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

Primary Purpose

Clear Cell Renal Cell Carcinoma, Metastatic Kidney Carcinoma, Stage III Renal Cell Cancer AJCC v7

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Aldesleukin
Computed Tomography
Entinostat
Fludeoxyglucose F-18
Laboratory Biomarker Analysis
Pharmacological Study
Positron Emission Tomography
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clear Cell Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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%

Sites / Locations

  • USC / Norris Comprehensive Cancer Center
  • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Roswell Park Cancer Institute
  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (entinostat, aldesleukin)

Arm 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.

Outcomes

Primary Outcome Measures

Dose-limiting Toxicities of Entinostat When Combined With Aldesleukin Within the Phase I
Number of dose-limiting toxicities of entinostat when combined with aldesleukin within the Phase I MEASUREMENT OF EFFECT Patients underwent CT scans at week 11 (+/- 7 days) of each cycle during aldesleukin administration and then every 8-12 weeks (+/- 2 weeks). Response Evaluation Criteria in Solid Tumors (RECIST V.1.0)
Overall Response Rate (Complete Plus Partial) (Phase II)
The proportion of patients who have a partial or complete response to treatment evaluated by RECIST V.1.0 criteria. MEASUREMENT OF EFFECT Patients underwent CT scans at week 11 (+/- 7 days) of each cycle during aldesleukin administration and then every 8-12 weeks (+/- 2 weeks). Response Evaluation Criteria in Solid Tumors (RECIST V.1.0)

Secondary Outcome Measures

Incidence of Toxicity (Phase I)
Count of participants with grade 4 toxicity. The frequency and grade of toxicities will be tabulated for each dose level.
Progression-free Survival
The median progression-free survival (PFS) was estimated using standard Kaplan-Meier methods, where estimates of the median were obtained with 95% confidence intervals (CIs). PFS was defined as the time from the start of treatment to progression or death due to any cause or last follow-up, patients who did not progress or die were censored. MEASUREMENT OF EFFECT Patients underwent CT scans at week 11 (+/- 7 days) of each cycle during aldesleukin administration and then every 8-12 weeks (+/- 2 weeks). Response Evaluation Criteria in Solid Tumors (RECIST V.1.0)
Overall Survival
The 3-year overall survival (OS) rate was estimated using standard Kaplan-Meier methods, where estimates of the median were obtained with 95% confidence intervals (CIs). OS was defined as the time from the start of treatment to death due to any cause or last follow-up, patients who did not die were censored.
Time-to-tumor Progression
The median time to tumor progression (TTP) was estimated using standard Kaplan-Meier methods, where estimates of the median were obtained with 95% confidence intervals (CIs). TTP was defined as the time from the start of treatment to progression or last follow-up. Patients that did not progress were censored.
Incidence of Toxicities
The number of participants with serious adverse events.
Changes in the Level of Specific T Lymphocytes
Mean percent change from baseline of T lymphocytes.
Changes in Tumor Metabolisms by FDG Positron Emission Tomography (PET)/Computed Tomography (CT) Scan
For binary predictors, the sensitivity and specificity with 95% confidence intervals will be reported. T tests will be used to compare the mean change between responders and non-responders. If there are sufficient numbers of responders, partial responders and non-responders an ANOVA will be used to compare changes in these three groups. If complete data are obtained for CD4+CD25^hi T cells at multiple time points post treatment, repeated measures ANOVA will be performed to evaluate data for trends over time.

Full Information

First Posted
December 18, 2009
Last Updated
August 2, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01038778
Brief Title
Entinostat in Combination With Aldesleukin in Treating Patients With Metastatic Kidney Cancer
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 29, 2009 (Actual)
Primary Completion Date
May 22, 2019 (Actual)
Study Completion Date
July 17, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clear Cell Renal Cell Carcinoma, Metastatic Kidney Carcinoma, Stage III Renal Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (entinostat, aldesleukin)
Arm Type
Experimental
Arm 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.
Intervention Type
Biological
Intervention Name(s)
Aldesleukin
Other Intervention Name(s)
125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Computed Tomography
Other Intervention Name(s)
CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography
Intervention Description
Undergo FDG-PET/CT
Intervention Type
Drug
Intervention Name(s)
Entinostat
Other Intervention Name(s)
HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275
Intervention Description
Given PO
Intervention Type
Radiation
Intervention Name(s)
Fludeoxyglucose F-18
Other Intervention Name(s)
18FDG, FDG, Fludeoxyglucose (18F), fludeoxyglucose F 18, Fludeoxyglucose F18, Fluorine-18 2-Fluoro-2-deoxy-D-Glucose, Fluorodeoxyglucose F18
Intervention Description
Undergo FDG-PET/CT
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
Positron Emission Tomography
Other Intervention Name(s)
Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT
Intervention Description
Undergo FDG-PET/CT
Primary Outcome Measure Information:
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
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
Secondary Outcome Measure Information:
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
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
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
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
Title
Incidence of Toxicities
Description
The number of participants with serious adverse events.
Time Frame
Up to 30 days
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 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%
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Saby George
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
USC / Norris Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

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

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