Neratinib +/- Fulvestrant in HER2+, ER+ Metastatic Breast Cancer
Neratinib +/- Fulvestrant in HER2+, ER+ Metastatic Breast Cancer
This research study is studying a drug called Neratinib with and without Fulvestrant as
 possible treatments for HER2-positive breast cancer .

 The interventions involved in this study are:

 -  Neratinib and Fulvestrant

 -  Neratinib alone
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
 and effectiveness of an investigational intervention to learn whether the intervention works
 in treating a specific disease. "Investigational" means that the intervention is being
 studied.

 The FDA (the U.S. Food and Drug Administration) has approved Neratinib as a treatment for
 breast cancer. Fulvestrant has been FDA approved for treatment of metastatic hormone receptor
 positive breast cancer.

 The purpose of this research study is to determine how well neratinib, by itself or together
 with Fulvestrant, works in treating breast cancer that has spread to other parts of the body.
 Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing
 abnormally by inhibiting (or blocking) members of a family of proteins that include Human
 Epidermal Growth Factor Receptor 2 (HER2).

 Neratinib has been used in other research studies and information from those other research
 studies suggests that neratinib may help to shrink or stabilize HER2-positive breast cancer
 in this research study.
Inclusion Criteria:

 -  Participants must have histologically or cytologically confirmed inoperable locally
 advanced or metastatic ER+ breast cancer. To fulfill the requirement for ER+ disease,
 a breast cancer must express, by immunohistochemistry (IHC), ER in ≥10% of cells, on
 the most recent biopsy. If ER quantification is not available, a determination of ER+
 by IHC will suffice. Central confirmation of ER status is not required.

 -  Participants must have documented HER2+ disease by overexpression and/or gene
 amplification on the most recent biopsy, per current ASCO-CAP (American Society of
 Clinical Oncology - College of American Pathologists) guidelines. Central confirmation
 of HER2 status is not required.

 -  Participants must have received prior therapy with the following agents in any
 combination, and in setting (i.e., neoadjuvant, adjuvant, metastatic, etc.). These
 therapies do not need to be the most recent line of therapy.

 -  Trastuzumab

 -  Pertuzumab

 -  Ado-trastuzumab emtansine (T-DM1)

 -  Participants must agree to undergo a research biopsy of a reasonably accessible
 metastatic lesion (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast,
 bones, lung, and liver metastases). If a reasonably accessible metastatic lesion is
 not available, the patient may go on study provided that archived tissue is available.
 However, if a reasonably accessible site is available for biopsy, the patient must
 agree to biopsy. Any patients not undergoing biopsy must be approved for study
 enrollment by the Overall Principal Investigator at DFCI. Biopsies may be done with
 local anesthesia or intravenous conscious sedation, according to institutional
 guidelines. If a biopsy requires general anesthesia, then it is only allowed if
 acquisition of tissue is clinically indicated, and excess tissue may be collected for
 research purposes. Patients without sites available for biopsy must have available
 tissue [archived formalin-fixed paraffin embedded blocks (FFPB), blocks from which
 slides can be created, or fresh frozen tissue from original diagnosis or metastatic
 setting] for correlative studies. Tissue needs to be located and available at the time
 of registration See Section 9.3 for more details.

 -  Women ≥ 18 years of age. Men are not eligible.

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A).

 -  Participants must have normal organ and marrow function as described below:

 -  Absolute neutrophil count ≥1,000/uL

 -  Platelets ≥75,000/uL

 -  Hemoglobin ≥8g/dL

 -  Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN); in case of
 known Gilbert's syndrome, <2 x ULN is allowed

 -  AST(SGOT)/ALT(SGPT) ≤3X institutional ULN without liver metastases, or ≤5X
 institutional ULN with liver metastases

 -  Creatinine clearance ≥ 50 mL/min

 -  Left ventricular ejection fraction ≥50%, as determined by RVG (MUGA) or
 echocardiogram (ECHO) within 60 days prior to initiation of protocol therapy

 -  Participants may have received any number of prior therapies as long as they have
 adequate performance status and meet all other eligibility criteria.

 -  Women of childbearing potential (including premenopausal women and women less than 12
 months after menopause) must have a negative β-human chorionic gonadotropin (hCG)
 urine pregnancy test within 4 weeks of registration.

 -  The effects of neratinib and fulvestrant on the developing human fetus are unknown.
 For this reason and because SERD agents are known to be teratogenic, women of
 child-bearing potential must agree to be abstinent, or to use a highly effective
 double barrier method of contraception (e.g, a combination of male condom with an
 intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with
 spermicide) or a non-hormonal method, while enrolled in the study, until at least 28
 days after the last dose of neratinib or 1 year after the last dose of fulvestrant.
 Should a woman become pregnant or suspect she is pregnant while she is participating
 in this study, she should inform her treating physician immediately. If a woman is of
 childbearing potential, she must agree to use adequate contraception prior to the
 study, for the duration of study participation, and for one year after completion of
 the study drug.

 -  Ability to understand and willingness to sign a written informed consent document.

 Exclusion Criteria:

 -  Participants who have a history of allergic reactions attributed to compounds of
 similar chemical or biologic composition to neratinib or fulvestrant.

 -  Participants who have known hypersensitivity to any component of loperamide or
 colestipol.

 -  Participants who have received previous therapy with neratinib.

 -  Participants who have received anti-cancer therapy (including chemotherapy, biological
 therapy, investigational agents, hormonal therapy, or other anti-cancer therapy) or
 radiotherapy within ≤14 days prior to the planned initiation of investigational
 products, or those who have not recovered to grade ≤1from adverse events due to their
 most recent therapy (excepting alopecia).

 -  Participants who have had any major surgery ≤28 days prior to the planned initiation
 of study therapy, or those who have not recovered from adverse events due to
 agents/surgery administered more than 4 weeks earlier.

 -  Participants who are receiving any other investigational agents.

 -  Participants with known brain metastases that are untreated, symptomatic, or require
 therapy to control symptoms. Participants with a history of treated central nervous
 system (CNS) metastases are eligible. Treated brain metastases are defined as those
 without ongoing requirement for corticosteroids, as ascertained by clinical
 examination and/or brain imaging (magnetic resonance imaging or CT scan) completed
 during screening. Any corticosteroid use for brain metastases must have been
 discontinued without the subsequent appearance of symptoms for ≥ 7 days prior to
 registration. Treatment for brain metastases may include whole brain radiotherapy,
 radiosurgery, surgery or a combination as deemed appropriate by the treating
 physician. Radiation therapy must be completed at least 14 days prior to registration.

 -  Participant has active, uncontrolled cardiac disease, including cardiomyopathy,
 congestive heart failure (New York Heart Association functional classification of ≥2),
 unstable angina, myocardial infarction within 12 months of enrollment, or ventricular
 arrhythmia.

 -  Participant has a QTc interval >470 ms or known history of QTc prolongation or Torsade
 de Pointes.

 -  Participant has an active infection or unexplained fever >38.5°C (101.3°F).

 -  Participant has had another malignancy within the past 5 years with the exception of
 a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid
 cancer; b) carcinoma in situ of the breast, cervix or vulva; or c) cancer considered
 cured by surgical resection or unlikely to impact survival during the duration of the
 study, such as localized transitional cell carcinoma of the bladder, or benign tumors
 of the adrenal or pancreas.

 -  Participant has significant chronic gastrointestinal disorder with diarrhea as a major
 symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 (NCI CTCAE v.4.0) diarrhea
 of any etiology at screening).

 -  Participant has known active infection with hepatitis B or hepatitis C virus.
 Hepatitis B and C serology testing is not required, unless active infection is
 suspected.

 -  Participant is unable or unwilling to swallow tablets.

 -  Participant has evidence of significant medical illness, abnormal laboratory finding,
 or psychiatric illness/social situations that would, in the Investigator's judgment,
 limit compliance with study requirements.

 -  Pregnant women are excluded from this study because fulvestrant is a SERD agent with
 the potential for teratogenic or abortifacient effects. Because there is an unknown
 but potential risk for adverse events in nursing infants secondary to treatment of the
 mother with neratinib and/or fulvestrant, breastfeeding should be discontinued if the
 mother is treated with neratinib and/or fulvestrant.