Ruxolitinib in Combination With Trastuzumab in Metastatic HER2 Positive Breast Cancer
Ruxolitinib in Combination With Trastuzumab in Metastatic HER2 Positive Breast Cancer
The purpose of this study is to examine the safety and efficacy of Ruxolitinib in combination
 with Trastuzumab in treatment of HER2 positive metastatic breast cancer. Ruxolitinib (Jakafi)
 is an Food and Drug Administration (FDA) approved treatment for myelofibrosis (a disease of
 the bone marrow), but its safety and efficacy in breast cancer patients is not known.
 Trastuzumab (Herceptin) is an FDA-approved treatment for HER2 positive breast cancer. The
 safety and efficacy of both treatments given in combination is not known. It is hypothesized
 that Ruxolitinib in combination with Trastuzumab will demonstrate efficacy in treating
 Metastatic HER2 Positive Breast Cancer subjects, and will have a tolerable safety profile in
 this patient population.
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.