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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. (see Contacts and Locations)
Verified February 2017 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02453620
First received: May 21, 2015
Last updated: March 10, 2017
Last verified: February 2017
  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 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.

Condition Intervention Phase
Breast Adenocarcinoma
HER2/Neu Negative
Invasive Breast Carcinoma
Metastatic Malignant Solid Neoplasm
Recurrent Breast Carcinoma
Stage III Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Unresectable Solid Neoplasm
Drug: Entinostat
Biological: Ipilimumab
Other: Laboratory Biomarker Analysis
Biological: Nivolumab
Other: Pharmacogenomic Study
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

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 [ 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.


Secondary Outcome Measures:
  • Changes in ratio of Teff to Treg 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 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, 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 RP2D, 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 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 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 RP2D, if any, will be pooled with patients in the dose expansion cohort for these analyses.


Other Outcome Measures:
  • 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 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 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 ]

Estimated Enrollment: 45
Study Start Date: November 2015
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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
  • 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, Sjögren'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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02453620

Locations
United States, California
City of Hope Comprehensive Cancer Center LAO Recruiting
Duarte, California, United States, 91010
Contact: George Somlo    626-301-8898    becomingapatient@coh.org   
Principal Investigator: George Somlo         
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: George Somlo    800-826-4673    becomingapatient@coh.org   
Principal Investigator: George Somlo         
United States, Connecticut
Smilow Cancer Center/Yale-New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Patricia M. LoRusso    203-785-5702      
Principal Investigator: Patricia M. LoRusso         
Yale University Cancer Center LAO Recruiting
New Haven, Connecticut, United States, 06520
Contact: Patricia M. LoRusso    203-785-4116    patricia.lorusso@yale.edu   
Principal Investigator: Patricia M. LoRusso         
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Patricia M. LoRusso    203-785-5702      
Principal Investigator: Patricia M. LoRusso         
United States, Maryland
JHU Sidney Kimmel Comprehensive Cancer Center LAO Recruiting
Baltimore, Maryland, United States, 21231
Contact: Roisin M. Connolly    410-614-9217    rconnol2@jhmi.edu   
Principal Investigator: Roisin M. Connolly         
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Roisin M. Connolly    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Roisin M. Connolly         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Shannon L. Puhalla    412-647-2811      
Principal Investigator: Shannon L. Puhalla         
University of Pittsburgh Cancer Institute LAO Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Shannon L. Puhalla    412-641-2294    puhallasl@upmc.edu   
Principal Investigator: Shannon L. Puhalla         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Roisin Connolly JHU Sidney Kimmel Comprehensive Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02453620     History of Changes
Other Study ID Numbers: 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 )
P30CA006973 ( US NIH Grant/Contract Award Number )
UM1CA186689 ( US NIH Grant/Contract Award Number )
UM1CA186690 ( US NIH Grant/Contract Award Number )
UM1CA186691 ( US NIH Grant/Contract Award Number )
UM1CA186717 ( US NIH Grant/Contract Award Number )
Study First Received: May 21, 2015
Last Updated: March 10, 2017

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma
Neoplasms
Adenocarcinoma
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Antibodies, Monoclonal
Nivolumab
Entinostat
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 27, 2017