Trastuzumab, Neratinib, Loperamide Hydrochloride, and Crofelemer in Reducing Severity of Diarrhea in Patients with Stage II-IIIC Breast Cancer

Status: Active


This phase II trial studies the side effects and how well trastuzumab, neratinib, loperamide hydrochloride, and crofelemer work in reducing severity of diarrhea in patients with stage II-IIIC breast cancer. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Loperamide hydrochloride and crofelemer may reduce the severity of diarrhea. Giving trastuzumab, neratinib, loperamide hydrochloride, and crofelemer may work better in treating patients with stage II-IIIC breast cancer.

Eligibility Criteria

Inclusion Criteria

  • 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 or be within 1 year of completing adjuvant trastuzumab monotherapy maintenance
  • Clinically no evidence of metastatic disease at the time of study entry
  • 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]
  • 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
  • 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/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
  • Patients with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer; patients with other non-mammary malignancies must have been disease-free for at least 5 years
  • 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

Locations & Contacts


San Francisco
UCSF Medical Center-Mount Zion
Status: Active
Contact: Amy Jo Chien
Phone: 415-885-7577

Trial Objectives and Outline


I. To characterize the incidence and severity of diarrhea in patients with early stage breast cancer receiving adjuvant trastuzumab and neratinib followed by 1 year of neratinib monotherapy in the setting of prophylactic anti-diarrheal management.


I. To evaluate the activity of crofelemer as a rescue anti-diarrheal medication.

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.


Patients receive loperamide hydrochloride orally (PO) twice daily (BID) and crofelemer PO BID for 2 courses. Patients also receive one of the following treatment regimen:

NERATINIB MONOTHERAPY: Patients receive neratinib PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

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 52 weeks. After completion of trastuzumab treatment, patients continue to receive neratinib monotherapy PO QD on days 1-21 for another 52 weeks in the absence of disease progression or unacceptable toxicity.

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

Trial Phase & Type

Trial Phase

Phase II

Trial Type


Lead Organization

Lead Organization
UCSF Medical Center-Mount Zion

Principal Investigator
Amy Jo Chien

Trial IDs

Primary ID 167514
Secondary IDs NCI-2017-01443, 16-21133 ID NCT03094052