Clinical Trials /

Pembrolizumab and Doxorubicin Hydrochloride or Anti-Estrogen Therapy in Treating Patients With Triple-Negative or Hormone Receptor-Positive Metastatic Breast Cancer

NCT02648477

Description:

This phase II trial studies how well pembrolizumab and doxorubicin hydrochloride works compared to pembrolizumab with anti-estrogen therapy (anastrozole, letrozole, or exemestane) in treating patients with triple-negative or hormone-receptor positive breast cancer that has spread from the primary site (place where it started) to other places in the body. Pembrolizumab is an antibody drug that blocks a molecule called programmed death (PD)-1. PD-1 is a molecule that shuts down the body's immune responses and prevents the immune system from attacking the cancer. Doxorubicin hydrochloride is a drug used in chemotherapy that works to stop the growth of tumor cells by stopping them from dividing and by causing them to die. Anti-estrogen therapy, including anastrozole, letrozole, and exemestane, lowers estrogen levels in the body, which may help treat cancer that is hormone receptor-positive. Giving pembrolizumab together with standard treatment of either doxorubicin hydrochloride (triple-negative cancer) or anti-estrogen therapy (hormone receptor-positive cancer) may be an effective treatment for these types of breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Pembrolizumab</span> and <span class="go-doc-concept go-doc-intervention">Doxorubicin</span> Hydrochloride or Anti-Estrogen Therapy in Treating Patients With <span class="go-doc-concept go-doc-keyword">Triple-Negative</span> or Hormone Receptor-Positive <span class="go-doc-concept go-doc-disease">Metastatic Breast Cancer</span>

Title

  • Brief Title: Pembrolizumab and Doxorubicin Hydrochloride or Anti-Estrogen Therapy in Treating Patients With Triple-Negative or Hormone Receptor-Positive Metastatic Breast Cancer
  • Official Title: MK-3475 (Pembrolizumab) in Combination With an Anthracycline or Anti-estrogen Therapy in Patients With Triple Negative and Hormone Receptor Positive (HR+ HER2-) Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02648477

    ORG ID: 15295

    NCI ID: NCI-2015-02194

    Trial Conditions

    Estrogen Receptor Negative

    Estrogen Receptor Positive

    HER2/Neu Negative

    Progesterone Receptor Negative

    Progesterone Receptor Positive

    Stage IV Breast Cancer

    Triple-Negative Breast Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Anastrozole Arimidex, ICI D1033, ICI-D1033, ZD-1033 Cohort 2 (pembrolizumab, anti-estrogen therapy)
    Doxorubicin Hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex Cohort 1 (pembrolizumab, doxorubicin hydrochloride)
    Exemestane Aromasin, FCE-24304 Cohort 2 (pembrolizumab, anti-estrogen therapy)
    Letrozole CGS 20267, Femara Cohort 2 (pembrolizumab, anti-estrogen therapy)

    Trial Purpose

    This phase II trial studies how well pembrolizumab and doxorubicin hydrochloride works
    compared to pembrolizumab with anti-estrogen therapy (anastrozole, letrozole, or exemestane)
    in treating patients with triple-negative or hormone-receptor positive breast cancer that
    has spread from the primary site (place where it started) to other places in the body.
    Pembrolizumab is an antibody drug that blocks a molecule called programmed death (PD)-1.
    PD-1 is a molecule that that shuts down the body's immune responses and prevents the immune
    system from attacking the cancer. Doxorubicin hydrochloride is a drug used in chemotherapy
    that works to stop the growth of tumor cells by stopping them from dividing and by causing
    them to die. Anti-estrogen therapy, including anastrozole, letrozole, and exemestane, lowers
    estrogen levels in the body, which may help treat cancer that is hormone receptor-positive.
    Giving pembrolizumab together with standard treatment of either doxorubicin hydrochloride
    (triple-negative cancer) or anti-estrogen therapy (hormone receptor-positive cancer) may be
    an effective treatment for these types of breast cancer.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate efficacy (overall response rate) of MK-3475 (pembrolizumab) and doxorubicin
    (doxorubicin hydrochloride) in patients with stage IV triple negative breast cancer.

    II. To evaluate efficacy (overall response rate) of MK-3475 and an oral aromatase inhibitor
    in patients with stage IV hormone receptor positive (HR+) human epidermal growth factor
    receptor 2 negative (HER2-) breast cancer.

    SECONDARY OBJECTIVES:

    I. To assess clinical benefit rate (lack of progression for > 24 weeks), duration of
    response, time-to-treatment failure, progression-free survival, and overall survival in
    triple negative (TN) stage IV breast cancer patients based primarily on Response Evaluation
    Criteria in Solid Tumors (RECIST) 1.1 and immune-related (ir)RECIST.

    II. To assess feasibility and toxicity. III. To assess clinical benefit rate (lack of
    progression for > 24 weeks), duration of response, time-to-treatment failure,
    progression-free survival, and overall survival in patients with stage IV HR+ breast cancer
    based primarily on RECIST 1.1, and irRECIST.

    IV. To assess feasibility and toxicities.

    TERTIARY OBJECTIVES:

    I. To procure serial tumor (primary and metastatic) and blood (cellular and serum/plasma)
    samples and analyze them to better our understanding of cellular and humoral immune response
    correlates and predictors of clinical benefits, leading to optimized selection of target
    populations in future phase II and subsequent phase III randomized prospective trials.

    OUTLINE: Patients are assigned to 1 of 2 treatment arms.

    COHORT 1 (TRIPLE-NEGATIVE): Patients receive pembrolizumab intravenously (IV) over 30
    minutes on day 1 and doxorubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks
    for 6 courses, and then continues for up to 24 months with pembrolizumab alone in the
    absence of disease progression or unacceptable toxicity.

    COHORT 2 (HORMONE/HER2+): Patients receive pembrolizumab IV over 30 minutes on day 1 and an
    aromatase inhibitor (exemestane, anastrozole, or letrozole) orally (PO) once daily (QD) on
    days 1-21. Treatment repeats every 3 weeks for 24 months in the absence of disease
    progression or unacceptable toxicity.

    In both arms, patients who stop pembrolizumab with stable disease or better may receive
    additional pembrolizumab therapy for up to 1 year if they progress after stopping study
    treatment.

    After completion of study treatment, patients are followed up every 8-12 weeks.

    Trial Arms

    Name Type Description Interventions
    Cohort 1 (pembrolizumab, doxorubicin hydrochloride) Experimental Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 6 courses, and then continues for up to 24 months with pembrolizumab alone in the absence of disease progression or unacceptable toxicity. Patients who stop pembrolizumab with stable disease or better may receive additional pembrolizumab therapy for up to 1 year if they progress after stopping study treatment. Doxorubicin Hydrochloride
    Cohort 2 (pembrolizumab, anti-estrogen therapy) Experimental Patients receive pembrolizumab IV over 30 minutes on day 1 and an aromatase inhibitor (exemestane, anastrozole, or letrozole) PO QD on days 1-21. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity. In both arms, patients who stop pembrolizumab with stable disease or better may receive additional pembrolizumab therapy for up to 1 year if they progress after stopping study treatment. Anastrozole, Exemestane, Letrozole

    Eligibility Criteria

    Inclusion Criteria:

    - Patients with 1) stage IV metastatic triple negative breast cancer 2) stage IV HR+
    HER2- (HR+) breast cancer

    - Be willing and able to provide written informed consent/assent for the trial

    - Have measurable disease based on RECIST 1.1

    - Be willing to provide tissue from a newly obtained core or excisional biopsy of a
    tumor lesion; newly-obtained in defined as a specimen obtained up to 6 weeks (42
    days) prior to initiation of treatment on day 1; subjects for whom newly-obtained
    samples cannot be provided (e.g. inaccessible or subject safety concern) may submit
    an archived specimen only upon agreement from the sponsor

    - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
    performance scale

    - Absolute neutrophil count (ANC) >= 1,500/mcL

    - Platelets >= 100,000/mcL

    - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
    dependency (within 7 days of assessment)

    - Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
    creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 x
    institutional ULN (glomerular filtration rate [GFR] can also be used in place of
    creatinine or creatinine clearance [CrCl]); creatinine clearance should be calculated
    per institutional standard

    - Left ventricular ejection fraction by multigated acquisition scan (MUGA) or
    echocardiogram >= 55% for patients with triple negative breast cancer; >= upper limit
    of institutional normal for patient with HR+ breast cancer

    - Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
    bilirubin levels > 1.5 ULN

    - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
    alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
    x ULN OR =< 5 x ULN for subjects with liver metastases

    - Albumin >= 2.5 mg/dL

    - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
    subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
    time (PTT) is within therapeutic range of intended use of anticoagulants

    - Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
    anticoagulant therapy as long as PT or PTT is within therapeutic range of intended
    use of anticoagulants

    - Reproductive status for cohort 2: HR+ stage IV post-menopausal breast cancer;
    post-menopausal is defined by at least one of the following criteria:

    - Prior bilateral oophorectomy OR amenorrheic for >= 12 months (if =< 55 years of
    age and prior chemotherapy or on medical ovarian ablative therapy or received
    ovarian radiation for ablation in the past 5 years and/or tamoxifen or an
    aromatase inhibitor (AI) within the past year, then follicle-stimulating hormone
    (FSH) and estradiol must be in the post-menopausal range and obtained within 28
    days prior to registration) OR

    - Previous hysterectomy with one or both ovaries left in place (or previous
    hysterectomy in which documentation of bilateral oophorectomy is unavailable AND
    FSH values consistent with the institutional normal values for the
    post-menopausal state; FSH levels must be obtained within 28 days prior to
    registration

    - Female subject of childbearing potential should have a negative urine or serum
    pregnancy within 72 hours prior to receiving the first dose of study medication; if
    the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
    will be required

    - Female subjects of childbearing potential should be willing to use 2 methods of birth
    control or be surgically sterile, or abstain from heterosexual activity for the
    course of the study through 120 days after the last dose of study medication;
    subjects of childbearing potential are those who have not been surgically sterilized
    or have not been free from menses for > 1 year

    - Male subjects should agree to use an adequate method of contraception starting with
    the first dose of study therapy through 120 days after the last dose of study therapy

    Exclusion Criteria:

    - Cohort 1: Has triple negative breast cancer, is considered for cohort 1
    participation, and received prior anthracycline therapy

    - Cohort 2: Has received prior aromatase inhibitor therapy and is deemed to be
    resistant to all three (anastrozole, letrozole, exemestane) approved AIs; resistance
    is defined as progression within 12 months or while on an AI

    - Patient is premenopausal (medical ovarian suppression is allowed); is currently
    participating and receiving study therapy or has participated in a study of an
    investigational agent and received study therapy or used an investigational device
    within 4 weeks of the first dose of treatment

    - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
    other form of immunosuppressive therapy within 7 days prior to the first dose of
    trial treatment

    - Has a known history of active TB (Bacillus tuberculosis)

    - Hypersensitivity to pembrolizumab or any of its excipients

    - Suboptimal cardiac function as defined by decreased left ventricular ejection
    fraction < 55% for cohort 1, and < 50% for cohort 2

    - Prior pembrolizumab

    - Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
    day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
    due to agents administered more than 4 weeks earlier

    - Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
    within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
    baseline) from adverse events due to a previously administered agent; Note: Subjects
    with =< grade 2 neuropathy are an exception to this criterion and may qualify for the
    study; Note: If subject received major surgery, they must have recovered adequately
    from the toxicity and/or complications from the intervention prior to starting
    therapy

    - Has a known additional malignancy that has progressed or required active treatment in
    the past 5 years; exceptions include basal cell carcinoma of the skin or squamous
    cell carcinoma of the skin that has undergone potentially curative therapy or in situ
    cervical cancer

    - Has known active central nervous system (CNS) metastases and/or carcinomatous
    meningitis; subjects with previously treated brain metastases may participate
    provided they are stable (without evidence of progression by imaging for at least
    four weeks prior to the first dose of trial treatment and any neurologic symptoms
    have returned to baseline), have no evidence of new or enlarging brain metastases,
    and are not using steroids for at least 7 days prior to trial treatment; this
    exception does not include carcinomatous meningitis which is excluded regardless of
    clinical stability

    - Has active autoimmune disease that has required systemic treatment in the past 2
    years (i.e. with use of disease modifying agents, corticosteroids or
    immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or
    physiologic corticosteroid replacement therapy for adrenal or pituitary
    insufficiency, etc.) is not considered a form of systemic treatment

    - Has a history of, active pneumonitis requiring treatment with steroids or history
    of/active interstitial lung disease

    - Has an active infection requiring systemic therapy

    - Has a history or current evidence of any condition, therapy, or laboratory
    abnormality that might confound the results of the trial, interfere with the
    subject's participation for the full duration of the trial, or is not in the best
    interest of the subject to participate, in the opinion of the treating investigator

    - Has known psychiatric or substance abuse disorders that would interfere with
    cooperation with the requirements of the trial

    - Is pregnant or breastfeeding, or expecting to conceive or father children within the
    projected duration of the trial, starting with the pre-screening or screening visit
    through 120 days after the last dose of trial treatment

    - Has received prior therapy with an anti-PD-1, anti-programmed death-ligand (PD-L)1,
    or anti-PD-L2 agent

    - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

    - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
    hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
    detected)

    - Has received a live vaccine within 30 days of planned start of study therapy; Note:
    Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
    are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
    attenuated vaccines, and are not allowed

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of toxicities, assessed by Common Terminology Criteria for Adverse Events, version 4.0 criteria

    Overall response rate in PD-L1 not enriched stage IV breast cancer when combining a previously untested combination of pembrolizumab and aromatase inhibitor (exemestane preferred) (Cohort 2)

    Overall response rate in PD-L1 not enriched stage IV breast cancer when combining a previously untested combination of pembrolizumab and doxorubicin hydrochloride (Cohort 1)

    Secondary Outcome Measures

    Clinical benefit rate

    Duration of response, assessed using the RECIST 1.1

    Overall survival (OS), assessed using the RECIST 1.1

    Progression-free survival (PFS), assessed using the RECIST 1.1

    Response, assessed using the RECIST 1.1

    Time-to-treatment failure, assessed using the RECIST 1.1

    Trial Keywords