A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer

The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a
dose-escalation phase and an expanded cohort (phase II) to evaluate the combination of
trastuzumab emtansine (T-DM1) with neratinib in women with metastatic, HER2-positive breast
cancer. The primary aim of the phase Ib portion of this study is to determine the safety and
tolerability of the two-drug combination. The primary aim of the phase II portion is to
demonstrate efficacy.

Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week (21
day) cycle and neratinib as a continuous daily oral dose. The neratinib dose-escalation will
include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg). At the recommended phase II dose
(RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated.

The sample size of the phase I portion of the study will be between 2 and 24 patients. The
sample size of the Phase II portion will be 42 patients. Approximately 6 patients at the
Phase I RP2D level will be included in the Phase II portion. The total study enrollment will
be a maximum of 63 patients. Accrual is expected to occur over 16 months.

Submission of diagnostic tumor samples and blood samples for FB-10 correlative science
studies will be a study requirement for all patients. Blood samples will be collected at
baseline, at Cycle 2, Day 1, and at progression. Blood samples for pharmacokinetic (PK)
determination will be collected at Phase 1 sites from consenting patients at various time
points during the first 24 hours of study therapy (Cycle 1, Days 1 and 2).

An optional tumor biopsy will be procured from consenting patients from an accessible site of
metastasis before study dose level assignment (after the patient has signed the consent form
and has been screened for eligibility), after Cycle 1 of treatment, and at the time of
disease progression.

Inclusion Criteria:

- The ECOG performance status must be less than or equal to 2.

- Patients must have the ability to swallow oral medication.

- Patients must have histologic or cytologic confirmation of the diagnosis of invasive
adenocarcinoma of the breast.

- Patients must have had anti-HER2 based therapy with pertuzumab and trastuzumab for
neoadjuvant therapy, adjuvant therapy or with first line therapy for metastatic
disease (which may include trastuzumab and pertuzumab either sequentially or in
combination).

- There must be documentation that the patient has evidence of measurable metastatic
breast cancer that is accessible to biopsy at study entry.

- Patients must have estrogen receptor (ER) analysis performed prior to study entry. If
ER analysis is negative, then progesterone receptor (PgR) analysis must also be
performed. (Patients are eligible with either hormone receptor-positive or hormone
receptor-negative tumors.)

- Breast cancer must be determined by local testing to be human epidermal growth factor
receptor 2 (HER2)-positive prior to study entry using American Society of Clinical
Oncology (ASCO) - College of American Pathologists (CAP) HER2 test guidelines.

- At the time of study entry, blood counts performed within 4 weeks prior to study entry
must meet the following criteria:

- absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3;

- platelet count must be greater than or equal to 100,000/mm3; and

- hemoglobin must be greater than or equal to 9 g/dL. (Note: Patient must have
discontinued growth factors greater than or equal to two weeks prior to entry
labs.)

- The following criteria for evidence of adequate hepatic function performed within 4
weeks prior to study entry must be met:

- Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN),
and

- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less
than or equal to 1.5 x ULN for the lab or less than or equal to 5 x ULN if liver
metastasis.

- Serum creatinine performed within 4 weeks prior to study entry must be less than or
equal to 1.5 x ULN for the lab.

- The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or
multi-gated acquisition (MUGA) scan performed within 90 days prior to study entry must
be greater than or equal to 50% regardless of the facility's lower limit of normal
(LLN).

- Patients with reproductive potential must agree to use an effective non-hormonal
method of contraception during therapy, and for at least 7 months after the last dose
of study therapy.

Exclusion Criteria

- Previous therapy with T-DM1 or any HER2 tyrosine kinase inhibitor (TKI) including
neratinib for any malignancy.

- Symptomatic brain metastases or brain metastases requiring chronic steroids to control
symptoms.

- Active hepatitis B or hepatitis C with abnormal liver function tests; HIV positive
patients receiving antivirals.

- Lung disease resulting in dyspnea at rest.

- Active infection or chronic infection requiring chronic suppressive antibiotics.

- Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
the stomach or small bowel, or other disease or condition significantly affecting
gastrointestinal function.

- Persistent greater than or equal to grade 2 diarrhea regardless of etiology.

- Conditions that would prohibit intermittent administration of corticosteroids for
T-DM1 premedication.

- Chronic daily treatment with corticosteroids with a dose of greater than or equal to
10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

- Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic
BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with
hypertension that is well controlled on medication are eligible.)

- Cardiac disease (history of and/or active disease) that would preclude the use of any
of the drugs included in the treatment regimen. This includes but is not confined to:

- Active cardiac disease: symptomatic angina pectoris within the past 90 days that
required the initiation of or increase in anti-anginal medication or other
intervention; ventricular arrhythmias except for benign premature ventricular
contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; conduction abnormality requiring a pacemaker;
valvular disease with documented compromise in cardiac function; and symptomatic
pericarditis

- History of cardiac disease: myocardial infarction documented by elevated cardiac
enzymes or persistent regional wall abnormalities on assessment of left
ventricular (LV) function; history of documented congestive heart failure (CHF);
and documented cardiomyopathy

- Other nonmalignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow up.

- Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be
performed within 14 days prior to study entry according to institutional standards for
women of childbearing potential.)

- The investigator should assess the patient to determine if she has any psychiatric or
addictive disorder or other condition that, in the opinion of the investigator, would
preclude her from meeting the study requirements.

- Use of any investigational agent within 4 weeks prior to study entry.