Ruxolitinib in Combination With Trastuzumab in Metastatic HER2 Positive Breast Cancer

Breast cancer is the most common female cancer and the second most common cause of cancer
death in women. Approximately 1,150,000 cases and 410,000 deaths from breast cancer occur
annually worldwide, and, in the U.S., there are an estimated 184,450 new cases and 40,480
deaths from breast cancer every year. The vast majority of patients who die from breast
cancer succumb to metastatic disease. The human epidermal growth factor receptor type 2 gene
(HER2) is amplified in 20% to 30% of breast cancers.

HER2+ breast cancers are associated with earlier recurrence and shorter overall survival and
are associated with other adverse prognostic markers, such as high tumor grade, high rates of
cell proliferation, increased nodal metastases, and relative resistance to certain types of
chemotherapy. The HER family of receptors is a group of related transmembrane receptor
tyrosine kinases that regulate normal cell survival, proliferation, differentiation, and
migration.

Inclusion Criteria:

- Subjects must have histologically or cytologically confirmed adenocarcinoma of the
breast with locally recurrent or metastatic disease. Locally recurrent disease must
not be amenable to any local treatment with curative intent. Metastatic disease must
be demonstrated either radiographically or histologically.

- Primary tumors and/or metastatic lesions must demonstrate HER2-neu overexpression, per
the 2013 recommendations, i.e. immunohistochemistry (IHC 3+) or amplification by in
situ hybridization based on the following:

1. Single-probe average HER2 copy number ≥6.0 signals/cell

2. Dual-probe HER2/Chromosome 17 centromere (CEP17) ratio ≥2.0 with an average HER2
copy number ≥4.0 signals/cell

3. Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number <4.0
signals/cell

4. Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number > 6.0
signals/cell

- Patients should have progressed on at least two lines of HER2-directed therapy in the
metastatic setting, and prior therapy for metastatic disease should include both
pertuzumab and ado-trastuzumab unless contraindicated or declined by the patient.

- There is no upper limit on the number prior therapies

- Patients may have measurable disease only, non-measurable disease only, or both
(RECIST 1.1). Concomitant treatment with bone-targeted therapies such as Receptor
activator of nuclear factor kappa-B ligand (RANKL) inhibitors or bisphosphonates is
allowed. It is anticipated that most patients will have measurable disease, given the
behavior of HER2+ metastatic breast cancer.

- Because no dosing or adverse event data are currently available on the use of
ruxolitinib in combination with trastuzumab in patients <18 years of age, children are
excluded from this study.

- Women and men of all races and ethnic groups are eligible for this trial.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky equal to
or greater than 60)

- Left ventricular ejection fraction greater than or equal to 50 percent by
transthoracic echocardiography or multi-gated acquisition scan (MUGA) within 28 days
prior to the first dose of the study drug.

- The subject has a baseline corrected QT interval less than or equal to 480ms.

- Patients must have normal organ and marrow function as defined below:

1. leukocytes greater than or equal to 3,000/microliter (mcL).

2. absolute neutrophil count greater than or equal to 1,500/mcL.

3. platelets greater than or equal to 100,000/mcL.

4. hemoglobin greater than or equal to 9 g/dL.

5. total bilirubin less than or equal to 1.5 times the upper limit of normal.

6. Aspartate Aminotransferase (AST/SGOT)/ Alanine Aminotransferase (ALT/SGPT) less
than or equal to 2.5 time institutional upper limit of normal.

7. Serum creatinine less than or equal to 1.5 times the upper limit of normal or
calculated creatinine clearance greater than or equal to 60 mL/min.

- Women of childbearing potential and men must use adequate contraception prior to study
entry and for the duration of study participation. Contraception should continue to be
used for a minimum of 5 mean half-lives after the last dose of study drugs (mean
Trastuzumab half-life at 6 mg/kg 16 days; mean half-life Ruxolitinib: 3 hours)

- Patient is able to swallow, retain, and absorb oral medication.

- Informed Consent. Ability to understand and the willingness to sign a written informed
consent document.

Exclusion Criteria:

- Patients who have had chemotherapy, hormonal therapy, or radiotherapy within 2 weeks
prior to entering the study or those who have not recovered from adverse events due to
agents administered more than 2 weeks earlier.

- Patients who are receiving any other investigational agents or have received other
investigational agents within 2 weeks or 5 half-lives of the compound or active
metabolites, whichever is longer before the first dose of the study treatment.

- Patients who have previously been treated with an interleukin-6 (IL-6), Janus kinase
(JAK) or Signal Transducers and Activators of Transcription (STAT) inhibitor for any
indication, such as ruxolitinib or tocilizumab.

- The subject has untreated, symptomatic, or progressive brain metastases. History of
Central Nervous System (CNS) metastases or cord compression is allowable if patient
has been clinically stable for at least 6 weeks since completion of definitive
treatment and is off steroids without symptoms for at least 28 days.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ruxolitinib or trastuzumab.

- The effects of ruxolitinib on the developing human fetus are unknown. For this reason
and because Janus kinase 2 (JAK2) inhibitor agents as well as other therapeutic agents
used in this trial are known to be teratogenic, women of child-bearing 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 she or her partner is
participating in this study, she should inform the principal investigator immediately.

- Patients receiving any medications or substances that are strong inhibitors of
cytochrome P450 (CYP450) 3A4 isoenzyme are ineligible. Patients must be off the strong
inhibitor for at least 1 week prior to being deemed eligible.

- Patients may not have an uncontrolled intercurrent illness including, but not limited
to, ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness that would limit compliance with
study requirements.

- Patients must not have clinically significant cardiovascular disease (New York Heart
Association Class III or IV heart failure), uncontrolled clinically significant atrial
or ventricular cardiac arrhythmias, or any of the following within the past 6 months:
myocardial infarction, new evidence of transmural infarction on electrocardiogram
(ECG), unstable angina, coronary angioplasty.

- Pregnant women are excluded from this study because ruxolitinib is a Class C agent
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with ruxolitinib, breastfeeding must be discontinued if the
mother is treated with ruxolitinib. These potential risks also apply to trastuzumab,
which can cause fetal harm when administered to a pregnant woman.

- Active Infections. Patients with known active infections with human immunodeficiency
virus (HIV), hepatitis A virus (HAV), hepatitis B (HBV), and hepatitis C virus (HCV)
infections will not be considered for this trial. HIV+ patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with ruxolitinib. In addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy. Testing for HIV or
hepatitis is not required.