A Phase II Study of Neratinib in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

Inclusion Criteria

Inclusion Criteria for Pre-registration:

- Histologically or cytologically confirmed stage IV breast cancer that is
HER2-negative (0 or 1+ by IHC or non-amplified by FISH).

- Administration of at least one line of prior systemic therapy for metastatic breast
cancer.

- Presence of measurable or non-measurable disease by RECIST 1.1.

- At least 18 years of age.

- ECOG performance status < or = 2.

- Adequate organ function as defined below within 2 weeks of pre-registration:

- Serum creatinine < or = 1.5 x ULN

- Total bilirubin < or = 1.5 x ULN )in case of known Gilbert's syndrome, < 2 x ULN
is allowed)

- AST and ALT < or = 3 x ULN

- Patient (or legally authorized representative if applicable) must be able to
understand and willing to sign an IRB approved written informed consent document.

Note: HER2 mutation testing may be performed while the patient is receiving active
systemic therapy for metastatic breast cancer so that the result can be used to determine
eligibility for study drug therapy in the future.

Exclusion Criteria for Pre-registration:

- Testing for LVEF is not required for pre-registration, but patient must not have a
recent LVEF < LLN or have symptoms of congestive heart failure.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

- Acute or currently active hepatic or biliary disease requiring antiviral therapy
(with the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases,
or stable chronic liver disease per investigator assessment).

- History of significant cardiac disease, cardiac risk factors, or uncontrolled
arrhythmias.

- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs
resulting in dyspnea at rest.

Inclusion Criteria for Registration

- Tumor tissue tested positive for HER2 mutation.

- ECOG performance status < or = 2.

- Adequate organ function as defined below within 2 weeks of registration:

- ANC > or = 1.5 x 10^9/L

- Platelet count > or = 100 x 10^9/L

- Serum creatinine < or = 1.5 x ULN

- Total bilirubin < or = 1.5 x ULN (in case of known Gilbert's syndrome, < 2 x ULN
is allowed)

- AST and ALT < or = 3 x ULN

- The patient must have completed radiation therapy and be at least 1 week from the
last systemic chemotherapy administration, with adequate recovery of bone marrow and
organ functions, before starting neratinib.

- Presence of disease that progressed on the most recent treatment regimen.

- Patients with known brain metastasis are eligible, but must have received radiation
and be off steroids and stable (without evidence of disease progression by imaging or
exam) for 3 months.

- QTc interval < or = 0.450 seconds within 2 weeks of registration.

- LVEF > or = institutional ILLN within 4 weeks of registration.

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she must inform her treating
physician immediately

- Patient (or legally authorized representative if applicable) must be able to
understand and willing to sign an IRB approved written informed consent document.

Exclusion Criteria for Registration:

- Currently receiving any other investigational agents or systemic cancer therapy.

- Currently taking medications and herbal or dietary supplements that are strong
cytochrome P450 (CYP) 3A4 inducers or inhibitors. The washout period must have been
completed prior to the start of neratinib if the patient was taking any of these
agents.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Acute or currently active/requiring antiviral therapy hepatic or biliary disease
(with the exception of patients with Gilbert's syndrome, asymptomatic gallstones,
liver metastases, or stable chronic liver disease per investigator assessment).

- Pregnant and/or breastfeeding.

- History of significant cardiac disease, cardiac risk factors, or uncontrolled
arrhythmias.

- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs
resulting in dyspnea at rest.