Clinical Trials /

Ruxolitinib in Combination With Trastuzumab in Metastatic HER2 Positive Breast Cancer

NCT02066532

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Phase I/II Trial of Ruxolitinib in Combination With <span class="go-doc-concept go-doc-intervention">Trastuzumab</span> in Metastatic <span class="go-doc-concept go-doc-biomarker">HER2</span> Positive <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Phase I/II Trial of Ruxolitinib in Combination With Trastuzumab in Metastatic HER2 Positive Breast Cancer
  • Official Title: Phase I/II Trial of Ruxolitinib in Combination With Trastuzumab in Metastatic HER2 Positive Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02066532

    ORG ID: AAAM1906

    Trial Conditions

    Metastatic Breast Cancer

    Breast Carcinoma

    HER-2 Positive Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Ruxolitinib Jakafi Ruxolitinib/Trastuzumab
    Trastuzumab Herceptin Ruxolitinib/Trastuzumab

    Trial Purpose

    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.

    Detailed Description

    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.

    Trial Arms

    Name Type Description Interventions
    Ruxolitinib/Trastuzumab Experimental Jakafi (Ruxolitinib) and Trastuzumab (Herceptin) - 21 day cycle until disease progression Ruxolitinib, Trastuzumab

    Eligibility Criteria

    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/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 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated dose of Ruxolitinib in combination with Trastuzumab (Phase I)

    Prevalence of progression free survival (PFS) (Phase II)

    Secondary Outcome Measures

    Objective Response Rate

    Number of participants with adverse events

    Trial Keywords

    Breast Neoplasms

    Breast Cancer

    Breast Carcinoma

    Breast tumors

    Cancer of the Breast

    Malignant tumor of the breast

    HER2 positive

    erythroblastosis virus oncogene B-2 (erbB-2)

    Metastatic Breast Cancer

    Secondary Breast Cancer