Ruxolitinib in Combination With Trastuzumab in 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 17 centromere (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 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:
• leukocytes greater than or equal to 3,000/microliter (mcL).
• absolute neutrophil count greater than or equal to 1,500/mcL.
• platelets greater than or equal to 100,000/mcL.
• hemoglobin greater than or equal to 9 g/dL.
• total bilirubin less than or equal to 1.5 times the upper limit of normal.
• Aspartate Aminotransferase (AST/SGOT)/ Alanine Aminotransferase (ALT/SGPT) less than or equal to 2.5 time institutional upper limit of normal.
• 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 indic