Ruxolitinib Phosphate and Trastuzumab in Treating Patients with Metastatic HER2-Positive Breast Cancer

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: * Single-probe average HER2 copy number >= 6.0 signals/cell * Dual-probe HER2/chromosome enumeration probe 17 (CEP17) ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell * Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell * Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number > 6.0 signals/cell * Patients may be estrogen and/or progesterone positive (>= 1%) or negative (< 1%); hormone receptor status will be a stratification factor
• Patients must have received at least two lines of HER2-directed therapy in the inoperable locally advanced and/or metastatic setting; prior therapy for inoperable locally advanced/metastatic disease should include trastuzumab plus pertuzumab as well as ado-trastuzumab; pertuzumab and ado-trastuzumab should have been previously used, unless for reasons that include, but are not limited, to the following: intolerance to pertuzumab and/or ado-trastuzumab, medical contraindication, regimen declined by patient, treating investigator discretion, or medical insurance coverage issues which prevented administration of pertuzumab or ado-trastuzumab; these reasons must be reviewed with the study chairs and documented in the medical record and care report form; patients who relapse within 12 months of completing neoadjuvant/adjuvant pertuzumab or ado-trastuzumab would be considered as having progressed on that regimen
• Patients may have measurable disease only, non-measurable disease only, or both (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1); concomitant treatment with bone-targeted therapies such as RANKL inhibitors or bisphosphonates is allowed; it is anticipated that most patients will have measurable disease, given the behavior of HER2+ metastatic breast cancer
• Women and men of all races and ethnic groups are eligible for this trial
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)
• Left ventricular ejection fraction >= 50% 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 =< 480 ms
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 x the upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Serum creatinine =< 1.5 x the upper limit of normal or calculated creatinine clearance >= 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
• Life expectancy of at least 12 weeks
• 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 IL-6, JAK or STAT inhibitor for any indication, such as ruxolitinib or tocilizumab
• Symptomatic or unstable brain metastases; (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to randomization are eligible to participate in the study)
• 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 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 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
• 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; testing for HIV or hepatitis is not required 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.