Anatomic Stage III Breast Cancer AJCC v8Phase 1NCT02453620
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
A Phase 1 study testing Biopsy Procedure, Blood Sample and Bone Scan in people with Anatomic Stage III Breast Cancer AJCC v8 and Anatomic Stage IV Breast Cancer AJCC v8, run by National Cancer Institute (NCI) at 5 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Breast Adenocarcinoma
- What is being tested?
- Biopsy Procedure, Blood Sample and Bone Scan
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 5 sitesUnited States
- Study dates
- 12 Feb 2016to 11 Sep 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
- Age ≥ 18 years.
- NOTE: Because no dosing or adverse event data are currently available on the use of these agents in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)
- Life expectancy of greater than 12 weeks
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- 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 x 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
- Patients must have measurable or evaluable/non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; patients with bone only disease are not eligible due to difficulties in obtaining serial bone biopsies for correlative analyses; 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 supplemental oxygen
- Patient must have an accessible non-bone tumor lesion from which serial core 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; if core biopsy is not possible, other methods may be approved in advance by the protocol chair/designee
- The effects of nivolumab, ipilimumab and entinostat on the developing human fetus are unknown; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) 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; WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at baseline; women must not be breastfeeding; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception; 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
- 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
Who cannot join
- 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
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- 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 (e.g., histone deacetylase [HDAC] inhibitors such as entinostat, panobinostat, vorinostat, romidepsin or demethylating agents such as 5-azacitidine or decitabine) 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
- 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; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, autoimmune hepatitis, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
- 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; NOTE: Patients with previously treated brain metastases must have stable neurologic status and magnetic resonance imaging (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 because the agents have 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, 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 antibody (HCV Ab)/ribonucleic acid (RNA) (HCV RNA) indicating acute or chronic infection are also ineligible (baseline testing required); these are because of the potential for pharmacokinetic interactions with the study agents; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
- 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; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
- Patients requiring concurrent administration of valproic acid are also excluded
- 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 any type; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer; any malignancy considered to be indolent and that has never required therapy may allowed at the discretion of the protocol chair
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, 06510
Yale University
New Haven, Connecticut, 06520
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
About this study
Official title: A Phase 1 Study Evaluating Safety, Tolerability, and Preliminary Antitumor Activity of Entinostat and Nivolumab With or Without Ipilimumab in Advanced Solid Tumors
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 is in a class of drugs called histone deacetylase (HDAC) inhibitors. It may stop the growth of cancer 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.
Read the detailed description
PRIMARY OBJECTIVES:
- To evaluate the safety and tolerability of the combination of entinostat and nivolumab with or without ipilimumab in subjects with advanced solid tumors.
II. To determine the recommended phase II dose (RP2D) of the combination of entinostat and nivolumab with ipilimumab in subjects with advanced solid tumors and to further confirm the safety of the combination therapy in subjects with advanced HER2-negative breast cancer.
SECONDARY OBJECTIVES:
- To evaluate whether treatment with entinostat alone or in combination with nivolumab and ipilimumab results in an increase in the ratio of tumor antigen-specific effector T cells (Teff) to regulatory T cell (Treg) in tumor biopsies 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 RP2D.
EXPLORATORY OBJECTIVES:
- To explore changes in immune-related biomarkers (e.g., expression of checkpoint receptors [PD-1/PD-L1], the number of myeloid derived suppressor cells [MDSCs], inflammatory T cell signature, T cell receptor [TCR] repertoire) in tumor biopsies or peripheral blood lymphocytes (PBL) pre- and post-therapy.
II. To correlate changes in immune-related biomarkers pre- and post-combination therapy with response.
III. To measure tumor-specific mutations and mutant neo-antigens recognized by patient T cells in tumor biopsies and to describe association with response.
IV. To evaluate changes in frequency of T cells recognizing tumor-specific mutant neo-antigens in peripheral blood lymphocytes (PBL) pre- and post-therapy.
- To evaluate changes in candidate gene expression, including the azacitidine (AZA) immune genes (AIM genes) in malignant tissue, gene methylation silencing in circulating deoxyribonucleic acid (DNA) and malignant tissue pre- and post-therapy.
VI. 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.
VII. To conduct pharmacogenomic association analyses to assess the potential clinical utility of CD86 gene polymorphisms as genetic determinants of immune mediated adverse events.
OUTLINE: This is a 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 weeks, and ipilimumab IV over 90 minutes on day 1 and then every 6 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) as clinically indicated throughout the trial. Patients may undergo positron emission tomography (PET)/CT or bone scan throughout the trial. Patients also undergo tissue biopsy and blood sample collection during screening and on the trial.
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.
- Conditions
- Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Breast Adenocarcinoma, Invasive Breast Carcinoma, Malignant Solid Neoplasm
- Being tested
- Biopsy Procedure, Blood Sample, Bone Scan, Computed Tomography, Entinostat
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo tissue biopsy
Blood SampleOther
Also called Blood, Blood Draw, Blood Specimen
Undergo blood sample collection
Bone ScanProcedure or surgery
Also called Bone Scintigraphy
Undergo bone scan
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT or PET/CT
EntinostatDrug
Also called HDAC inhibitor SNDX-275, MS 27-275, MS 275, MS-275
Given PO
IpilimumabBiological
Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016
Given IV
NivolumabBiological
Also called ABP 206, BCD-263, BMS 936558, BMS-936558
Given IV
Pharmacogenomic StudyOther
Also called PHARMACOGENOMIC
Correlative studies
Correlative studies
Positron Emission TomographyProcedure or surgery
Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)
Undergo PET/CT
| Study group | Role | What they receive |
|---|---|---|
| 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 weeks, and ipilimumab IV over 90 minutes on day 1 and then every 6 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT as clinically indicated throughout the trial. Patients may undergo PET/CT or bone scan throughout the trial. Patients also undergo tissue biopsy and blood sample collection during screening and on the trial. Receives: Procedure: Biopsy Procedure; Other: Blood Sample; Procedure: Bone Scan; Procedure: Computed Tomography; Drug: Entinostat; Biological: Ipilimumab; Biological: Nivolumab; Other: Pharmacogenomic Study; Other: Pharmacological Study; Procedure: Positron Emission Tomography |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of adverse events of entinostat and nivolumab in combination with ipilimumab
Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Safety and tolerability will be analyzed through the incidence of adverse events, serious adverse events, and specific laboratory abnormalities (worst grade) in each arm. Toxicities will be tabulated by type and grade for all doses and presented using frequencies and percentages based on the CTCAE v5.0. The proportion of dose-limiting toxicities at each dose level will be reported with exact 95% confidence intervals.
Measured: Up to 100 days after last dose of nivolumab
Secondary outcomes (6)
Changes in ratio of effector T cell (Teff) to regulatory T cell (Treg) in tumor biopsies
Measured by immunohistochemistry (IHC) staining of paraffin embedded tumor specimens. Changes will be treated as a continuous variable and summarized with descriptive statistics. Changes will also be graphically depicted using exploratory plots (e.g. bar plots, boxplots) and means will be estimated with 95% confidence intervals. A paired t-tests or nonparametric Wilcoxon signed-rank test may be used to determine whether or not the data shows evidence of changes from baseline.
Measured: Baseline to up to 2 weeks post-entinostat
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). Tumor assessment will be based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and immune related response criteria (irRC).
Measured: Up to 5 years
Disease control rate (expansion cohort of patients with advanced breast cancer)
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. Estimated by the number of patients who achieve a confirmed response plus the number of patients who have stable disease for a duration of at least 6 months divided by the total number of evaluable patients.
Measured: Up to 5 years
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). Exact binomial 95% confidence intervals will be provided. The distribution of PFS, duration of response, and duration of stable disease will be described using the method of Kaplan-Meier, if warranted. Advanced breast cancer patients in the dose escalation portion treated at the recommended phase 2 dose (RP2D), if any, will be pooled with patients in the dose expansion cohort for these analyses.
Measured: Time from start of treatment to time of disease progression or death, whichever occurs first, assessed at 6 months
Duration of overall response (expansion cohort of patients with advanced breast cancer)
Duration of response will be described using the method of Kaplan-Meier, if warranted. Advanced breast cancer patients in the dose escalation portion treated at the RP2D, if any, will be pooled with patients in the dose expansion cohort for these analyses.
Measured: Time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or death, assessed up to 5 years
Duration of stable disease (expansion cohort of patients with advanced breast cancer)
Based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and immune related response criteria (irRC). Duration of stable disease will be described using the method of Kaplan-Meier, if warranted. Advanced breast cancer patients in the dose escalation portion treated at the RP2D, if any, will be pooled with patients in the dose expansion cohort for these analyses.
Measured: Time measurement criteria are met for SD until the first date that recurrent or progressive disease is objectively documented or death, assessed up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2015 (estimated)
- Study start12 Feb 2016
- Primary completion22 Apr 2021
- Study completion11 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Anatomic Stage III Breast Cancer AJCC v8Studies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Roisin M Connolly, Principal investigator, JHU Sidney Kimmel Comprehensive Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02453620
- Sponsor's protocol ID
- NCI-2015-00741
- Other IDs
- NCI-2015-00741, SKCCC J15221, L9844, J15221, 9844, 9844, UM1CA186689, UM1CA186690
- Status last verified
- Sep 2026
- First submitted
- 21 May 2015
- Last updated
- 15 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Study Evaluating Safety, Tolerability, and Preliminary Antitumor Activity of Entinostat and Nivolumab With or Without Ipilimumab in Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT02453620
- Acronym / sponsor ID
- NCI-2015-00741
- Conditions
- Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Breast Adenocarcinoma, Invasive Breast Carcinoma, Malignant Solid Neoplasm
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 57 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 12 Feb 2016 (actual)
- Primary completion
- 22 Apr 2021 (actual)
- Study completion
- 11 Sep 2027 (estimated)
- First posted
- 25 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 is in a class of drugs called histone deacetylase (HDAC) inhibitors. It may stop the growth of cancer 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.
Detailed description
PRIMARY OBJECTIVES:
- To evaluate the safety and tolerability of the combination of entinostat and nivolumab with or without ipilimumab in subjects with advanced solid tumors.
II. To determine the recommended phase II dose (RP2D) of the combination of entinostat and nivolumab with ipilimumab in subjects with advanced solid tumors and to further confirm the safety of the combination therapy in subjects with advanced HER2-negative breast cancer.
SECONDARY OBJECTIVES:
- To evaluate whether treatment with entinostat alone or in combination with nivolumab and ipilimumab results in an increase in the ratio of tumor antigen-specific effector T cells (Teff) to regulatory T cell (Treg) in tumor biopsies 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 RP2D.
EXPLORATORY OBJECTIVES:
- To explore changes in immune-related biomarkers (e.g., expression of checkpoint receptors [PD-1/PD-L1], the number of myeloid derived suppressor cells [MDSCs], inflammatory T cell signature, T cell receptor [TCR] repertoire) in tumor biopsies or peripheral blood lymphocytes (PBL) pre- and post-therapy.
II. To correlate changes in immune-related biomarkers pre- and post-combination therapy with response.
III. To measure tumor-specific mutations and mutant neo-antigens recognized by patient T cells in tumor biopsies and to describe association with response.
IV. To evaluate changes in frequency of T cells recognizing tumor-specific mutant neo-antigens in peripheral blood lymphocytes (PBL) pre- and post-therapy.
- To evaluate changes in candidate gene expression, including the azacitidine (AZA) immune genes (AIM genes) in malignant tissue, gene methylation silencing in circulating deoxyribonucleic acid (DNA) and malignant tissue pre- and post-therapy.
VI. 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.
VII. To conduct pharmacogenomic association analyses to assess the potential clinical utility of CD86 gene polymorphisms as genetic determinants of immune mediated adverse events.
OUTLINE: This is a 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 weeks, and ipilimumab IV over 90 minutes on day 1 and then every 6 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) as clinically indicated throughout the trial. Patients may undergo positron emission tomography (PET)/CT or bone scan throughout the trial. Patients also undergo tissue biopsy and blood sample collection during screening and on the trial.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (entinostat, nivolumab, ipilimumab) | Experimental | Procedure: Biopsy Procedure, Other: Blood Sample, Procedure: Bone Scan, Procedure: Computed Tomography, Drug: Entinostat, Biological: Ipilimumab, Biological: Nivolumab, Other: Pharmacogenomic Study, Other: Pharmacological Study, Procedure: Positron Emission TomographyPatients receive entinostat PO on days -14 and -7 and then weekly, nivolumab IV over 60 minutes on day 1 and then every 2 weeks, and ipilimumab IV over 90 minutes on day 1 and then every 6 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT as clinically indicated throughout the trial. Patients may undergo PET/CT or bone scan throughout the trial. Patients also undergo tissue biopsy and blood sample collection during screening and on the trial. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)
- Life expectancy of greater than 12 weeks
Key exclusion criteria (24 listed)
- 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:
- 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; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, autoimmune hepatitis, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biopsy ProcedureAlso: Biopsy, BIOPSY_TYPE, BxUndergo tissue biopsy | Procedure or surgery | Treatment (entinostat, nivolumab, ipilimumab) |
| Blood SampleAlso: Blood, Blood Draw, Blood SpecimenUndergo blood sample collection | Other | Treatment (entinostat, nivolumab, ipilimumab) |
| Bone ScanAlso: Bone ScintigraphyUndergo bone scan | Procedure or surgery | Treatment (entinostat, nivolumab, ipilimumab) |
| Computed TomographyAlso: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial TomographyUndergo CT or PET/CT | Procedure or surgery | Treatment (entinostat, nivolumab, ipilimumab) |
| EntinostatAlso: HDAC inhibitor SNDX-275, MS 27-275, MS 275, MS-275Given PO | Drug | Treatment (entinostat, nivolumab, ipilimumab) |
| IpilimumabAlso: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016Given IV | Biological | Treatment (entinostat, nivolumab, ipilimumab) |
| NivolumabAlso: ABP 206, BCD-263, BMS 936558, BMS-936558Given IV | Biological | Treatment (entinostat, nivolumab, ipilimumab) |
| Pharmacogenomic StudyAlso: PHARMACOGENOMICCorrelative studies | Other | Treatment (entinostat, nivolumab, ipilimumab) |
| Pharmacological StudyCorrelative studies | Other | Treatment (entinostat, nivolumab, ipilimumab) |
| Positron Emission TomographyAlso: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)Undergo PET/CT | Procedure or surgery | Treatment (entinostat, nivolumab, ipilimumab) |
Primary outcome
Incidence of adverse events of entinostat and nivolumab in combination with ipilimumab
Time frame: Up to 100 days after last dose of nivolumab
Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Safety and tolerability will be analyzed through the incidence of adverse events, serious adverse events, and specific laboratory abnormalities (worst grade) in each arm. Toxicities will be tabulated by type and grade for all doses and presented using frequencies and percentages based on the CTCAE v5.0. The proportion of dose-limiting toxicities at each dose level will be reported with exact 95% confidence intervals.
6 secondary outcomes
Changes in ratio of effector T cell (Teff) to regulatory T cell (Treg) in tumor biopsies
Time frame: Baseline to up to 2 weeks post-entinostat
Objective response rate
Time frame: Up to 5 years
Disease control rate (expansion cohort of patients with advanced breast cancer)
Time frame: Up to 5 years
Progression-free survival (PFS)
Time frame: Time from start of treatment to time of disease progression or death, whichever occurs first, assessed at 6 months
Duration of overall response (expansion cohort of patients with advanced breast cancer)
Time frame: Time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or death, assessed up to 5 years
Duration of stable disease (expansion cohort of patients with advanced breast cancer)
Time frame: Time measurement criteria are met for SD until the first date that recurrent or progressive disease is objectively documented or death, assessed up to 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Sep 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roisin M Connolly principal investigator
JHU Sidney Kimmel Comprehensive Cancer Center LAO
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Biopsy Procedure, Blood Sample and Bone Scan in people with Anatomic Stage III Breast Cancer AJCC v8 and Anatomic Stage IV Breast Cancer AJCC v8, run by National Cancer Institute (NCI) at 5 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 15 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of adverse events of entinostat and nivolumab in combination with ipilimumab (time frame: Up to 100 days after last dose of nivolumab). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2026.