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

Sponsor

Gruppo Italiano Mammella (GIM) (Other)

Overall Status

Unknown status

CT.gov ID

NCT00688194

Collaborator

(none)

396

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: anastrozole Drug: exemestane Drug: fulvestrant Drug: lapatinib ditosylate Drug: letrozole Other: placebo	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

396 participants

Allocation:

Randomized

Masking:

Double

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2008

Anticipated Primary Completion Date :

May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: fulvestrant Given intramuscularly Other: placebo Given orally
Active Comparator: 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.	Drug: anastrozole Patients receive aromatase inhibitor therapy according to standard treatment regulations. Drug: exemestane Patients receive aromatase inhibitor therapy according to standard treatment regulations. Drug: fulvestrant Given intramuscularly Drug: letrozole Patients receive aromatase inhibitor therapy according to standard treatment regulations. Other: placebo Given orally
Active Comparator: 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.	Drug: fulvestrant Given intramuscularly Drug: lapatinib ditosylate Given orally
Active Comparator: 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.	Drug: anastrozole Patients receive aromatase inhibitor therapy according to standard treatment regulations. Drug: exemestane Patients receive aromatase inhibitor therapy according to standard treatment regulations. Drug: fulvestrant Given intramuscularly Drug: lapatinib ditosylate Given orally Drug: letrozole Patients receive aromatase inhibitor therapy according to standard treatment regulations.

Outcome Measures

Primary Outcome Measures

Progression-free survival []

Secondary Outcome Measures

Time to progression []
Overall survival []
Response rate []
Clinical benefit rate []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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