A Study Looking the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide

This is an open-label, Phase 2 study that will investigate the incidence and severity of
diarrhea in early-stage HER2+ breast cancer patients receiving neratinib with loperamide,
alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant
treatment, who have previously undergone a course of trastuzumab therapy in the adjuvant
setting.

Patients will receive:

- Neratinib 240 mg orally once daily with food for thirteen (13) 28-day cycles.

- Loperamide daily for two (2) 28-day cycles and then as needed.

- Amendment 3, an anti-inflammatory treatment for 1 cycle and loperamide to be
administered daily for two (2) 28-day cycles and then as needed. Closed to enrollment.

- Amendment 4, colestipol for 1 cycle and loperamide to be administered 1 cycle and then
as needed. Closed to enrollment.

- Amendment 5, colestipol for 1 cycle and loperamide as needed. Closed to enrollment.

- Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1-C1D7), followed by 160 mg neratinib
for Week 2 (C1D8- C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15
to end of treatment). Loperamide as needed.

- Amendment 7, 160 mg neratinib for the first 2 weeks (C1D1 - C1D14), followed by 200 mg
neratinib for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib thereafter
(C2D1 to end of treatment). Loperamide as needed.

Inclusion Criteria:

- Age ≥18; male or female, early breast cancer (stage I-3c)

- Documented HER2+ tumor1: HER2 immunohistochemistry (IHC) 3+ or ISH+

- Documented hormone receptor (HR)-positive disease, defined as estrogen receptor
(ER)-positive and/or progesterone (PR)-positive (for patients enrolled starting with
Amendment 7.0)

- Prior course of adjuvant trastuzumab given >2 weeks and ≤1 from enrollment

- No evidence of local/regional recurrence or metastatic disease

- Radiologic assessment (Chest X-ray at a minimum) others if abnormal labs during
screening

- Eastern Cooperative Oncology Group (ECOG) PS ≤1 (0 or 1)

- Endocrine therapy and other prior HER2-directed therapy, including pertuzumab, TDM-1
is permitted

- Male patient with female partners of childbearing potential must agree and commit to
use a condom and Women of childbearing potential must agree and commit to the use of a
highly effective non-hormonal method of contraception

Exclusion Criteria:

- Major surgery < 30 days

- Chemotherapy, investigational agents, other cancer therapy < 14 days

- Normal Left Ventricular Ejection Fraction (LVEF) < 50%, Corrected QT Interval (QTc)
>0.450 seconds (males) or >0.470 (females) or other active cardiac disease

- Significant chronic GI disorder with diarrhea as a major symptom

- No evidence of metastatic breast cancer with negative chest x-ray and other imaging if
abnormal lab value