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

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ClinicalTrials.gov Identifier: NCT01038778
Recruitment Status : Active, not recruiting
First Posted : December 24, 2009
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE December 18, 2009
First Posted Date  ICMJE December 24, 2009
Last Update Posted Date October 15, 2019
Actual Study Start Date  ICMJE October 29, 2009
Actual Primary Completion Date May 22, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • Recommended dose of entinostat when combined with aldesleukin based on the dose-limiting toxicity (Phase I) [ Time Frame: 45 days ]
  • Overall response rate (complete plus partial) (Phase II) [ Time Frame: Up to 12 months ]
    Logistic regression will be used to assess the significance of associations individually (univariate) and while adjusting for other variables (multivariate). The Cox proportional hazards model will be used to model the effect of these parameters on time-to-event outcomes.
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2009)
To evaluate the safety and tolerability of high dose interleukin 2 (aldesleukin) and entinostat in patients with metastatic renal cell carcinoma (RCC). [ Time Frame: 84 days ]
Change History Complete list of historical versions of study NCT01038778 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2018)
  • Incidence of toxicity (Phase I) [ Time Frame: 84 days ]
    An exact binomial proportion with a 95% confidence interval will be given for prolonged grade 4 toxicity. The frequency and grade of toxicities will be tabulated for each dose level. Summary statistics (mean, standard deviation, frequency) will be used to record the number of doses of aldesleukin administered during the first course of therapy and the toxicity after the scheduled 9th dose aldesleukin.
  • Progression-free survival (Phase II) [ Time Frame: Up to 12 months ]
    The association between responses (e.g. response, progression free and overall survival) and baseline laboratory parameters (e.g. CD4+, CD4+/Foxp3, CD8+, Ki 67, Tunel) will be summarized graphically (boxplots, scatterplots, Kaplan-Meier curves) and numerically (means, medians).
  • Survival (Phase II) [ Time Frame: Up to 12 months ]
    The association between responses (e.g. response, progression free and overall survival) and baseline laboratory parameters (e.g. CD4+, CD4+/Foxp3, CD8+, Ki 67, Tunel) will be summarized graphically (boxplots, scatterplots, Kaplan-Meier curves) and numerically (means, medians).
  • Time-to-tumor progression (Phase II) [ Time Frame: Up to 12 months ]
    For binary outcomes such as response, logistic regression will be used to assess the significance of associations individually (univariate) and while adjusting for other variables (multivariate). The Cox proportional hazards model will be used to model the effect of these parameters on time-to-event outcomes.
  • Incidence of toxicities (Phase II) [ Time Frame: Up to 30 days ]
    The exact binomial proportion for prolonged grade 4 toxicities with the 95% confidence interval will be given. Additional toxicity frequencies, proportions, and 95% CIs will be given by type and grade of toxicity.
  • Changes in the level of specific T lymphocytes [ Time Frame: Baseline up to 4 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 analysis of variance (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.
  • Changes in tumor metabolisms by FDG positron emission tomography (PET)/computed tomography (CT) scan [ Time Frame: Baseline up to week 5 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2009)
  • To compare the time-to-tumor progression, progression-free survival and overall survival of patients with metastatic RCC treated with high dose aldesleukin plus entinostat to high dose aldesleukin alone. [ Time Frame: 2 years ]
  • To assess the toxicity of high dose aldesleukin combined with entinostat. [ Time Frame: 84 days ]
  • To evaluate entinostat pharmacodynamics (PD) in blood and tumor samples. [ Time Frame: 84 days ]
  • To measure the association between baseline laboratory parameters (e.g. CD4+, CD8+, CD4+/Foxp3), tumor blood metabolism and a variety of response variables (e.g. toxicity, response and survival). [ Time Frame: 84 days ]
  • To explore the relationship between entinostat exposure with PD endpoints (e.g. toxicity and histone acetylation in peripheral blood mononuclear cells or PBMNCs and changes in T cell subset population). [ Time Frame: 84 days ]
  • To evaluate the modulation of tumor metabolism by FDG PET CT scan. [ Time Frame: 84 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Entinostat in Combination With Aldesleukin in Treating Patients With Metastatic Kidney Cancer
Official Title  ICMJE 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
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.
Detailed Description

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Clear Cell Renal Cell Carcinoma
  • Metastatic Kidney Carcinoma
  • Stage III Renal Cell Cancer AJCC v7
  • Stage IV Renal Cell Cancer AJCC v7
Intervention  ICMJE
  • 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
    • 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
Study Arms  ICMJE 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.

Interventions:
  • Biological: Aldesleukin
  • Procedure: Computed Tomography
  • Drug: Entinostat
  • Radiation: Fludeoxyglucose F-18
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Procedure: Positron Emission Tomography
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 12, 2019)
48
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2009)
7
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date May 22, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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%
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01038778
Other Study ID Numbers  ICMJE NCI-2012-02900
NCI-2012-02900 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000662915
I 145208
7870 ( Other Identifier: Roswell Park Cancer Institute )
7870 ( Other Identifier: CTEP )
P30CA016056 ( U.S. NIH Grant/Contract )
R21CA137649 ( U.S. NIH Grant/Contract )
U01CA062505 ( U.S. NIH Grant/Contract )
U01CA070095 ( U.S. NIH Grant/Contract )
U01CA076576 ( U.S. NIH Grant/Contract )
UM1CA186691 ( U.S. NIH Grant/Contract )
UM1CA186712 ( U.S. NIH Grant/Contract )
UM1CA186717 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Saby George Roswell Park Cancer Institute
PRS Account National Cancer Institute (NCI)
Verification Date June 2019

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