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.
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. EXPLORATORY OBJECTIVES: I. 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. 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 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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
57
Undergo tissue biopsy
Undergo blood sample collection
Undergo bone scan
Undergo CT or PET/CT
Given PO
Given IV
Given IV
Correlative studies
Correlative studies
Undergo PET/CT
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
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.
Time frame: Up to 100 days after last dose of nivolumab
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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
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)
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.
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)
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.
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
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