This is an open-label, phase 2 study that will investigate colon pathology in patients with
HER2-positive breast cancer treated with neratinib as monotherapy.
All patients will receive neratinib for the first 28 days as a single daily dose of 240 mg.
Colonoscopy will be performed after eligibility has been confirmed, but prior to
administration of the first dose of neratinib and at Day 30 (± 3 days) the conclusion of
Cycle 1 (28 days).
Following the second study colonoscopy procedure:
- For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant
setting, neratinib will continue to be administered at a single daily dose of 240 mg
until completion of one year of therapy from start of treatment, or until disease
recurrence (as determined by the Investigator), death, unacceptable toxicity, or other
specified withdrawal criterion.
- For patients being treated for metastatic breast cancer (mBC), capecitabine will be
introduced after the second study colonoscopy procedure at a dose of 750mg/m2 twice
daily for 14 days of each 21 day treatment cycle, with neratinib administered
continuously throughout at 240 mg daily, until disease progression, death, unacceptable
toxicity, or other specified withdrawal criterion.
All patients will receive loperamide diarrhea prophylaxis daily for one 28-day cycle and then
1. Aged ≥18 years.
2. Histologically confirmed stage 1 through stage 4 primary adenocarcinoma of the breast.
3. Documented HER2 overexpression or gene-amplified tumor by a validated approved method.
4. Participants with confirmed stage 1 to stage 3c breast cancer receiving extended
adjuvant treatment with neratinib monotherapy must have completed a course of prior
adjuvant trastuzumab or experienced side effects that resulted in early
discontinuation of trastuzumab that have since resolved.
5. Participants with mBC must have had at least 2 prior HER2-directed regimens.
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition
scan (MUGA) or echocardiogram (ECHO).
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.
8. Negative β-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
9. Women of childbearing potential must agree and commit to the use of a highly effective
non-hormonal method of contraception, i.e., intrauterine device, bilateral tubal
ligation, vasectomized partner, or abstinence (only when it is the preferred lifestyle
of the participant), from the time of informed consent until 28 days after the last
dose of the investigational products. Men (male participant) with a female partner of
childbearing potential must agree and commit to use condom and the female partner must
agree and commit to use a highly effective method of contraception (i.e., any of the
above methods, or for females, hormonal contraception associated with inhibition of
ovulation) while on treatment and for 3 months after last dose of investigational
10. Recovery (i.e., to Grade 1 or baseline) from all clinically significant adverse events
related to prior therapies (excluding alopecia, neuropathy, and nail changes).
11. No major bleeding diathesis or use of anticoagulants that would pose a high risk for
12. Provide written, informed consent to participate in the study and follow the study
1. Participants with confirmed stage 1 to stage 3c currently receiving chemotherapy,
radiation therapy, immunotherapy, or biotherapy for breast cancer.
2. Participants with mBC who have received prior capecitabine or HER2 directed tyrosine
kinase inhibitor (TKI) therapy.
3. Currently using drugs that have been implicated as causing microscopic colitis/watery
diarrhea, such as acarbose, aspirin, proton pump inhibitors, nonsteroidal
anti-inflammatory drugs (NSAIDs), histamine H2 receptor antagonists, selective
serotonin reuptake inhibitors, and ticlopidine (Pardi, 2017).
4. Major surgery within <28 days of starting treatment or received chemotherapy,
investigational agents, or other cancer therapy, except hormonal therapy (e.g.,
tamoxifen, aromatase inhibitors), <14 days prior to the initiation of investigational
5. 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.
6. Corrected QT Interval (QTc) interval >0.450 seconds (males) or >0.470 (females), or
known history of QTc prolongation or Torsade de Pointes (TdP).
7. Diagnosis of inflammatory bowel disease
8. Screening laboratory assessments outside the following limits:
Laboratory Parameters Required Limit for Exclusion Absolute neutrophil count (ANC)
<1,000/µl (<1.0 x 109/L) Platelet count <50,000/µl (<100 x 109/L) Hemoglobin <8 g/dL
(transfusions allowed) Transfusions must be at least 14 days prior to initiation of
treatment Total bilirubin >1.5 x institutional upper limit of normal (ULN) (in case of
known Gilbert's syndrome, <2 x ULN is allowed) Aspartate aminotransferase (AST) and/or
alanine aminotransferase (ALT) >2.5 x institutional ULN (>5 x ULN if liver metastases
are present) Creatinine Creatinine clearance <30 mL/min (as calculated by
Cockcroft-Gault formula A or Modification of Diet in Renal Disease formula B)
International Normalized Ratio (INR) >1.5 a Cockcroft and Gault, 1976 b Levey et al,
9. Active, unresolved infections.
10. Participants with a second malignancy, other than adequately treated non-melanoma skin
cancers, in situ melanoma or in situ cervical cancer. Participants with other
non-mammary malignancies must have been disease free for at least 5 years.
11. Currently pregnant or breast-feeding.
12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg,
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).
13. Clinically active infection with hepatitis B or hepatitis C virus.
14. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric
illness/social situations that could, in the Investigator's judgment, make the person
inappropriate for this study.
15. Known hypersensitivity to any component of the investigational products; known
allergies to any of the medications or components of medications used in the trial.
16. Unable or unwilling to swallow tablets