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Entinostat and Aldesleukin in Treating Patients With Metastatic Kidney Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01038778
First received: December 18, 2009
Last updated: November 6, 2014
Last verified: July 2014
  Purpose

This phase I/II trial studies the side effects and best dose of entinostat when given 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 kill more tumor cells.


Condition Intervention Phase
Clear Cell Renal Cell Carcinoma
Stage IV Renal Cell Cancer
Drug: entinostat
Biological: aldesleukin
Other: pharmacological study
Other: laboratory biomarker analysis
Radiation: fludeoxyglucose F 18
Procedure: positron emission tomography
Procedure: computed tomography
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Recommended dose of entinostat when combined with aldesleukin (Phase I) [ Time Frame: 45 days ] [ Designated as safety issue: Yes ]
  • Overall response rate (complete plus partial) (Phase II) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Incidence of toxicities (Phase I) [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
    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 cycle of therapy and the toxicity after the scheduled 9th dose aldesleukin.

  • Progression-free survival (Phase II) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 PET/CT scan [ Time Frame: Baseline up to week 5 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 54
Study Start Date: October 2009
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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. Courses 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 courses of high-dose aldesleukin therapy. Patients with stable disease by RECIST V.1.0 criteria, but without evidence of tumor shrinkage after two courses will receive only entinostat until disease progression is documented.

Drug: entinostat
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Biological: aldesleukin
Given IV
Other Names:
  • IL-2
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
Radiation: fludeoxyglucose F 18
Undergo FDG-PET/CT
Other Names:
  • 18FDG
  • FDG
Procedure: positron emission tomography
Undergo FDG-PET/CT
Other Names:
  • FDG-PET
  • PET
  • PET scan
  • tomography, emission computed
Procedure: computed tomography
Undergo FDG-PET/CT
Other Name: tomography, computed

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. Courses 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 courses of high-dose aldesleukin therapy. Patients with stable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.0 criteria, but without evidence of tumor shrinkage after two courses 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • No prior systemic therapies for RCC are allowed; 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 (FEV) 1 >= 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
  • 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 prior systemic therapy for metastatic RCC are not eligible
  • 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; 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
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: NCT01038778

Locations
United States, California
USC Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: David I. Quinn    323-865-0451    diquinn@usc.edu   
Principal Investigator: David I. Quinn         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Michael A. Carducci    410-614-3977    carducci@jhmi.edu   
Principal Investigator: Michael A. Carducci         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roberto Pili    716-845-3117    Roberto.Pili@RoswellPark.org   
Principal Investigator: Roberto Pili         
United States, Ohio
Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: J. P. Monk    614-293-6196      
Principal Investigator: J. P. Monk         
Sponsors and Collaborators
Investigators
Principal Investigator: Roberto Pili Roswell Park Cancer Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01038778     History of Changes
Obsolete Identifiers: NCT01043159
Other Study ID Numbers: NCI-2012-02900, NCI-2012-02900, CDR0000662915, I 145208, 7870, U01CA070095, U01CA062505, P30CA016056, U01CA076576, UM1CA186691
Study First Received: December 18, 2009
Last Updated: November 6, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Adenocarcinoma
Kidney Diseases
Kidney Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
Aldesleukin
Entinostat
Fluorodeoxyglucose F18
Histone Deacetylase Inhibitors
Interleukin-2
Analgesics
Analgesics, Non-Narcotic
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antineoplastic Agents
Antiviral Agents
Central Nervous System Agents
Diagnostic Uses of Chemicals
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on November 25, 2014