Neratinib +/- Fulvestrant in HER2+, ER+ Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Neratinib; Fulvestrant
Intervention description: 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); Fulvestrant, works in treating breast cancer that has spread to other parts of the body
Intervention MeSH terms: Fulvestrant
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer

Summary:

      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
    

Eligibility criteria:

        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.