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

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) version 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

- 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

- 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

- 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%