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Entinostat in Combination With Aldesleukin in Treating Patients With Metastatic Kidney Cancer

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT01038778
Collaborator
(none)
47
Enrollment
4
Locations
1
Arm
164.6
Anticipated Duration (Months)
11.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: Aldesleukin
  • Procedure: Computed Tomography
  • Drug: Entinostat
  • Radiation: Fludeoxyglucose F-18
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Procedure: Positron Emission Tomography
 Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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)
  2. To monitor toxicity and estimate the efficacy of high dose aldesleukin combined with entinostat in patients with metastatic RCC. (Phase II)
SECONDARY OBJECTIVES:
  1. 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 Design

Study Type:
Interventional
Actual Enrollment :
47 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I/II Study of High Dose Interleukin 2, Aldesleukin, in Combination With the Histone Deacetylase Inhibitor Entinostat in Patients With Metastatic Renal Cell Carcinoma
Actual Study Start Date :
Oct 29, 2009
Actual Primary Completion Date :
May 22, 2019
Anticipated Study Completion Date :
Jul 17, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (entinostat, aldesleukin)

Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented.

Biological: Aldesleukin
Given IV
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2

    • Procedure: Computed Tomography
    Undergo FDG-PET/CT
    Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

    • Drug: Entinostat
    Given PO
    Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275

    • Radiation: Fludeoxyglucose F-18
    Undergo FDG-PET/CT
    Other Names:
  • 18FDG
  • FDG
  • Fludeoxyglucose (18F)
  • fludeoxyglucose F 18
  • Fludeoxyglucose F18
  • Fluorine-18 2-Fluoro-2-deoxy-D-Glucose
  • Fluorodeoxyglucose F18

    • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Procedure: Positron Emission Tomography
    Undergo FDG-PET/CT
    Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Dose-limiting Toxicities of Entinostat When Combined With Aldesleukin Within the Phase I [84 days]

      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)

    2. Overall Response Rate (Complete Plus Partial) (Phase II) [Up to 12 months]

      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)

    Secondary Outcome Measures

    1. Incidence of Toxicity (Phase I) [84 days]

      Count of participants with grade 4 toxicity. The frequency and grade of toxicities will be tabulated for each dose level.

    2. Progression-free Survival [up to 12-months after the last subject enrolls]

      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)

    3. Overall Survival [up to 12-months after the last subject enrolls]

      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.

    4. Time-to-tumor Progression [up to 12-months after the last subject enrolls]

      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.

    5. Incidence of Toxicities [Up to 30 days]

      The number of participants with serious adverse events.

    6. Changes in the Level of Specific T Lymphocytes [Baseline to approximately 4 weeks post-treatment, up to 1 year]

      Mean percent change from baseline of T lymphocytes.

    7. Changes in Tumor Metabolisms by FDG Positron Emission Tomography (PET)/Computed Tomography (CT) Scan [Baseline to approximately 5 weeks post-treatment]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Patients must have pathological diagnosis of renal cell carcinoma that is metastatic or surgically unresectable; the histology must be clear cell carcinoma or predominant clear cell carcinoma

    • Patients may have received up to two prior therapies including vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR) and programmed cell death (PD)-1/PD ligand 1 (L1) inhibitors; prior palliative radiation to metastatic lesion(s) is permitted, provided there is at least one measurable and/or evaluable lesion(s) that has not been irradiated

    • Patients must have measurable or evaluable disease

    • Eastern Cooperative Oncology Group (ECOG) performance status 0

    • Life expectancy of greater than 6 months

    • Hemoglobin >= 12 g/dL

    • Leukocytes >= 3,000/mm^3

    • Absolute neutrophil count >= 1,500/mm^3

    • Platelets >= 100,000/mm^3

    • Total bilirubin =< 1.5 x laboratory upper limit of normal

    • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x laboratory upper limit of normal

    • Creatinine =< 1.5 x laboratory upper limit of normal or calculated creatinine clearance of >= 50 ml/min

    • Lactate dehydrogenase (LDH) within normal limits (WNL)

    • Corrected calcium =< 10 mg/dL

    • Prothrombin time (PT)/international normalized ratio (INR) =< 1.5

    • Urine protein < 1+; if >= 1+, 24 hour urine protein should be obtained and should be < 1000 mg

    • Forced expiratory volume in 1 second (FEV1) >= 2.0 liters or >= 75% of predicted for height and age; (pulmonary function tests [PFTs] are required for patients over 50 or with significant pulmonary or smoking history)

    • No evidence of congestive heart failure, symptoms of coronary artery disease, myocardial infarction less than 6 months prior to entry, serious cardiac arrhythmias, or unstable angina; patients who are over 40 or have had previous myocardial infarction greater than 6 months prior to entry will be required to have a negative or low probability cardiac stress test for cardiac ischemia

    • No history of cerebrovascular accident or transient ischemic attacks

    • The effects of entinostat on the developing human fetus at the recommended therapeutic dose are unknown; for this reason Women of child-bearing potential 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; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; men with female partners of child bearing potential must also agree to use adequate contraception

    • Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:

    • Patients who have received more than two prior therapies

    • Concurrent use of valproic acid is not allowed

    • Patients may not be receiving any other investigational agents

    • Patients with untreated central nervous system (CNS) metastases; patients should have a head CT/magnetic resonance imaging (MRI) within 28 days prior to treatment initiation; patients with previously excised/gamma knifed solitary or oligometastases and controlled disease are eligible

    • Any medical condition that would preclude adequate evaluation of the safety and toxicity of the study combination

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the last 6 months), cardiac arrhythmia, history of cerebrovascular accident (CVA) within 6 months, hypertension (defined as blood pressure of > 160 mmHg systolic and/or > 90 mmHg diastolic on medication) history of peripheral vascular disease, or psychiatric illness/social situations that would limit compliance with study requirements

    • Patients with a history of allergy to entinostat or other medications that have a benzamide structure (i.e. tiapride, remoxipride, and clebopride)

    • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with entinostat

    • Human immunodeficiency virus (HIV)-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with entinostat. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

    • Serious or non-healing wound, ulcer or bone fracture

    • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 therapy

    • Anticipation of need for major surgical procedures during the course of the study

    • Left ventricular ejection function < 45%

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 USC / Norris Comprehensive Cancer Center Los Angeles California United States 90033
    2 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    3 Roswell Park Cancer Institute Buffalo New York United States 14263
    4 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Saby George, Roswell Park Cancer Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01038778
    Other Study ID Numbers:
    • NCI-2012-02900
    • NCI-2012-02900
    • CDR0000662915
    • I 145208
    • 7870
    • 7870
    • P30CA016056
    • R21CA137649
    • U01CA062505
    • U01CA070095
    • U01CA076576
    • UM1CA186691
    • UM1CA186712
    • UM1CA186717
    • NCT01043159
    First Posted:
    Dec 24, 2009
    Last Update Posted:
    Jul 19, 2022
    Last Verified:
    May 1, 2022
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Renal Cell
    Kidney Neoplasms
    Aldesleukin
    Deoxyglucose
    Interleukin-2
    Entinostat
    Fluorodeoxyglucose F18
    Histone Deacetylase Inhibitors

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Phase I Dose Level 1 Phase I Dose Level 2 Phase 2 Dose Level 2
    Arm/Group Description Dose Level 1 Entinostat (3 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV)
    Period Title: Overall Study
    STARTED 3 8 36
    COMPLETED 3 6 33
    NOT COMPLETED 0 2 3

    Baseline Characteristics

    Arm/Group Title Dose Level 1 Dose Level 2 Total
    Arm/Group Description Dose Level 1 Entinostat (3 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Total of all reporting groups
    Overall Participants 3 44 47
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    54.0
    (14.73)
    55.64
    (8.35)
    55.53
    (8.65)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    7
    15.9%
    7
    14.9%
    Male
    3
    100%
    37
    84.1%
    40
    85.1%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    1
    2.3%
    1
    2.1%
    Asian
    0
    0%
    4
    9.1%
    4
    8.5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    3
    100%
    39
    88.6%
    42
    89.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Dose-limiting Toxicities of Entinostat When Combined With Aldesleukin Within the Phase I
    Description 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

    Outcome Measure Data

    Analysis Population Description
    All treated and eligible Phase 1 patients
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Dose Level 1 Entinostat (3 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV)
    Measure Participants 3 8
    Count of Participants [Participants]
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Overall Response Rate (Complete Plus Partial) (Phase II)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    All Phase II treated and eligible patients
    Arm/Group Title Treatment (Entinostat, Aldesleukin)
    Arm/Group Description Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. Aldesleukin: Given IV Computed Tomography: Undergo FDG-PET/CT Entinostat: Given PO Fludeoxyglucose F-18: Undergo FDG-PET/CT Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Positron Emission Tomography: Undergo FDG-PET/CT
    Measure Participants 36
    Number (95% Confidence Interval) [Proportion of participants]
    .39
    13%
    3. Secondary Outcome
    Title Incidence of Toxicity (Phase I)
    Description Count of participants with grade 4 toxicity. The frequency and grade of toxicities will be tabulated for each dose level.
    Time Frame 84 days

    Outcome Measure Data

    Analysis Population Description
    All Phase I patients
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Dose Level 1 Entinostat (3 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV)
    Measure Participants 3 8
    Count of Participants [Participants]
    1
    33.3%
    0
    0%
    4. Secondary Outcome
    Title Progression-free Survival
    Description 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

    Outcome Measure Data

    Analysis Population Description
    All Phase 2 patients. PFS only assessed for Phase 2.
    Arm/Group Title Treatment (Entinostat, Aldesleukin)
    Arm/Group Description Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. Aldesleukin: Given IV Computed Tomography: Undergo FDG-PET/CT Entinostat: Given PO Fludeoxyglucose F-18: Undergo FDG-PET/CT Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Positron Emission Tomography: Undergo FDG-PET/CT
    Measure Participants 36
    Median (95% Confidence Interval) [months]
    14.0
    5. Secondary Outcome
    Title Overall Survival
    Description 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

    Outcome Measure Data

    Analysis Population Description
    All Phase 2 patients. Overall Survival only assessed for Phase 2.
    Arm/Group Title Treatment (Entinostat, Aldesleukin)
    Arm/Group Description Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. Aldesleukin: Given IV Computed Tomography: Undergo FDG-PET/CT Entinostat: Given PO Fludeoxyglucose F-18: Undergo FDG-PET/CT Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Positron Emission Tomography: Undergo FDG-PET/CT
    Measure Participants 36
    Number (95% Confidence Interval) [percentage of participants]
    82.1
    2736.7%
    6. Secondary Outcome
    Title Time-to-tumor Progression
    Description 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

    Outcome Measure Data

    Analysis Population Description
    All Phase 2 patients.TTP only assessed for Phase 2.
    Arm/Group Title Treatment (Entinostat, Aldesleukin)
    Arm/Group Description Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. Aldesleukin: Given IV Computed Tomography: Undergo FDG-PET/CT Entinostat: Given PO Fludeoxyglucose F-18: Undergo FDG-PET/CT Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Positron Emission Tomography: Undergo FDG-PET/CT
    Measure Participants 36
    Median (95% Confidence Interval) [months]
    14
    7. Secondary Outcome
    Title Incidence of Toxicities
    Description The number of participants with serious adverse events.
    Time Frame Up to 30 days

    Outcome Measure Data

    Analysis Population Description
    All Phase 2 patients. Toxicities only assessed for Phase 2.
    Arm/Group Title Treatment (Entinostat, Aldesleukin)
    Arm/Group Description Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. Aldesleukin: Given IV Computed Tomography: Undergo FDG-PET/CT Entinostat: Given PO Fludeoxyglucose F-18: Undergo FDG-PET/CT Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Positron Emission Tomography: Undergo FDG-PET/CT
    Measure Participants 36
    Count of Participants [Participants]
    9
    300%
    8. Secondary Outcome
    Title Changes in the Level of Specific T Lymphocytes
    Description Mean percent change from baseline of T lymphocytes.
    Time Frame Baseline to approximately 4 weeks post-treatment, up to 1 year

    Outcome Measure Data

    Analysis Population Description
    All treated and evaluable patients
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Dose Level 1 Entinostat (3 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV)
    Measure Participants 1 35
    Mean (Standard Deviation) [percentage of cells count]
    26.3
    (NA)
    10.5
    (70.8)
    9. Secondary Outcome
    Title Changes in Tumor Metabolisms by FDG Positron Emission Tomography (PET)/Computed Tomography (CT) Scan
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Data for this outcome was not collected. The investigator transferred from Hopkins to Roswell Park and the data for this outcome was not collected.
    Arm/Group Title Treatment (Entinostat, Aldesleukin)
    Arm/Group Description Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin 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 RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented. Aldesleukin: Given IV Computed Tomography: Undergo FDG-PET/CT Entinostat: Given PO Fludeoxyglucose F-18: Undergo FDG-PET/CT Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Positron Emission Tomography: Undergo FDG-PET/CT
    Measure Participants 0

    Adverse Events

    Time Frame From the start date of intervention until 30 days after the last intervention, up to 1 year
    Adverse Event Reporting Description
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Dose Level 1 Entinostat (3 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV) Dose Level 2 Entinostat (5 mg, every 2 weeks, PO) Aldesleukin (600,000 IU/kg, every 8hrs, IV)
    All Cause Mortality
    Dose Level 1 Dose Level 2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 6/44 (13.6%)
    Serious Adverse Events
    Dose Level 1 Dose Level 2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/3 (0%) 9/44 (20.5%)
    Cardiac disorders
    Pericarditis 0/3 (0%) 0 1/44 (2.3%) 1
    Supraventricular tachycardia 0/3 (0%) 0 1/44 (2.3%) 1
    General disorders
    Chest pain 0/3 (0%) 0 1/44 (2.3%) 1
    Death 0/3 (0%) 0 1/44 (2.3%) 1
    Fatigue 0/3 (0%) 0 1/44 (2.3%) 1
    Infections and infestations
    Bacteraemia 0/3 (0%) 0 1/44 (2.3%) 1
    Pneumonia 0/3 (0%) 0 1/44 (2.3%) 1
    Sepsis 0/3 (0%) 0 1/44 (2.3%) 1
    Investigations
    White blood cell count 0/3 (0%) 0 2/44 (4.5%) 2
    Metabolism and nutrition disorders
    Hypocalcaemia 0/3 (0%) 0 1/44 (2.3%) 1
    Hypophosphataemia 0/3 (0%) 0 2/44 (4.5%) 2
    Musculoskeletal and connective tissue disorders
    Neck pain 0/3 (0%) 0 1/44 (2.3%) 1
    Vascular disorders
    Hypotension 0/3 (0%) 0 1/44 (2.3%) 1
    Other (Not Including Serious) Adverse Events
    Dose Level 1 Dose Level 2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/3 (33.3%) 35/44 (79.5%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 3 27/44 (61.4%) 117
    Leukocytosis 0/3 (0%) 0 6/44 (13.6%) 9
    Neutropenia 0/3 (0%) 0 2/44 (4.5%) 3
    Cardiac disorders
    Atrial fibrillation 0/3 (0%) 0 1/44 (2.3%) 2
    Atrial flutter 0/3 (0%) 0 1/44 (2.3%) 1
    Bradycardia 0/3 (0%) 0 1/44 (2.3%) 3
    Extrasystoles 0/3 (0%) 0 1/44 (2.3%) 1
    Myocarditis 0/3 (0%) 0 2/44 (4.5%) 2
    Palpitations 0/3 (0%) 0 3/44 (6.8%) 3
    Pericarditis 0/3 (0%) 0 1/44 (2.3%) 2
    Sinus bradycardia 0/3 (0%) 0 1/44 (2.3%) 1
    Sinus tachycardia 1/3 (33.3%) 2 12/44 (27.3%) 18
    Supraventricular tachycardia 0/3 (0%) 0 1/44 (2.3%) 1
    Tachycardia 1/3 (33.3%) 1 9/44 (20.5%) 22
    Ventricular arrhythmia 1/3 (33.3%) 1 0/44 (0%) 0
    Ear and labyrinth disorders
    Tinnitus 0/3 (0%) 0 1/44 (2.3%) 1
    Endocrine disorders
    Hypothyroidism 0/3 (0%) 0 3/44 (6.8%) 3
    Eye disorders
    Dry eye 0/3 (0%) 0 3/44 (6.8%) 4
    Eye pain 0/3 (0%) 0 1/44 (2.3%) 1
    Vision blurred 0/3 (0%) 0 2/44 (4.5%) 2
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0 1/44 (2.3%) 1
    Abdominal pain 0/3 (0%) 0 5/44 (11.4%) 5
    Constipation 0/3 (0%) 0 14/44 (31.8%) 24
    Dental caries 0/3 (0%) 0 1/44 (2.3%) 1
    Diarrhoea 0/3 (0%) 0 1/44 (2.3%) 1
    Dry mouth 1/3 (33.3%) 1 9/44 (20.5%) 13
    Dyspepsia 0/3 (0%) 0 5/44 (11.4%) 6
    Glossodynia 0/3 (0%) 0 2/44 (4.5%) 2
    Haemorrhoidal haemorrhage 0/3 (0%) 0 1/44 (2.3%) 1
    Haemorrhoids 0/3 (0%) 0 2/44 (4.5%) 2
    Lip dry 0/3 (0%) 0 1/44 (2.3%) 2
    Lip swelling 0/3 (0%) 0 1/44 (2.3%) 1
    Nausea 1/3 (33.3%) 2 30/44 (68.2%) 83
    Oral pain 0/3 (0%) 0 3/44 (6.8%) 3
    Stomatitis 0/3 (0%) 0 1/44 (2.3%) 1
    Swollen tongue 0/3 (0%) 0 1/44 (2.3%) 1
    Tongue coated 0/3 (0%) 0 1/44 (2.3%) 1
    Toothache 0/3 (0%) 0 1/44 (2.3%) 1
    Vomiting 1/3 (33.3%) 1 23/44 (52.3%) 43
    General disorders
    Chest discomfort 0/3 (0%) 0 3/44 (6.8%) 4
    Chest pain 0/3 (0%) 0 2/44 (4.5%) 2
    Chills 1/3 (33.3%) 1 21/44 (47.7%) 51
    Fatigue 1/3 (33.3%) 5 32/44 (72.7%) 97
    Generalised oedema 0/3 (0%) 0 1/44 (2.3%) 2
    Influenza like illness 0/3 (0%) 0 2/44 (4.5%) 2
    Malaise 0/3 (0%) 0 2/44 (4.5%) 3
    Mucosal inflammation 1/3 (33.3%) 1 2/44 (4.5%) 3
    Non-cardiac chest pain 0/3 (0%) 0 1/44 (2.3%) 1
    Oedema 0/3 (0%) 0 8/44 (18.2%) 15
    Oedema peripheral 1/3 (33.3%) 1 9/44 (20.5%) 17
    Pain 0/3 (0%) 0 1/44 (2.3%) 1
    Polyp 0/3 (0%) 0 1/44 (2.3%) 1
    Pyrexia 1/3 (33.3%) 4 23/44 (52.3%) 83
    Xerosis 0/3 (0%) 0 1/44 (2.3%) 1
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/3 (0%) 0 1/44 (2.3%) 1
    Infections and infestations
    Appendicitis 0/3 (0%) 0 1/44 (2.3%) 1
    Bacteraemia 0/3 (0%) 0 1/44 (2.3%) 1
    Candida infection 0/3 (0%) 0 6/44 (13.6%) 12
    Conjunctivitis 0/3 (0%) 0 1/44 (2.3%) 1
    Ear infection 0/3 (0%) 0 1/44 (2.3%) 1
    Nasopharyngitis 0/3 (0%) 0 2/44 (4.5%) 2
    Oral candidiasis 0/3 (0%) 0 1/44 (2.3%) 1
    Pneumonia 0/3 (0%) 0 1/44 (2.3%) 1
    Scrotal infection 0/3 (0%) 0 1/44 (2.3%) 1
    Sinusitis 0/3 (0%) 0 1/44 (2.3%) 1
    Skin infection 0/3 (0%) 0 1/44 (2.3%) 2
    Tooth infection 0/3 (0%) 0 1/44 (2.3%) 2
    Upper respiratory tract infection 0/3 (0%) 0 3/44 (6.8%) 4
    Urinary tract infection 0/3 (0%) 0 2/44 (4.5%) 2
    Wound infection 0/3 (0%) 0 1/44 (2.3%) 1
    Injury, poisoning and procedural complications
    Contusion 0/3 (0%) 0 1/44 (2.3%) 1
    Fall 0/3 (0%) 0 1/44 (2.3%) 2
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 0 1/44 (2.3%) 2
    Adjusted calcium 0/3 (0%) 0 1/44 (2.3%) 1
    Alanine aminotransferase 1/3 (33.3%) 1 0/44 (0%) 0
    Alanine aminotransferase decreased 1/3 (33.3%) 1 0/44 (0%) 0
    Alanine aminotransferase increased 0/3 (0%) 0 6/44 (13.6%) 7
    Aspartate aminotransferase 0/3 (0%) 0 3/44 (6.8%) 3
    Aspartate aminotransferase increased 0/3 (0%) 0 2/44 (4.5%) 3
    Blood albumin 0/3 (0%) 0 1/44 (2.3%) 2
    Blood albumin decreased 0/3 (0%) 0 1/44 (2.3%) 1
    Blood alkaline phosphatase increased 0/3 (0%) 0 2/44 (4.5%) 5
    Blood bilirubin 1/3 (33.3%) 4 20/44 (45.5%) 62
    Blood creatine phosphokinase increased 0/3 (0%) 0 1/44 (2.3%) 1
    Blood creatinine 1/3 (33.3%) 3 2/44 (4.5%) 4
    Blood lactate dehydrogenase decreased 1/3 (33.3%) 1 0/44 (0%) 0
    Blood thyroid stimulating hormone increased 1/3 (33.3%) 1 0/44 (0%) 0
    Electrocardiogram abnormal 0/3 (0%) 0 1/44 (2.3%) 1
    Haemoglobin 1/3 (33.3%) 3 0/44 (0%) 0
    Haemoglobin decreased 1/3 (33.3%) 2 0/44 (0%) 0
    International normalised ratio increased 0/3 (0%) 0 6/44 (13.6%) 7
    Lymphocyte count 1/3 (33.3%) 1 18/44 (40.9%) 82
    Neutrophil count 0/3 (0%) 0 1/44 (2.3%) 1
    Neutrophil count decreased 0/3 (0%) 0 8/44 (18.2%) 21
    Troponin increased 0/3 (0%) 0 1/44 (2.3%) 1
    Weight decreased 1/3 (33.3%) 1 0/44 (0%) 0
    Weight increased 0/3 (0%) 0 9/44 (20.5%) 25
    White blood cell count 1/3 (33.3%) 5 19/44 (43.2%) 58
    Metabolism and nutrition disorders
    Decreased appetite 1/3 (33.3%) 1 23/44 (52.3%) 46
    Dehydration 1/3 (33.3%) 1 5/44 (11.4%) 5
    Fluid retention 0/3 (0%) 0 1/44 (2.3%) 1
    Hypercalcaemia 1/3 (33.3%) 1 1/44 (2.3%) 1
    Hyperglycaemia 0/3 (0%) 0 25/44 (56.8%) 61
    Hyperkalaemia 1/3 (33.3%) 3 11/44 (25%) 15
    Hypermagnesaemia 0/3 (0%) 0 7/44 (15.9%) 20
    Hypernatraemia 0/3 (0%) 0 7/44 (15.9%) 8
    Hypertriglyceridaemia 0/3 (0%) 0 2/44 (4.5%) 2
    Hypoalbuminaemia 1/3 (33.3%) 5 28/44 (63.6%) 126
    Hypocalcaemia 1/3 (33.3%) 8 27/44 (61.4%) 154
    Hypoglycaemia 1/3 (33.3%) 2 2/44 (4.5%) 2
    Hypokalaemia 1/3 (33.3%) 1 11/44 (25%) 18
    Hypomagnesaemia 1/3 (33.3%) 1 12/44 (27.3%) 34
    Hyponatraemia 1/3 (33.3%) 4 23/44 (52.3%) 73
    Hypophosphataemia 1/3 (33.3%) 3 27/44 (61.4%) 123
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0 5/44 (11.4%) 11
    Back pain 0/3 (0%) 0 7/44 (15.9%) 8
    Muscle twitching 0/3 (0%) 0 1/44 (2.3%) 1
    Muscular weakness 0/3 (0%) 0 3/44 (6.8%) 4
    Musculoskeletal chest pain 0/3 (0%) 0 2/44 (4.5%) 2
    Musculoskeletal discomfort 0/3 (0%) 0 1/44 (2.3%) 1
    Musculoskeletal pain 0/3 (0%) 0 2/44 (4.5%) 4
    Myalgia 0/3 (0%) 0 11/44 (25%) 15
    Neck pain 0/3 (0%) 0 1/44 (2.3%) 2
    Pain in extremity 0/3 (0%) 0 1/44 (2.3%) 1
    Pain in jaw 0/3 (0%) 0 1/44 (2.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus 0/3 (0%) 0 1/44 (2.3%) 1
    Nervous system disorders
    Amnesia 0/3 (0%) 0 1/44 (2.3%) 1
    Dizziness 0/3 (0%) 0 5/44 (11.4%) 6
    Dysgeusia 0/3 (0%) 0 10/44 (22.7%) 16
    Encephalopathy 0/3 (0%) 0 1/44 (2.3%) 1
    Headache 0/3 (0%) 0 13/44 (29.5%) 32
    Lethargy 0/3 (0%) 0 3/44 (6.8%) 3
    Neuropathy peripheral 0/3 (0%) 0 3/44 (6.8%) 4
    Paraesthesia 0/3 (0%) 0 2/44 (4.5%) 3
    Psychiatric disorders
    Abnormal dreams 0/3 (0%) 0 1/44 (2.3%) 1
    Anxiety 0/3 (0%) 0 6/44 (13.6%) 8
    Confusional state 0/3 (0%) 0 15/44 (34.1%) 23
    Delirium 0/3 (0%) 0 1/44 (2.3%) 1
    Depression 0/3 (0%) 0 9/44 (20.5%) 14
    Hallucination 0/3 (0%) 0 2/44 (4.5%) 4
    Insomnia 1/3 (33.3%) 1 7/44 (15.9%) 12
    Irritability 0/3 (0%) 0 1/44 (2.3%) 1
    Restlessness 0/3 (0%) 0 1/44 (2.3%) 1
    Renal and urinary disorders
    Dysuria 0/3 (0%) 0 1/44 (2.3%) 1
    Haematuria 0/3 (0%) 0 6/44 (13.6%) 15
    Micturition urgency 0/3 (0%) 0 2/44 (4.5%) 2
    Oliguria 0/3 (0%) 0 1/44 (2.3%) 1
    Pollakiuria 0/3 (0%) 0 2/44 (4.5%) 2
    Proteinuria 0/3 (0%) 0 6/44 (13.6%) 8
    Urinary incontinence 0/3 (0%) 0 1/44 (2.3%) 1
    Urinary retention 0/3 (0%) 0 5/44 (11.4%) 7
    Reproductive system and breast disorders
    Erectile dysfunction 0/3 (0%) 0 1/44 (2.3%) 1
    Vaginal haemorrhage 0/3 (0%) 0 1/44 (2.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 0/3 (0%) 0 12/44 (27.3%) 21
    Dry throat 0/3 (0%) 0 1/44 (2.3%) 2
    Dysphonia 0/3 (0%) 0 1/44 (2.3%) 1
    Dyspnoea 0/3 (0%) 0 23/44 (52.3%) 53
    Epistaxis 0/3 (0%) 0 3/44 (6.8%) 3
    Nasal congestion 0/3 (0%) 0 3/44 (6.8%) 3
    Oropharyngeal pain 0/3 (0%) 0 3/44 (6.8%) 3
    Pleural effusion 0/3 (0%) 0 1/44 (2.3%) 1
    Productive cough 0/3 (0%) 0 1/44 (2.3%) 3
    Pulmonary oedema 0/3 (0%) 0 2/44 (4.5%) 2
    Rales 0/3 (0%) 0 1/44 (2.3%) 1
    Rhinitis allergic 0/3 (0%) 0 1/44 (2.3%) 1
    Rhinorrhoea 0/3 (0%) 0 1/44 (2.3%) 1
    Sinus congestion 0/3 (0%) 0 1/44 (2.3%) 1
    Sneezing 0/3 (0%) 0 1/44 (2.3%) 1
    Throat irritation 0/3 (0%) 0 1/44 (2.3%) 1
    Wheezing 0/3 (0%) 0 4/44 (9.1%) 6
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0 7/44 (15.9%) 10
    Dermatitis 0/3 (0%) 0 1/44 (2.3%) 1
    Dermatitis acneiform 0/3 (0%) 0 1/44 (2.3%) 1
    Dry skin 0/3 (0%) 0 13/44 (29.5%) 20
    Erythema 0/3 (0%) 0 4/44 (9.1%) 5
    Hyperhidrosis 0/3 (0%) 0 1/44 (2.3%) 1
    Photosensitivity reaction 0/3 (0%) 0 1/44 (2.3%) 1
    Pruritus 0/3 (0%) 0 21/44 (47.7%) 32
    Rash 0/3 (0%) 0 5/44 (11.4%) 7
    Rash maculo-papular 0/3 (0%) 0 2/44 (4.5%) 2
    Rash pruritic 0/3 (0%) 0 1/44 (2.3%) 1
    Skin exfoliation 0/3 (0%) 0 1/44 (2.3%) 1
    Swelling face 0/3 (0%) 0 3/44 (6.8%) 5
    Surgical and medical procedures
    Central venous catheterisation 0/3 (0%) 0 1/44 (2.3%) 1
    Tooth extraction 0/3 (0%) 0 1/44 (2.3%) 1
    Vascular disorders
    Capillary leak syndrome 0/3 (0%) 0 4/44 (9.1%) 5
    Flushing 1/3 (33.3%) 3 10/44 (22.7%) 22
    Hypertension 1/3 (33.3%) 1 5/44 (11.4%) 7
    Hypotension 1/3 (33.3%) 3 26/44 (59.1%) 73

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Senior Administrator, Compliance - Clinical Research Services
    Organization Roswell Park Cancer Institute
    Phone 7168451300
    Email adrienne.groman@roswellpark.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01038778
    Other Study ID Numbers:
    • NCI-2012-02900
    • NCI-2012-02900
    • CDR0000662915
    • I 145208
    • 7870
    • 7870
    • P30CA016056
    • R21CA137649
    • U01CA062505
    • U01CA070095
    • U01CA076576
    • UM1CA186691
    • UM1CA186712
    • UM1CA186717
    • NCT01043159
    First Posted:
    Dec 24, 2009
    Last Update Posted:
    Jul 19, 2022
    Last Verified:
    May 1, 2022