This is a Phase II, open-label, safety, pharmacodynamic and efficacy study of entinostat in
combination with nivolumab and ipilimumab in subjects with metastatic renal cell carcinoma
(RCC) who have progressed on ipilimumab + nivolumab regimen. Prior to Phase II, a safety
lead-in will be conducted to establish the RP2D of entinostat when used in combination with
ipilimumab + nivolumab. Subjects will initially be treated with the combination of oral
entinostat and intravenous (IV) nivolumab plus ipilimumab. Entinostat will be dosed weekly,
and nivolumab and ipilimumab will be dosed every 3 weeks, for a total of four, 3-week cycles.
Following these first four cycles, entinostat will continue to be administered weekly in
combination with nivolumab every 2 weeks (ipilimumab will be discontinued), with treatment
continued until disease progression or prohibitive toxicity. Anti-tumor activity will be
assessed by radiological tumor assessments conducted at baseline and every 6 weeks thereafter
using RECIST version 1.1.
- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
- Age ≥ 18 years at the time of consent.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 28 days
prior to registration.
- Histological or cytological evidence of renal cell carcinoma (initial diagnosis).
- Metastatic disease
- Progressive disease (PD) on nivolumab + ipilimumab regimen. Note: Patients who have
completed at least one dose of ipilimumab + nivolumab and progress or have completed
the 4 doses of ipilimumab + nivolumab and progress during nivolumab monotherapy
maintenance are eligible unless they have received additional treatment(s) for their
renal cell carcinoma prior to registration. Patients who discontinue prior ipilimumab
+ nivolumab or nivolumab monotherapy for toxicity are excluded. Patients who receive
nivolumab or other anti-PD-1/PD-L1 agents as subsequent therapy after ipilimumab +
nivolumab are excluded.
- Target lesions according to RECIST v1.1 or non-target bone lesions assessed by bone
scan or positron emission tomography (PET) scan.
- A subject with prior brain metastasis may be considered if they have completed their
treatment for brain metastasis at least 4 weeks prior to study registration, have been
off corticosteroids for ≥ 4 weeks, and are asymptomatic.
- Prior cancer treatment (excluding nivo/ipi) must be completed at least 28 days prior
to registration and the subject must have recovered from all reversible acute toxic
effects of the regimen (other than alopecia or neuropathy) to ≤Grade 1 or baseline. If
subject underwent major surgery or radiation therapy of >30 Gy, they must have
recovered from the toxicity and/or complications from the intervention.
- Demonstrate adequate organ function as defined in the table below; all screening labs
to be obtained within 28 days prior to registration
- Platelets ≥100 x 109/L
- Absolute Neutrophil Count (ANC) ≥1.5 x 109/L
- Hemoglobin (Hgb) ≥9 g/dL or ≥5.6 mmol/L
- Creatinine OR Measured or calculated creatinine clearance (CrCl) (glomerular
filtration rate [GFR] can also be used in place of CrCl) Creatinine clearance
should be calculated per institutional standard ≤1.5 x the upper limit of normal
(ULN) OR ≥60 mL/min for subject with creatinine levels >1.5 x institutional ULN
- Bilirubin ≤1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin
levels > 1.5 x ULN
- Aspartate aminotransferase (AST) ≤3 x ULN
- Alanine aminotransferase (ALT) ≤3 x ULN
- International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial
Thromboplastin Time (aPTT) ≤ 1.5 × ULN unless subject is receiving anticoagulant
therapy as long as PT/INR/PTT is within therapeutic range of intended use of
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
during screening and a negative urine pregnancy test within 3 days prior to first dose
of study drug. If the screening serum test is done within 3 days prior to receiving
the first dose of study drug, a urine test is not required.
- Women of childbearing potential must be willing to abstain from heterosexual activity
or to use an effective method of contraception from the time of informed consent until
5 months after the last dose of study drug.
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving study drugs and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 7
months after the last dose of study drug.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study.
- Life expectancy of at least 6 months per investigator discretion.
- Subjects meeting any of the criteria below may not participate in the study:
- History or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest
of the subject to participate, in the opinion of the treating investigator,
including, but not limited to:
- Myocardial infarction or arterial thromboembolic events within 6 months
prior to screening or severe or unstable angina, New York Heart Association
(NYHA) Class III or IV disease, or a corrected QT interval (QTc) interval >
- Uncontrolled hypertension or diabetes mellitus.
- Another known malignancy that is progressing or requires active treatment.
- Any prior history of other cancer within the prior 5 years with the
exception of adequately treated basal cell carcinoma or cervical
intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in
- Active infection requiring systemic therapy.
- Known active central nervous system (CNS) metastases and/or carcinomatous
- Pregnant or breastfeeding. Note: breast milk cannot be stored for future use
while the mother is being treated on study.
- Any contraindication to oral agents or significant nausea and vomiting,
malabsorption, or significant small bowel resection that, in the opinion of the
investigator, would preclude adequate absorption.
- Allergy to benzamide or inactive components of entinostat.
- Hypersensitivity to nivolumab, ipilimumab, or any of their excipients.
- Treatment with any investigational drug or device within 4 weeks prior to
- Treatment with systemic steroids within 4 weeks prior to registration. Note:
adrenal replacement doses of steroids (for example prednisone 10mg daily) are
permitted while on study.
- Evidence of active autoimmune disease requiring systemic treatment within the
past 90 days or a documented history of clinically severe autoimmune disease, or
a syndrome that requires systemic steroids or immunosuppressive agents. Subjects
with vitiligo or resolved childhood asthma/atopy would be an exception to this
rule. Subjects that require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Subjects with hypothyroidism
stable on hormone replacement or Sjogren's syndrome will not be excluded from the
- Interstitial lung disease or history of pneumonitis requiring treatment with
- Diagnosis of immunodeficiency; or is receiving chronic systemic corticosteroid
therapy or other immunosuppressive therapy (excludes inhaled corticosteroids)
within 4 weeks prior to registration.
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Testing
during screening is not required.
- Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or
hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Subjects
with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as
the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are
eligible. HBV DNA test must be performed in these subjects prior to study
treatment, and results must be negative to be eligible. Subjects with a history
of hepatitis C must be tested for presence of hepatitis C virus (HCV) antibody.
If HCV antibody positive, subjects will only be eligible if polymerase chain
reaction is negative for HCV RNA.
- Has received a live vaccine within 30 days prior to planned start of study
therapy. Note: Seasonal influenza vaccines for injection are generally
inactivated flu vaccines and are allowed; however, intranasal influenza vaccines
(e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.