Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib
Condition: HER2-positive Breast Cancer; Breast Adenocarcinoma; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7
MeSH terms: Breast Neoplasms; Diarrhea
Intervention: Neratinib; Trastuzumab; Loperamide; Diphenoxylate Hydrochloride/Atropine Sulfate
Intervention description: Given orally (PO); Given Intravenously (IV); Given PO; Given PO
Intervention MeSH terms: Trastuzumab; Atropine; Diphenoxylate; Loperamide; Antidiarrheals; Atropine sulfate-diphenoxylate hydrochloride drug combination
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neratinib; Trastuzumab

Summary:

      This phase II trial studies the incidence and severity of diarrhea in patients with stage
      II-IIIC HER2 Positive breast cancer treated with trastuzumab and neratinib. Trastuzumab is a
      form of targeted therapy because it attaches itself to specific molecules (receptors) on the
      surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2
      receptors, the signals that tell the cells to grow are blocked and the cancer cell may be
      marked for destruction by the body's immune system. Neratinib may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and
      neratinib may work better in treating patients with stage II-IIIC HER2 positive breast
      cancer.
    

Eligibility criteria:

        INCLUSION CRITERIA:

          -  Age >= 18 years

          -  Histologically confirmed clinical or pathological stage 2 through stage 3c primary
             adenocarcinoma of the breast

          -  Documented human epidermal growth factor receptor 2 (HER2) overexpression or
             gene-amplified tumor by a validated approved method

          -  Patients can have hormone receptor (HR)+ or HR-negative disease

          -  Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed

          -  Patients can be premenopausal or postmenopausal

          -  Completion of neoadjuvant or adjuvant chemotherapy

          -  Completion of adjuvant locoregional radiation, if indicated, is required prior to
             starting study treatment

          -  Histologically confirmed clinical or pathological stage 2 through stage 3c primary
             adenocarcinoma of the breast

          -  Documented HER2 overexpression or gene-amplified tumor by a validated approved method

          -  Patients can have hormone receptor (HR)+ or HR-negative disease

          -  Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed

          -  Patients can be premenopausal or postmenopausal

          -  Completion of neoadjuvant or adjuvant chemotherapy

          -  Completion of adjuvant locoregional radiation, if indicated, is required prior to
             starting study treatment

          -  At the time of study enrollment, patients can still be receiving adjuvant trastuzumab
             monotherapy or be within 2 years of completing adjuvant trastuzumab +/- pertuzumab
             maintenance, or adjuvant T-DM1.

               -  Patients who are within 2 years of completing trastuzumab +/- pertuzumab or T-DM1
                  will receive neratinib monotherapy (and not neratinib + trastuzumab)

               -  Adjuvant T-DM1 is the standard of care for patients who have residual disease
                  after neoadjuvant chemotherapy. Patients with residual disease after neoadjuvant
                  chemotherapy should receive T-DM1 before enrolling on the study. If not, the
                  option of T-DM1 should be discussed with the patient

          -  Clinically no evidence of metastatic disease at the time of study entry. Patients with
             fully resected locoregional recurrence with no evidence of disease are eligible

          -  Left ventricular ejection fraction (LVEF) >= 50% measured by multiple-gated
             acquisition scan (MUGA) or echocardiogram (ECHO)

          -  Eastern Cooperative Oncology Group (ECOG) status of 0 to 1

          -  Negative beta-human chorionic gonadotropin (hCG) pregnancy test for premenopausal
             women of reproductive capacity (those who are biologically capable of having children)
             and for women less than 12 months after menopause; (women are considered
             postmenopausal if they are >= 12 months without menses, in the absence of endocrine or
             anti-endocrine therapies)

          -  Trastuzumab can cause embryo-fetal harm when administered during pregnancy and the
             effects of neratinib on the developing human fetus are unknown. Women of child-bearing
             potential must agree and commit to use of 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, from the signing of informed consent until 28 days after the last dose of
             neratinib and 7 months after the last dose of trastuzumab, or consent to total sexual
             abstinence (abstinence must occur from randomization and continue for 28 days after
             the last dose of neratinib and 7 months after the last dose of trastuzumab). Men
             without confirmed vasectomy must agree and commit to use a barrier method of
             contraception while on treatment and for 3 months after the last dose of
             investigational products, or consent to total sexual abstinence (abstinence must occur
             from randomization and continue for 3 months after the last dose of study medication)

          -  Recovery (i.e., to grade 1 or baseline) from all clinically significant adverse event
             (AE)s related to prior therapies (excluding alopecia, neuropathy, and nail changes)

          -  Provide written, informed consent to participate in the study and follow the study
             procedures

        EXCLUSION CRITERIA:

          -  Clinical or radiologic evidence of metastatic disease prior to or at the time of study
             entry. Locoregional recurrent disease that is resected is allowed

          -  Currently receiving chemotherapy, radiation therapy, investigational immunotherapy, or
             investigational biotherapy for breast cancer

          -  Major surgery (including breast surgery) within < 30 days of starting treatment or
             received chemotherapy, investigational agents, or other cancer therapy < 14 days prior
             to the initiation of investigational products (except adjuvant endocrine therapy)

          -  Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart
             failure (New York Heart Association functional classification of >= 2; including
             individuals who currently use digitalis, beta-blockers, or calcium channel blockers
             specifically for congestive heart failure), unstable angina, myocardial infarction
             within 12 months of enrollment, or ventricular arrhythmia

          -  Corrected QT (QTc) interval > 0.450 seconds (males) or > 0.470 seconds (females), or
             known history of QTc prolongation or Torsade de Pointes (TdP)

          -  Absolute neutrophil count (ANC) =< 1,000/microliter (uL)

          -  Platelets =< 100,000/uL

          -  Hemoglobin =< 9 g/dL

          -  Serum creatinine >= 1.5 x upper limit of normal (ULN) OR calculated creatinine
             clearance =< 30 mL/min for patients with creatinine levels > 1.5 x institutional ULN

             * Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin >= 1.5 x ULN OR direct bilirubin >= ULN for patients with total
             bilirubin levels > 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase ([SGOT)) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) >= 2.5 x
             ULN

          -  Second malignancy for which the patient will be receiving active treatment during the
             time of study participation.

          -  Currently pregnant or breast-feeding

          -  Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g.,
             Crohn's disease, malabsorption, or grade >= 2 National Cancer Institute (NCI) Common
             Terminology Criteria for Adverse Events Version 4.0 (CTCAE v.4.0) diarrhea of any
             etiology at baseline)

          -  Clinically active infection with hepatitis B or hepatitis C virus

          -  Evidence of significant medical illness, abnormal laboratory finding, or psychiatric
             illness/social situations that could, in the investigator's judgment, make the patient
             inappropriate for this study

          -  Known hypersensitivity to any component of the investigational products

          -  Unable or unwilling to swallow tablets