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

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.

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