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 Evaluating Safety, Tolerability, and Preliminary Antitumor Activity of Entinostat and Nivolumab With or Without Ipilimumab in Advanced Solid Tumors
9 other identifiers
interventional
57
1 country
5
Brief 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 (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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Feb 2016
Longer than P75 for phase_1
5 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 21, 2015
CompletedFirst Posted
Study publicly available on registry
May 25, 2015
CompletedStudy Start
First participant enrolled
February 12, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 22, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
September 17, 2026
ExpectedApril 13, 2026
March 1, 2026
5.2 years
May 21, 2015
April 9, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
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.
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
Baseline to up to 2 weeks post-entinostat
Objective response rate
Up to 5 years
Disease control rate (expansion cohort of patients with advanced breast cancer)
Up to 5 years
Progression-free survival (PFS)
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 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
- +1 more secondary outcomes
Other Outcomes (8)
Changes in number of myeloid derived suppressor cells (MDSCs) in peripheral blood and tumor biopsies
Baseline to up to 8 weeks
Post-combination therapy expression of checkpoint inhibitors (PD-1/PD-L1) in tumor biopsies
Up to 8 weeks
Changes in other immune-related biomarkers (e.g., ratio of effector T cells: regulatory T cells, inflammatory T cell signature, T cell receptor [TCR] repertoire) in tumor biopsies or peripheral blood lymphocytes (PBL) pre and post therapy
Baseline to up to 8 weeks
- +5 more other outcomes
Study Arms (1)
Treatment (entinostat, nivolumab, ipilimumab)
EXPERIMENTALPatients 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.
Interventions
Given PO
Given IV
Given IV
Correlative studies
Undergo tissue biopsy
Undergo blood sample collection
Undergo bone scan
Undergo CT or PET/CT
Undergo PET/CT
Eligibility Criteria
You may qualify if:
- 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
- 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)
- +6 more criteria
You may not qualify if:
- 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 (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)
- +9 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (5)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, 06510, United States
Yale University
New Haven, Connecticut, 06520, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Roisin M Connolly
JHU Sidney Kimmel Comprehensive Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 21, 2015
First Posted
May 25, 2015
Study Start
February 12, 2016
Primary Completion
April 22, 2021
Study Completion (Estimated)
September 17, 2026
Last Updated
April 13, 2026
Record last verified: 2026-03