This phase I/II trial studies the side effects and best dose of entinostat when given together with aldesleukin and to see how well this works in treating patients with kidney cancer that has spread to other places in the body. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Aldesleukin may stimulate the white blood cells to kill kidney cancer cells. Giving entinostat together with aldesleukin may be a better treatment for metastatic kidney cancer.
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of high dose interleukin 2 (aldesleukin) in combination with entinostat in patients with metastatic renal cell carcinoma (RCC). (Phase I) II. To monitor toxicity and estimate the efficacy of high dose aldesleukin combined with entinostat in patients with metastatic RCC. (Phase II) SECONDARY OBJECTIVES: I. To compare the time-to-tumor progression, progression-free survival and overall survival of patients with metastatic RCC treated with high dose aldesleukin combined with entinostat to the historical data of patients treated with high dose aldesleukin alone. (Phase II) II. To assess the toxicity of high dose aldesleukin combined with entinostat. (Phase II) III. To evaluate entinostat pharmacodynamics (PD) in blood and tumor samples. (Phase II) IV. To measure the association between baseline laboratory parameters (e.g. cluster of differentiation \[CD\]4+, CD8+, CD4+/forkhead box P3 \[Foxp3\]), tumor blood metabolism, and a variety of response variables (e.g. toxicity, response and survival). (Phase II) V. To explore the relationship between entinostat exposure with PD endpoints (e.g. toxicity and histone acetylation in peripheral blood mononuclear cells or peripheral blood mononuclear cells \[PBMNCs\] and changes in T cell subset population). (Phase II) VI. To evaluate the modulation of tumor metabolism by fluorodeoxyglucose (FDG, fludeoxyglucose F 18) positron emission tomography (PET)/computed tomography (CT) scan. (Phase II) OUTLINE: This is a phase I, dose-escalation study of entinostat followed by a phase II study. Patients receive entinostat orally (PO) every 2 weeks beginning on day -14 and high-dose aldesleukin intravenously (IV) every 8 hours on days 1-5 and 15-19. Cycles repeat every 84 days\* in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients with evidence of tumor shrinkage may receive up to 3 cycles of high-dose aldesleukin therapy. Patients with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
47
Given IV
Undergo FDG-PET/CT
Given PO
Undergo FDG-PET/CT
Correlative studies
Correlative studies
Undergo FDG-PET/CT
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Dose-limiting Toxicities of Entinostat When Combined With Aldesleukin Within the Phase I
Number of dose-limiting toxicities of entinostat when combined with aldesleukin within the Phase I MEASUREMENT OF EFFECT Patients underwent CT scans at week 11 (+/- 7 days) of each cycle during aldesleukin administration and then every 8-12 weeks (+/- 2 weeks). Response Evaluation Criteria in Solid Tumors (RECIST V.1.0)
Time frame: 84 days
Overall Response Rate (Complete Plus Partial) (Phase II)
The proportion of patients who have a partial or complete response to treatment evaluated by RECIST V.1.0 criteria. MEASUREMENT OF EFFECT Patients underwent CT scans at week 11 (+/- 7 days) of each cycle during aldesleukin administration and then every 8-12 weeks (+/- 2 weeks). Response Evaluation Criteria in Solid Tumors (RECIST V.1.0)
Time frame: Up to 12 months
Incidence of Toxicity (Phase I)
Count of participants with grade 4 toxicity. The frequency and grade of toxicities will be tabulated for each dose level.
Time frame: 84 days
Progression-free Survival
The median progression-free survival (PFS) was estimated using standard Kaplan-Meier methods, where estimates of the median were obtained with 95% confidence intervals (CIs). PFS was defined as the time from the start of treatment to progression or death due to any cause or last follow-up, patients who did not progress or die were censored. MEASUREMENT OF EFFECT Patients underwent CT scans at week 11 (+/- 7 days) of each cycle during aldesleukin administration and then every 8-12 weeks (+/- 2 weeks). Response Evaluation Criteria in Solid Tumors (RECIST V.1.0)
Time frame: up to 12-months after the last subject enrolls
Overall Survival
The 3-year overall survival (OS) rate was estimated using standard Kaplan-Meier methods, where estimates of the median were obtained with 95% confidence intervals (CIs). OS was defined as the time from the start of treatment to death due to any cause or last follow-up, patients who did not die were censored.
Time frame: up to 12-months after the last subject enrolls
Time-to-tumor Progression
The median time to tumor progression (TTP) was estimated using standard Kaplan-Meier methods, where estimates of the median were obtained with 95% confidence intervals (CIs). TTP was defined as the time from the start of treatment to progression or last follow-up. Patients that did not progress were censored.
Time frame: up to 12-months after the last subject enrolls
Incidence of Toxicities
The number of participants with serious adverse events.
Time frame: Up to 30 days
Changes in the Level of Specific T Lymphocytes
Mean percent change from baseline of T lymphocytes.
Time frame: Baseline to approximately 4 weeks post-treatment, up to 1 year
Changes in Tumor Metabolisms by FDG Positron Emission Tomography (PET)/Computed Tomography (CT) Scan
For binary predictors, the sensitivity and specificity with 95% confidence intervals will be reported. T tests will be used to compare the mean change between responders and non-responders. If there are sufficient numbers of responders, partial responders and non-responders an ANOVA will be used to compare changes in these three groups. If complete data are obtained for CD4+CD25\^hi T cells at multiple time points post treatment, repeated measures ANOVA will be performed to evaluate data for trends over time.
Time frame: Baseline to approximately 5 weeks post-treatment
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