Fulvestrant With or Without Lapatinib in Treating Postmenopausal Women With Stage III or Stage IV Breast Cancer That is Hormone Receptor-Positive
Condition: 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
MeSH terms: Carcinoma; Breast Neoplasms
Intervention: Fulvestrant; Laboratory Biomarker Analysis; Lapatinib Ditosylate; Placebo Administration
Intervention description: Given IM; Correlative studies; Given PO; Given PO
Intervention MeSH terms: Fulvestrant; Lapatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 295.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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