Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib

PRIMARY OBJECTIVE:

I. To characterize the incidence and severity of diarrhea in patients with early stage breast cancer receiving adjuvant neratinib with or without trastuzumab in the setting of anti-diarrheal strategies.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of grade 3 or higher diarrhea using the dose-escalation strategy and anti-diarrhea medications as needed (prn) in patients who received prior trastuzumab emtansine (T-DM1).

II. To assess neratinib adherence, holds, delays, and early discontinuation throughout the course of study therapy which includes patients receiving neratinib for > 1 year.

III. To assess overall toxicity including constipation and cardiac toxicity with concomitant neratinib and trastuzumab.

OUTLINE: This is a dose-escalation study of neratinib. Patients receive one of the following treatment regimen:

NERATINIB MONOTHERAPY: Patients receive neratinib orally (PO) once daily (QD) on days 1-21. Cycles repeats every 21 days for up to 55 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive loperamide and/or diphenoxylate hydrochloride/atropine sulfate as needed per physician discretion for symptom management.

NERATINIB AND TRASTUZUMAB: Patients receive neratinib PO QD on days 1-21. Patients also receive trastuzumab maintenance therapy as determined by treating physician. Treatment repeats every 21 days for up to 55 weeks in the absence of disease progression or unacceptable toxicity. After completion of trastuzumab treatment, patients may continue on neratinib monotherapy for the remainder of the 55 weeks. Patients may receive loperamide and/or diphenoxylate hydrochloride/atropine sulfate as needed per physician discretion for symptom management.

After completion of studies treatment, patients are followed up for 28 days.

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