Clinical Trials /

Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer

NCT02453620

Description:

This phase I trial studies the side effects and best dose of entinostat and nivolumab when given together with ipilimumab in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (metastatic) or that cannot be removed by surgery (unresectable) or human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread from where it started to nearby tissue or lymph nodes or other parts of the body. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth (locally advanced/metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving entinostat and nivolumab together with ipilimumab may work better in treating in patients with solid tumors.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Entinostat</span>, Nivolumab, and <span class="go-doc-concept go-doc-intervention">Ipilimumab</span> in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic <span class="go-doc-concept go-doc-biomarker">HER2</span>-Negative <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer
  • Official Title: A Phase 1 Study Evaluating Safety, Tolerability, and Preliminary Antitumor Activity of Entinostat and Nivolumab in Combination With Ipilimumab in Advanced Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02453620

    ORG ID: NCI-2015-00741

    NCI ID: NCI-2015-00741

    Trial Conditions

    Adult Solid Neoplasm

    Breast Adenocarcinoma

    HER2/Neu Negative

    Invasive Breast Carcinoma

    Recurrent Breast Carcinoma

    Stage IIIA Breast Cancer

    Stage IIIB Breast Cancer

    Stage IIIC Breast Cancer

    Stage IV Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Entinostat HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275 Treatment (entinostat, nivolumab, ipilimumab)

    Trial Purpose

    This phase I trial studies the side effects and best dose of entinostat and nivolumab when
    given together with ipilimumab in treating patients with solid tumors that have spread to
    other places in the body and usually cannot be cured or controlled with treatment
    (metastatic) or that cannot be removed by surgery (unresectable) or human epidermal growth
    factor receptor 2 (HER2)-negative breast cancer that has spread from where it started to
    nearby tissue or lymph nodes or other parts of the body. Entinostat may stop the growth of
    tumor cells by blocking some of the enzymes needed for cell growth (locally
    advanced/metastatic). Monoclonal antibodies, such as nivolumab and ipilimumab, may block
    tumor growth in different ways by targeting certain cells. Giving entinostat and nivolumab
    together with ipilimumab may be a better treatment in patients with solid tumors.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate the safety and tolerability of the combination of entinostat and nivolumab
    with or without ipilimumab in patients with advanced solid tumors.

    II. To determine the maximum tolerated dose (MTD) of the combination of entinostat and
    nivolumab with ipilimumab in patients with advanced solid tumors.

    SECONDARY OBJECTIVES:

    I. To evaluate whether there is an increased expression of checkpoint inhibitors (programmed
    death [PD]-1/programmed death ligand [PD-L]1) in tumor biopsies after 2-week treatment with
    entinostat alone compared to baseline.

    II. To describe preliminary anti-tumor activity of entinostat and nivolumab in combination
    with or without ipilimumab in patients with advanced solid tumors.

    III. To assess preliminary anti-tumor activity in an expansion cohort of patients with
    advanced breast cancer treated at the MTD.

    TERTIARY OBJECTIVES:

    I. To explore changes in the number of myeloid derived suppressor cells (MDSCs) in
    peripheral blood and in tumor biopsies pre- and post-therapy.

    II. To explore expression of checkpoint inhibitors (PD-1/PD-L1) post-combination therapy and
    to correlate with response.

    III. To explore changes in other immune-related biomarkers (e.g., the ratio of effector T
    cells [Teffs]: regulatory T cells [Tregs], inflammatory T cell signature, T cell receptor
    [TCR] repertoire) in tumor biopsies or peripheral blood lymphocytes (PBL) pre- and
    post-therapy.

    IV. To measure tumor-specific mutations and mutant neo-antigens recognized by patient T
    cells in tumor biopsies and to describe association with response.

    V. To evaluate changes in frequency of T cells recognizing tumor-specific mutant
    neo-antigens in peripheral blood lymphocytes (PBL) pre- and post-therapy.

    VI. To evaluate changes in candidate gene expression, including the azacitidine (AZA) immune
    genes (5-AZA immune gene set [AIM] genes) in malignant tissue, gene methylation silencing in
    circulating deoxyribonucleic acid (DNA) and malignant tissue pre- and post-therapy.

    VII. To correlate the pharmacodynamic outcomes (e.g., safety, efficacy, and changes in gene
    methylation status) with the exposure of entinostat (i.e., pharmacokinetics) when
    co-administered with nivolumab with or without ipilimumab.

    VIII. To conduct pharmacogenomic association analyses to assess the potential clinical
    utility of cluster of differentiation (CD)86 gene polymorphisms as genetic determinants of
    immune mediated adverse events.

    OUTLINE: This is a phase I, dose-escalation study.

    Patients receive entinostat orally (PO) on days -14 and -7 and then weekly, nivolumab
    intravenously (IV) over 60 minutes on day 1 and then every 2-3 weeks, and ipilimumab IV over
    90 minutes on day 1 and then every 3 weeks for 4 doses. Courses repeat every 21-28 days in
    the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up every 3 months until disease
    progression and then every 6 months for up to 5 years.

    Trial Arms

    Name Type Description Interventions
    Treatment (entinostat, nivolumab, ipilimumab) Experimental Patients receive entinostat PO on days -14 and -7 and then weekly, nivolumab IV over 60 minutes on day 1 and then every 2-3 weeks, and ipilimumab IV over 90 minutes on day 1 and then every 3 weeks for 4 doses. Courses repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. Entinostat

    Eligibility Criteria

    Inclusion Criteria:

    - Dose escalation: patients must have histologically or cytologically confirmed solid
    tumor malignancy that is metastatic or unresectable and for whom either standard
    curative or palliative measures do not exist or are no longer effective, or for whom
    anti-PD-L1/cytotoxic T-lymphocyte antigen (CTLA)-4 is appropriate

    - Dose expansion: patients must have histologically or cytologically confirmed invasive
    adenocarcinoma of the breast (human epidermal growth factor receptor 2
    [HER2]-negative) that is locally advanced/metastatic and has progressed despite
    standard therapy; at least 1 prior chemotherapy regimen in the metastatic setting,
    and two lines of hormonal therapy (administered in the adjuvant or metastatic
    setting) for patients with hormone receptor-positive disease; NOTE: HER2-negativity
    will be defined per American Society of Clinical Oncology (ASCO)-College of American
    Pathologists (CAP) Guidelines; patients whose tumors have HER2 immunohistochemistry
    (IHC) 3+, in situ hybridization (ISH) >= 2.0, or average HER2 copy number >= 6.0
    signals per cell are not eligible

    - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >=
    70%)

    - Life expectancy of greater than 12 weeks

    - Hemoglobin (HgB) >= 9.0 g/dL

    - Leukocytes >= 3,000/mcL

    - Absolute neutrophil count >= 1,500/mcL

    - Platelets >= 100,000/mcL

    - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception to
    this may be allowed for participants with Gilbert's syndrome with documented approval
    by the Protocol Chair

    - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
    [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
    =< 2.5 institutional ULN

    - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min
    using the Modified Cockcroft-Gault formula

    - Negative (serum or urine) pregnancy test, for women of childbearing potential only;
    NOTE: all women of childbearing potential (WOCBP) MUST have a negative pregnancy test
    within 72 hours before receiving ipilimumab

    - Patients must have measurable disease per Response Evaluation Criteria in Solid
    Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured
    in at least one dimension (longest diameter to be recorded for non-nodal lesions and
    short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm
    (>= 15 mm for nodal lesions) with spiral computed tomography (CT) scan, magnetic
    resonance imaging (MRI), or calipers by clinical exam; NOTE: for patients with
    metastatic disease in the liver, tumor burden should not be deemed significant (e.g.,
    to no more than 30% of total liver volume as assessed by local review/investigator)

    - Adequate pulmonary function as assessed by oxygen saturation >= 90% when ambulating
    and not requiring oxygen

    - Patient must have an accessible tumor lesion from which a biopsy specimen can be
    obtained; NOTE: if baseline biopsy is attempted and is unsuccessful (e.g., patient
    intolerance, inadequate tissue), the patient will still be considered eligible for
    the study

    - Women of child-bearing potential (WOCPB) 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 her treating physician immediately; men who are sexually
    active with WOCBP must use any contraceptive method with a failure rate of less than
    1% per year; men and WOCBP must agree to adhere to contraception for the duration of
    study participation and for a period of 31 weeks after completion of agent
    administration; NOTE: a WOCBP is defined as any female who has experienced menarche
    and who has not undergone surgical sterilization (hysterectomy or bilateral
    oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12
    months of amenorrhea in a woman over 45 in the absence of other biological or
    physiological causes; in addition, women under the age of 55 must have a documented
    serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

    - Patients with a requirement for steroid treatment or other immunosuppressive
    treatment: patients should be excluded if they have a condition requiring systemic
    treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other
    immunosuppressive medications within 14 days of study drug administration; inhaled or
    topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
    are permitted in the absence of active autoimmune disease

    - Willingness to provide tissue and blood samples for mandatory translational research

    - Willingness to return to the enrolling institution for follow-up

    - Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:

    - Patients who have had chemotherapy or other systemic therapy or radiotherapy, or
    those who have not recovered from adverse events due to prior administered agents as
    follows:

    - Chemotherapy < 3 weeks prior to registration

    - Hormone therapy < 2 weeks prior to registration

    - Targeted therapy (other than below) < 2 weeks prior to registration (e.g.,
    tyrosine kinase inhibitors)

    - Trastuzumab < 6 weeks prior to registration

    - Bevacizumab < 6 weeks prior to registration

    - Nitrosoureas/mitomycin C < 6 weeks prior to registration

    - Radiotherapy < 3 weeks prior to registration (NOTE: a previously irradiated
    lesion may not be used as a target lesion unless there is evidence of
    post-radiation progression)

    - Surgery < 3 weeks prior to registration

    - Other approved or investigational agents <3 weeks prior to registration unless
    otherwise noted by the Protocol Chair

    - Patients who have received prior epigenetic, immunomodulatory or other
    checkpoint inhibitors should only be considered after discussion with the
    Protocol Chair

    - Those who have not recovered from acute adverse events to grade < 2 or baseline
    due to agents administered, with exception of alopecia, unless approved by the
    Protocol Chair

    - The following recent and concurrent systemic medications are excluded:

    - Systemic corticosteroid (> 10 mg daily prednisone equivalents) or other
    immunosuppressive medication use within 2 weeks prior to study drug
    administration

    - Concurrent administration of valproic acid

    - Known sensitivity to or history of allergic reactions attributed to compounds of
    similar chemical or biologic composition entinostat, nivolumab, or ipilimumab;
    history of severe hypersensitivity reaction to any monoclonal antibody

    - Patients with active autoimmune disease or history of autoimmune disease that might
    recur, which may affect vital organ function or require immune suppressive treatment
    including systemic corticosteroids, should be excluded; patients with a history of
    hepatitis, inflammatory bowel disease, including ulcerative colitis and Crohn's
    disease, are excluded from this study, as are patients with a history of symptomatic
    disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma],
    systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's
    Granulomatosis]); central nervous system (CNS) or motor neuropathy considered of
    autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis, multiple
    sclerosis); patients with a history of toxic epidermal necrolysis (TEN),
    Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with
    known immune impairment who may be unable to respond to anti-CTLA 4 antibody should
    also be excluded

    - NOTE: patients are permitted to enroll if they have vitiligo, type I diabetes
    mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
    replacement, psoriasis not requiring systemic treatment, or conditions not expected
    to recur in the absence of an external trigger (precipitating event)

    - Subjects with interstitial lung disease that is symptomatic or may interfere with the
    detection or management of suspected drug-related pulmonary toxicity; NOTE: subjects
    must have baseline oxygen/saturation level requirements as above

    - Patients with active or untreated brain metastases or leptomeningeal metastases are
    excluded from this clinical trial; NOTE: patients with previously treated brain
    metastases must have stable neurologic status and MRI imaging following local therapy
    (surgery or radiation) for at least 4 weeks, with no requirement for
    immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
    equivalents) for at least 2 weeks prior to study drug administration (stable low dose
    dexamethasone allowed at discretion of Protocol Chair)

    - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
    arrhythmia, or psychiatric illness/social situations that in the judgment of the
    investigator would limit compliance with study requirements

    - Pregnant women are excluded from this study; breastfeeding should be discontinued

    - Known human immunodeficiency virus (HIV)-positive patients on combination
    antiretroviral therapy are ineligible; patients who have a positive test for
    hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid
    (HCV antibody) indicating acute or chronic infection are also ineligible (baseline
    testing required)

    - Patients who have had evidence of active or acute diverticulitis, intra-abdominal
    abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
    known risk factors for bowel perforation should be evaluated for the potential need
    for additional treatment before coming on study

    - Another active malignancy =< 3 years prior to registration with the exception of
    non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a
    history of prior malignancy, they must not be receiving other specific treatment for
    their cancer

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of adverse events of entinostat and nivolumab in combination with ipilimumab per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0

    Secondary Outcome Measures

    Changes in expression of checkpoint inhibitors (PD-1/PD-L1) in tumor biopsies, measured by IHC staining of paraffin embedded tumor specimens

    Disease control rate, defined as the percentage of patients who have achieved CR, PR or stable disease (SD) among all response evaluable patients based on RECIST v1.1 and irRC (expansion cohort of patients with advanced breast cancer)

    Duration of overall response (expansion cohort of patients with advanced breast cancer)

    Duration of stable disease based on RECIST v1.1 and irRC (expansion cohort of patients with advanced breast cancer)

    Objective response rate, defined as the total number of patients with either complete response (CR) or partial response (PR) divided by the total number of patients in the population of interest (expansion cohort of patients with advanced breast cancer)

    Progression-free survival (PFS), defined as the proportion of patients remaining alive and free of disease progression (expansion cohort of patients with advanced breast cancer)

    Trial Keywords