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: July 28, 2014
Last verified: July 2014

December 18, 2009
July 28, 2014
October 2009
December 2014   (final data collection date for primary outcome measure)
  • 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.
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 ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01038778 on ClinicalTrials.gov Archive Site
  • 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.
  • 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 ] [ Designated as safety issue: No ]
  • To assess the toxicity of high dose aldesleukin combined with entinostat. [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
  • To evaluate entinostat pharmacodynamics (PD) in blood and tumor samples. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • To evaluate the modulation of tumor metabolism by FDG PET CT scan. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Entinostat and Aldesleukin in Treating Patients With Metastatic Kidney Cancer
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

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.

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.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Clear Cell Renal Cell Carcinoma
  • Stage IV Renal Cell Cancer
  • 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
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.

Interventions:
  • Drug: entinostat
  • Biological: aldesleukin
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
  • Radiation: fludeoxyglucose F 18
  • Procedure: positron emission tomography
  • Procedure: computed tomography
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
54
Not Provided
December 2014   (final data collection date for primary outcome measure)

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%
Both
18 Years and older
No
United States
 
NCT01038778
NCI-2012-02900, NCI-2012-02900, CDR0000662915, I 145208, 7870, U01CA070095, U01CA062505, UM1CA186691, P30CA016056, U01CA076576
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Roberto Pili Roswell Park Cancer Institute
National Cancer Institute (NCI)
July 2014

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