Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer
Condition: Recurrent Breast Carcinoma; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7
MeSH terms: Breast Neoplasms
Intervention: Endoxifen Hydrochloride; Laboratory Biomarker Analysis; Pharmacological Study; Tamoxifen Citrate
Intervention description: Given PO; Correlative studies; Correlative studies; Given PO
Intervention MeSH terms: Tamoxifen
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 81.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well tamoxifen citrate works compared with
      z-endoxifen hydrochloride in treating patients with breast cancer that has spread to nearby
      tissue or lymph nodes or other parts of the body and has estrogen receptors but not human
      epidermal growth factor receptor 2 (HER2) receptors on the surface of its cells. Estrogen can
      cause the growth of tumor cells. Hormone therapy using tamoxifen citrate or z-endoxifen
      hydrochloride may fight breast cancer by lowering the amount of estrogen the body makes. It
      is not yet known whether tamoxifen citrate or z-endoxifen hydrochloride is more effective in
      treating patients with breast cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  PRE-REGISTRATION ELIGIBILITY CRITERIA

          -  Women who agree to undergo a standard of care core biopsy of recurrent or metastatic
             breast cancer to confirm the ER+ (>= 10% nuclear staining) and HER2 negative status

          -  Patient must have been previously treated with an aromatase inhibitor (either
             letrozole, anastrozole or exemestane) either in the adjuvant or metastatic setting,
             and have one of the following types of primary or secondary endocrine resistant
             disease

               -  Primary clinical resistance is defined as one of the following:

                    -  Recurrence within the first 2 years of adjuvant endocrine therapy while on
                       aromatase inhibitor therapy

                    -  Progression within first 6 months of initiating first-line endocrine therapy
                       (either aromatase inhibitor or fulvestrant containing regimen) for the
                       treatment of metastatic breast cancer

               -  Secondary clinical resistance is defined as one of the following:

                    -  Recurrence after year 2 while receiving adjuvant aromatase inhibitor
                       therapy, or within 12 months of completing adjuvant aromatase inhibitor
                       therapy

                    -  Progression occurring 6 or more months after initiating the first endocrine
                       therapy for metastatic disease (either fulvestrant or aromatase inhibitor
                       containing regimen)

          -  Patients with a history of measurable disease as defined by RECIST criteria or bone
             only disease are eligible; Note: those patients with non-measurable disease and bone
             metastases are eligible

          -  No history of tumors involving spinal cord or heart

          -  No current evidence of visceral crisis or lymphangitic spread

          -  No known brain metastases

          -  Women must be postmenopausal

               -  Postmenopausal status is verified by:

                    -  Prior bilateral surgical oophorectomy, or

                    -  Age >= 60 years, or

                    -  Age < 60 with no menses for > 1 year with follicle-stimulating hormone (FSH)
                       and estradiol levels within post menopausal range, according to
                       institutional standard

          -  Prior treatment

               -  No more than two prior chemotherapy regimens in the metastatic setting

               -  Prior treatment with an aromatase inhibitor (either anastrozole, letrozole or
                  exemestane), either in the adjuvant or metastatic setting is required

               -  Unlimited prior endocrine regimens in the metastatic setting, which may have
                  included an everolimus or cyclin dependent kinase (CDK) 4/6 inhibitor (such as
                  palbociclib, abemaciclib or ribociclib) containing regimen

               -  Prior tamoxifen treatment is allowed in the adjuvant setting, but patients must
                  not have experienced relapse within 1 year of stopping tamoxifen

               -  No prior treatment with tamoxifen in the metastatic setting

               -  No prior treatment with endoxifen

               -  Patients who have not fully recovered from acute, reversible effects of prior
                  therapy regardless of interval since last treatment are not eligible to
                  participate in this study

                    -  EXCEPTION: neuropathies-if grade 2 neuropathies have been stable for at
                       least 3 months since completion of prior treatment patient is eligible

          -  Not receiving any medications or substances that are strong inhibitors of cytochrome
             P450 family 2, subfamily D, polypeptide 6 (CYP2D6)

          -  Not receiving any other investigational agents

          -  No uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection

               -  Symptomatic congestive heart failure

               -  Unstable angina pectoris

               -  Uncontrolled symptomatic cardiac arrhythmia

               -  Uncontrolled hypertension (defined as blood pressure > 160/90)

          -  None of the following co-morbid conditions:

               -  Cataracts of grade 2 or greater as per Common Terminology Criteria for Adverse
                  Events (CTCAE) version 4.0

               -  Retinopathy of grade 2 or greater as per CTCAE version 4.0

                    -  Note: patients that have cataracts that do not require surgery are eligible

                    -  Note: serious adverse events will be reported on CTEP-Adverse Event
                       Reporting System (AERS) using CTCAE version (v)5.0

               -  Deep vein thrombosis/pulmonary embolism (DVT/PE) within the past 6 months

                    -  Note: patients that are on anticoagulant therapy for maintenance are
                       eligible as long as the DVT and/or PE occurred > 6 months prior to
                       enrollment, and there is no evidence for active thrombosis (either DVT or
                       PE)

          -  No other active second malignancy other than non-melanoma skin cancers within 3 years
             of pre-registration; a second malignancy is not considered active if all treatment for
             that malignancy is completed and the patient has been disease-free for at least 3
             years prior to pre-registration

          -  Eastern Cooperative Oncology Group (ECOG) performance status: 0-2

          -  Able to swallow oral formulation of the study agent

          -  Hemoglobin >= 9 g/dL

          -  Platelet count >= 75,000/mm^3

          -  Creatinine =< 1.5 x upper limits of normal (ULN)

          -  Total bilirubin =< 1.5 x upper limits of normal (ULN)

          -  Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN); for patients
             with liver metastasis: =< 5 x upper limits of normal (ULN)

          -  REGISTRATION ELIGIBILITY CRITERIA

          -  Patients with either measurable disease as defined by RECIST criteria or bone only
             disease are eligible; Note: those patients with both non-measurable disease and bone
             metastases are eligible

               -  Non-measurable bone only disease: Non-measurable bone only disease may include
                  any of the following: blastic bone lesions, lytic bone lesions without a
                  measurable soft-tissue component, or mixed lytic-blastic bone lesions without a
                  measurable soft-tissue component

               -  Lytic bone lesions, with an identifiable soft tissue component, evaluated by
                  computed tomography (CT) or magnetic resonance imaging (MRI), can be considered
                  as measurable lesions if the soft tissue component otherwise meets the definition
                  of measurability previously described

          -  No tumors involving spinal cord or heart

          -  No visceral crisis, lymphangitic spread or known brain metastases: visceral crisis is
             not the mere presence of visceral metastases, but implies severe organ dysfunction as
             assessed by symptoms and signs, laboratory studies, and rapid progression of disease

          -  Histologic confirmation, from the A011203 pre-registration biopsy, by
             institutional/local pathologist of either locally advanced or metastatic breast cancer
             that is estrogen receptor positive and HER2 negative; those patients with bone only
             disease with either no tumor or insufficient tumor for ER/progesterone receptor (PR)
             and HER2 staining after the bone biopsy are still eligible to participate in this
             study

          -  Estrogen receptor positive disease is defined as > 10% nuclear staining

          -  HER2 negative disease as per 2013 American Society of Clinical Oncology (ASCO)/College
             of American Pathologists (CAP) guidelines, one of the following must apply:

               -  0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization
                  (ISH)

               -  0 or 1+ by IHC and ISH not done

               -  2+ by IHC and not amplified by ISH or

               -  IHC not done and not amplified by ISH

          -  None of the following therapies are allowed prior to registration:

               -  Chemotherapy =< 2 weeks

               -  Immunotherapy =< 2 weeks

               -  Biologic therapy =< 2 weeks

               -  Hormonal therapy =< 2 weeks

               -  Monoclonal antibodies =< 2 weeks

               -  Radiation therapy =< 2 weeks

               -  Anti-Her-2 or other "targeted" (e.g. mammalian target of rapamycin [mTOR])
                  therapy =< 2 weeks

                    -  NOTE : Any toxicities derived from these therapies must be =< grade 2 prior
                       to starting study therapy