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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Clear Cell Renal Cell Carcinoma, Stage IV Renal Cell Cancer

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Trial Information

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


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)


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. CD4+, CD8+,
CD4+/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) positron emission tomography (PET)/computed tomography (CT) scan.
(Phase II)

OUTLINE: This is a dose-escalation study of entinostat.

Patients receive entinostat orally (PO) every 2 weeks 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.

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 glutamic 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

- 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 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 central nervous system (CNS) metastases; patients should have a head
CT/MRI within 28 days prior to treatment initiation; any imaging abnormality
indicative of CNS metastases will exclude the patient from the study; 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

- Pregnant women are excluded from this study because entinostat is a histone
deacetylase (HDAC) inhibitor agent with the potential for teratogenic or
abortifacient effects; because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with entinostat,
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

- 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%

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended dose of the biologic agent, entinostat, when combined with IL-2 (Phase I)

Outcome Time Frame:

45 days

Safety Issue:


Principal Investigator

Roberto Pili

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Stage IV Renal Cell Cancer
  • Carcinoma
  • Carcinoma, Renal Cell



Johns Hopkins UniversityBaltimore, Maryland  21205
Roswell Park Cancer InstituteBuffalo, New York  14263
H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Ohio State University Medical CenterColumbus, Ohio  43210
USC Norris Comprehensive Cancer CenterLos Angeles, California  90089