longer) since prior investigational agents More than 14 days since prior and no concurrent CYP3A4 inducers*, including any of the following: Rifampin, rifapentine, rifabutin, or other rifamycin class agents Phenytoin, carbamazepine, or barbiturates (e.g., phenobarbital) Efavirenz or nevirapine Oral glucocorticoids (e.g., cortisone [> 50 mg], hydrocortisone [> 40 mg], prednisone [> 10 mg], methylprednisolone [> 8 mg], or dexamethasone [> 1.5 mg]) Modafinil More than 14 days since prior and no concurrent herbal or dietary supplements*, including any of the following: St. John's wort Ginkgo biloba Kava Grape seed Valerian Ginseng Echinacea Evening primrose oil More than 7 days since prior and no concurrent CYP3A4 inhibitors*, including any of the following: Clarithromycin, erythromycin, or troleandomycin Itraconazole, ketoconazole, fluconazole (> 150 mg daily), or voriconazole Delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, or lopinavir Verapamil or diltiazem Nefazodone or fluvoxamine Cimetidine or aprepitant Grapefruit or grapefruit juice More than 6 months since prior and no concurrent amiodarone* No prior fulvestrant and/or lapatinib tosylate No prior resection of the stomach or small bowel No other concurrent anticancer therapy, including chemotherapy, immunotherapy, and biologic therapy Concurrent bisphosphonates allowed No other concurrent investigational therapy No concurrent participation in another clinical trial NOTE: *For patients randomized to receive lapatinib

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive fulvestrant intramuscularly (IM) on days 0, 14, and 28 of course 1 and on day 1 of all subsequent courses. Patients also receive oral placebo once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: fulvestrant<br>* Given intramuscularly<br>Other: placebo<br>* Given orally<br>|
| Active Comparator: Arm II<br>Patients receive fulvestrant and placebo as in arm I. Patients also receive aromatase inhibitor (AI) therapy (e.g., exemestane, anastrozole, or letrozole) according to standard treatment regulations. | Drug: anastrozole<br>* Patients receive aromatase inhibitor therapy according to standard treatment regulations.<br>Drug: exemestane<br>* Patients receive aromatase inhibitor therapy according to standard treatment regulations.<br>Drug: fulvestrant<br>* Given intramuscularly<br>Drug: letrozole<br>* Patients receive aromatase inhibitor therapy according to standard treatment regulations.<br>Other: placebo<br>* Given orally<br>|
| Active Comparator: Arm III<br>Patients receive fulvestrant as in arm I and oral lapatinib tosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: fulvestrant<br>* Given intramuscularly<br>Drug: lapatinib ditosylate<br>* Given orally<br>|
| Active Comparator: Arm IV<br>Patients receive fulvestrant as in arm I and lapatinib as in arm III. Patients also receive AI therapy according to standard treatment regulations. | Drug: anastrozole<br>* Patients receive aromatase inhibitor therapy according to standard treatment regulations.<br>Drug: exemestane<br>* Patients receive aromatase inhibitor therapy according to standard treatment regulations.<br>Drug: fulvestrant<br>* Given intramuscularly<br>Drug: lapatinib ditosylate<br>* Given orally<br>Drug: letrozole<br>* Patients receive aromatase inhibitor therapy according to standard treatment regulations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression |  |  | 
| Overall survival |  |  | 
| Response rate |  |  | 
| Clinical benefit rate |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, recurrent breast cancer