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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

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02453620
First Posted: May 25, 2015
Last Update Posted: November 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
May 21, 2015
May 25, 2015
November 7, 2017
November 6, 2015
June 30, 2018   (Final data collection date for primary outcome measure)
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 [ Time Frame: Up to 100 days after last dose of nivolumab ]
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 v4.0. The proportion of dose-limiting toxicities at each dose level will be reported with exact 95% confidence intervals.
Same as current
Complete list of historical versions of study NCT02453620 on ClinicalTrials.gov Archive Site
  • Changes in ratio of Teff to Treg in tumor biopsies, measured by immunohistochemistry (IHC) staining of paraffin embedded tumor specimens [ Time Frame: Baseline to up to 2 weeks post-entinostat ]
    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.
  • Disease control rate (expansion cohort of patients with advanced breast cancer) [ Time Frame: Up to 5 years ]
    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.
  • 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 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.
  • Duration of stable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and immune related response criteria (irRC) (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 ]
    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.
  • 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) [ Time Frame: Up to 5 years ]
    Tumor assessment will be based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and immune related response criteria (irRC).
  • 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) [ Time Frame: Time from start of treatment to time of disease progression or death, whichever occurs first, assessed at 6 months ]
    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.
  • Changes in expression of checkpoint inhibitors (PD-1/PD-L1) in tumor biopsies, measured by IHC staining of paraffin embedded tumor specimens [ Time Frame: Baseline to up to 2 weeks post-entinostat ]
    Changes will be estimated as a ratio change (post/pre) 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. Proportion of patients who achieve a statistically significant increase in PD-L1 will be estimated with an exact 95% confidence interval. 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.
  • 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) [ Time Frame: Up to 5 years ]
    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.
  • 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 response will be described using the method of Kaplan-Meier, if warranted. Advanced breast cancer patients in the dose escalation portion treated at the MTD, if any, will be pooled with patients in the dose expansion cohort for these analyses.
  • Duration of stable disease based on RECIST v1.1 and irRC (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 ]
    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 MTD, if any, will be pooled with patients in the dose expansion cohort for these analyses.
  • 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) [ Time Frame: Up to 5 years ]
    Tumor assessment will be based on RECIST v1.1 and immune related response criteria (irRC).
  • 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) [ Time Frame: Time from start of treatment to time of disease progression or death, whichever occurs first, assessed at 6 months ]
    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 MTD, if any, will be pooled with patients in the dose expansion cohort for these analyses.
  • CD86 gene polymorphisms as genetic determinants of immune mediated adverse events [ Time Frame: Up to 8 weeks ]
    Pharmacogenomic association analyses will be performed using Fisher's exact test or Cochran-Armitage trend test to explore the potential clinical utility of CD86 gene polymorphisms as genetic determinants of immune mediated adverse events. Methods such as logistic or proportional hazards regression will likely be used for these analyses as appropriate.
  • Changes in candidate gene re-expression in malignant tissue, gene methylation silencing in circulating deoxyribonucleic acid (DNA) and malignant tissue pre and post-therapy [ Time Frame: Baseline to up to 8 weeks ]
    Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate to induce symmetry and stabilize the variability. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots. Change in these parameters with tumor response evaluated using Jonckheere-Terpstra trend test,
  • Changes in frequency of T cells recognizing tumor-specific mutant neo-antigens in tumor biopsies pre and post-therapy [ Time Frame: Baseline to up to 8 weeks ]
  • Changes in number of myeloid derived suppressor cells (MDSCs) in peripheral blood and tumor biopsies as measured by flow cytometry pre and post-therapy [ Time Frame: Baseline to up to 8 weeks ]
    Summarized with descriptive statistics and graphically displayed by exploratory plots for overall and by tumor type if warranted. Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots.
  • 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 [ Time Frame: Baseline to up to 8 weeks ]
    Summarized with descriptive statistics and graphically displayed by exploratory plots for overall and by tumor type if warranted. Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots.
  • Pharmacodynamic outcomes (e.g., safety, efficacy, and changes in gene methylation status) with the exposure of entinostat when coadministered with nivolumab with or without ipilimumab [ Time Frame: Up to 5 years ]
    Association of baseline and change in these parameters with clinical response will be evaluated using Wilcoxon rank sum tests.
  • Post-combination therapy expression of checkpoint inhibitors (PD-1/PD-L1) in tumor biopsies as measured by immunohistochemistry (IHC) [ Time Frame: Up to 8 weeks ]
    Summarized with descriptive statistics and graphically displayed by exploratory plots for overall and by tumor type if warranted. Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots.
  • Tumor-specific mutations and mutant neo-antigens recognized by patient T cells in tumor biopsies as measured by whole-exome sequencing [ Time Frame: Up to 8 weeks ]
  • CD86 gene polymorphisms as genetic determinants of immune mediated adverse events [ Time Frame: Up to 8 weeks ]
    Pharmacogenomic association analyses will be performed using Fisher's exact test or Cochran-Armitage trend test to explore the potential clinical utility of CD86 gene polymorphisms as genetic determinants of immune mediated adverse events. Methods such as logistic or proportional hazards regression will likely be used for these analyses as appropriate
  • Changes in candidate gene re-expression in malignant tissue, gene methylation silencing in circulating DNA and malignant tissue pre and post-therapy [ Time Frame: Baseline to up to 8 weeks ]
    Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate to induce symmetry and stabilize the variability. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots. Change in these parameters with clinical response evaluated using Wilcoxon rank sum tests.
  • Changes in frequency of T cells recognizing tumor-specific mutant neo-antigens in tumor biopsies pre and post-therapy [ Time Frame: Baseline to up to 8 weeks ]
  • Changes in number of MDSCs in peripheral blood and tumor biopsies as measured by flow cytometry pre and post-therapy [ Time Frame: Baseline to up to 8 weeks ]
    Summarized with descriptive statistics and graphically displayed by exploratory plots for overall and by tumor type if warranted. Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots.
  • Changes in other immune-related biomarkers(e.g., ratio of effector T cells: regulatory T cells, inflammatory T cell signature, TCR repertoire) in tumor biopsies or PBL pre and post therapy [ Time Frame: Baseline to up to 8 weeks ]
    Summarized with descriptive statistics and graphically displayed by exploratory plots for overall and by tumor type if warranted. Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots.
  • Pharmacodynamic outcomes (e.g., safety, efficacy, and changes in gene methylation status) with the exposure of entinostat when coadministered with nivolumab with or without ipilimumab [ Time Frame: Up to 5 years ]
    Association of baseline and change in these parameters with clinical response will be evaluated using Wilcoxon rank sum tests.
  • Post-combination therapy expression of checkpoint inhibitors (PD-1/PD-L1) in tumor biopsies as measured by IHC [ Time Frame: Up to 8 weeks ]
    Summarized with descriptive statistics and graphically displayed by exploratory plots for overall and by tumor type if warranted. Changes will be estimated as a ratio change (post/pre) and data will be log transformed as appropriate. Difference between pre- and post-therapy will be explored using paired t-tests or Wilcoxon signed rank tests as appropriate for continuous variables and McNemar's test for dichotomous or categorical variables. Distributions of immune parameters across clinical responders and non-responders will be evaluated and graphically displayed using box plots.
  • Tumor-specific mutations and mutant neo-antigens recognized by patient T cells in tumor biopsies as measured by whole-exome sequencing [ Time Frame: Up to 8 weeks ]
 
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
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 interfere with the ability of tumor cells to grow and spread. Giving entinostat and nivolumab together with ipilimumab may be a better treatment in patients with solid tumors.

PRIMARY OBJECTIVES:

I. 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:

I. 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.

TERTIARY OBJECTIVES:

I. To explore changes in immune-related biomarkers (e.g., expression of checkpoint receptors (programmed cell death 1 [PD-1]/programmed cell death ligand-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.

V. 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 cluster of differentiation (CD)86 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. Courses repeat every 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.

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Breast Adenocarcinoma
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Metastatic Malignant Solid Neoplasm
  • Stage III Breast Cancer AJCC v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Stage IV Breast Cancer AJCC v6 and v7
  • Unresectable Solid Neoplasm
  • Drug: Entinostat
    Given PO
    Other Names:
    • HDAC inhibitor SNDX-275
    • MS 27-275
    • MS-275
    • SNDX-275
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Other: Pharmacogenomic Study
    Correlative studies
    Other Name: PHARMACOGENOMIC
  • Other: Pharmacological Study
    Correlative studies
Experimental: Treatment (entinostat, nivolumab, ipilimumab)
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. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Entinostat
  • Biological: Ipilimumab
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab
  • Other: Pharmacogenomic Study
  • Other: Pharmacological Study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
45
Not Provided
June 30, 2018   (Final data collection date for primary outcome measure)

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
  • 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; 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
  • 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; 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

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 (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; 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; 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 (hepatitis C virus [HCV] Ab)/ribonucleic acid (HCV RNA) indicating acute or chronic infection are also ineligible (baseline testing required)
  • 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 the cervix; 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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
United States
 
 
NCT02453620
NCI-2015-00741
NCI-2015-00741 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
J15221
L9844
SKCCC J15221
9844 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
9844 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
UM1CA186690 ( U.S. NIH Grant/Contract )
UM1CA186691 ( U.S. NIH Grant/Contract )
UM1CA186717 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Roisin Connolly JHU Sidney Kimmel Comprehensive Cancer Center LAO
National Cancer Institute (NCI)
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP