Clinical Trials /

Pembrolizumab, Letrozole, and Palbociclib in Treating Postmenopausal Patients With Newly Diagnosed Metastatic Stage IV Estrogen Receptor Positive Breast Cancer

NCT02778685

Description:

This phase II trial studies how well pembrolizumab works when given together with letrozole and palbociclib in treating postmenopausal patients with newly diagnosed stage IV estrogen receptor positive breast cancer that has spread to other parts of the body. . Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast cancer cells. Antihormone therapy, such as letrozole, may lessen the amount of estrogen made by the body. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab, letrozole, and palbociclib may be an effective treatment for patients with stage IV estrogen receptor positive 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> Letrozole, and <span class="go-doc-concept go-doc-intervention">Palbociclib</span> in Treating Patients With Stage IV <span class="go-doc-concept go-doc-alteration">Estrogen Receptor Positive</span> Breast Cancer With Stable Disease That Has Not Responded to Letrozole and <span class="go-doc-concept go-doc-intervention">Palbociclib</span>

Title

  • Brief Title: Pembrolizumab, Letrozole, and Palbociclib in Treating Patients With Stage IV Estrogen Receptor Positive Breast Cancer With Stable Disease That Has Not Responded to Letrozole and Palbociclib
  • Official Title: Phase II Study of the Addition of MK-3475 (Pembrolizumab) to Letrozole and Palbociclib in Patients With Metastatic Estrogen Receptor Positive Breast Cancer Who Have Stable Disease But Are Not Responding to Letrozole and Palbociclib
  • Clinical Trial IDs

    NCT ID: NCT02778685

    ORG ID: 16058

    NCI ID: NCI-2016-00694

    Trial Conditions

    Estrogen Receptor Positive

    HER2/Neu Negative

    Postmenopausal

    Recurrent Breast Carcinoma

    Stage IV Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Letrozole CGS 20267, Femara Treatment (letrozole, palbociclib, pembrolizumab)
    Palbociclib Ibrance, PD-0332991, PD-332991 Treatment (letrozole, palbociclib, pembrolizumab)

    Trial Purpose

    This phase II trial studies the how well pembrolizumab works when given together with
    letrozole and palbociclib in patients with stage IV estrogen receptor positive breast cancer
    with stable disease that has not responded to letrozole and palbociclib. Monoclonal
    antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and
    spread. Estrogen can cause the growth of breast cancer cells. Antihormone therapy, such as
    letrozole, may lessen the amount of estrogen made by the body. Palbociclib may stop the
    growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving
    pembrolizumab, letrozole, and palbociclib may be an effective treatment for patients with
    stage IV estrogen receptor positive breast cancer.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate the objective response rate (ORR), based on Response Evaluation Criteria In
    Solid Tumors [RECIST], version 1.1), of pembrolizumab in combination with letrozole and
    palbociclib in patients with metastatic estrogen receptor (ER)+human epidermal growth factor
    receptor (HER)2- breast cancer, and determine if the addition of pembrolizumab in patients
    with stable disease (SD) on letrozole and palbociclib can achieve a response (complete
    response [CR], partial response [PR], and ORR) measured from the study baseline, based on
    RECIST version 1.1.

    SECONDARY OBJECTIVES:

    I. To determine the safety and tolerability of adding pembrolizumab (200 mg every 3 weeks)
    to ongoing treatment with letrozole (2.5 mg) and palbociclib (3 weeks on, one week off: dose
    of palbociclib can vary secondary to individual patient tolerance, range 75-125 mg) in
    patients with metastatic ER+HER2- breast cancer.

    II. To evaluate progression-free survival (PFS). III. To evaluate overall survival (OS). IV.
    To evaluate duration of response (DOR) using RECIST version 1.1. V. To evaluate clinical
    benefit rate (CBR) using RECIST version 1.1. VI. To evaluate toxicities (using the National
    Cancer Institute [NCI] Common Terminology Criteria for adverse Events [CTCAE], version 4.0)
    associated with the triple drug combination (pembrolizumab, letrozole, and palbociclib) in
    patients with metastatic ER+HER2- breast cancer.

    VII. To evaluate CR, PR, ORR, PFS, DOR, and CBR using immune-related Response Criteria In
    Solid Tumors (irRECIST); time to treatment failure will also be assessed.

    TERTIARY OBJECTIVES:

    I. To study cellular/humoral immune response by analyzing immune and stromal cell
    characteristics before and after treatment that correlate with clinical response; this
    includes programmed cell death 1 ligand 1 (PD-L1) expression levels.

    II. To study the peripheral serum thymidine kinase (TK) level and its association with
    treatment response.

    III. To study circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and the effect of
    combining pembrolizumab, letrozole, and palbociclib on ctDNA profiles.

    OUTLINE:

    Patients receive letrozole orally (PO) once daily (QD) on days 1-28 and palbociclib PO QD
    for 3 weeks. Courses with letrozole and palbociclib repeat every 28 days in the absence of
    disease progression or unacceptable toxicity. Patients also receive pembrolizumab
    intravenously (IV) over 30 minutes on day 1. Courses with pembrolizumab repeat every 21 days
    in the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up at 30 days, every 6 months for
    3 years, and then every 12 months for 1 year.

    Trial Arms

    Name Type Description Interventions
    Treatment (letrozole, palbociclib, pembrolizumab) Experimental Patients receive letrozole PO QD on days 1-28 and palbociclib PO QD for 3 weeks. Courses with letrozole and palbociclib repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Courses with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity. Letrozole, Palbociclib

    Eligibility Criteria

    Inclusion Criteria:

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

    - Willing and able to comply with all aspects of the treatment protocol

    - Postmenopausal women defined by at least one of the following criteria:

    - Prior bilateral oophorectomy OR amenorrheic for >= 12 months (if =< 55 years of
    age and prior to 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 (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)

    - Presence of measurable disease meeting the following criteria: at least 1 lesion of >
    10 mm in long axis diameter for non-lymph nodes or > 15 mm in short axis diameter for
    lymph nodes that is serially measurable according to RECIST version 1.1 using
    computerized tomography, magnetic resonance imaging, or panoramic and close-up color
    photography

    - Stage IV metastatic ER+HER2- breast cancer histologically proven per current American
    Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines

    - Life expectancy of >= 3 months

    - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1

    - Patients must have been undergoing treatment with letrozole and palbociclib for >= 6
    months with SD per RECIST version 1.1 and have tumors that have ceased to decrease
    (up to 20% of tumor growth allowed); patients who initially achieved best response as
    PR by ceased to continue to decrease and became SD (based on the PR nadir) during
    later courses are eligible (6 months SD disease)

    - Received 1-3 lines of previous therapy including endocrine and/or chemotherapy in
    advanced setting

    - Resolution of grade >= 2 toxicities of most recent therapy except for stable sensory
    neuropathy (=< grade 2) and alopecia

    - Willing to provide tissue from a newly obtained core or excisional biopsy of a tumor
    lesion; newly-obtained is 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 study primary investigator (PI)

    - 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 (glomerular filtration rate [GFR] can also be used in place of
    creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
    levels > 1.5 x institutional ULN

    - 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 (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 along as PT or PTT is within therapeutic range of intended
    use of anticoagulants

    - Female subjects 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 two 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

    Exclusion Criteria:

    - Patients currently participating and receiving study therapy or who have participated
    in a study of an investigational agent and received study therapy or used and
    investigational device within 4 weeks of the first dose of treatment

    - Previously received pembrolizumab or other anti-programmed cell death-1 (PD-1) or
    anti-PD-L1 immunotherapy

    - Does not have measurable disease per RECIST 1.1

    - Currently responding to letrozole and palbociclib with recent restaging imaging
    showing CR or PR (by RECIST 1.1)

    - 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

    - Known history of active TB (bacillus tuberculosis)

    - Hypersensitivity to pembrolizumab or any of its excipients

    - Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or
    has not recovered (i.e., =< grade 1 or at baseline) for adverse events (AEs) due to
    agents administered > 4 weeks earlier

    - Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
    weeks prior to stay day 1 or has not recovered (i.e. =< grade 1 or at baseline) from
    AEs due to a previously administered agent;

    - Note: Patients with =< grade 2 neuropathy are an exception to this criterion and
    may qualify for the study;

    - Note: If patient received major surgery, she must have recovered adequately from
    the toxicity and/or complications from the intervention prior to starting
    therapy

    - Known additional malignancy that is progressing or requires active treatment;
    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

    - Known active central nervous system (CNS) metastases and/or carcinomatous meningitis;
    patients with previously treated brain metastases may participate provided they are
    stable (without evidence of progression by imaging for at least 4 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

    - 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

    - Known history of, or any evidence of active, non-infectious pneumonitis that require
    treatment with steroids

    - History of interstitial lung disease

    - Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI)
    obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)

    - Active infection requiring systemic therapy

    - History of significant cardiovascular disease, defined as: congestive heart failure
    greater than New York Heart Association (NYHA) class II according to the NYHA
    functional classification; unstable angina or myocardial infarction within 6 months
    of enrollment; or serious cardiac arrhythmia

    - Clinically significant electrocardiogram (ECG) abnormality, including a marked
    baseline prolonged QT/corrected QT (QTc) ([QT interval/corrected QT interval], e.g.,
    a repeated demonstration of a QTc interval > 480 ms), a family or personal history of
    long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or
    Torsade de Pointes (TdP)

    - Concurrent use of drugs that are known to be moderate or strong cytochrome P450,
    family 3, subfamily A (CYP3A) inhibitors or inducers or drugs that are known to
    prolong the QT interval

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

    - Pregnant or breastfeeding, or expecting to conceive 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

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

    - Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

    - 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)

    - 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: Female

    Primary Outcome Measures

    Response rate (CR or PR) assessed using RECIST version 1.1

    Secondary Outcome Measures

    Clinical Benefit Response assessed using RECIST version 1.1

    Duration Of Response assessed using RECIST version 1.1

    Incidence of adverse events assessed by NCI CTCAE, version 4

    Overall Survival assessed using RECIST version 1.1

    Progression Free Survival assessed using RECIST version 1.1

    Time to treatment failure assessed using irRECIST

    Trial Keywords