This is an open-label, single arm, multi-center Phase II trial of entinostat given as a 5 mg
oral dose every week (days 1, 8, 15, and 22 of a 4-week cycle) in patients with relapsed or
refractory abdominal neuroendocrine (NE) tumors. Patients will continue on treatment until
disease progression or intolerable toxicity occurs.
Neuroendocrine tumors (NETs) are derived from NE cells that reside widely in the endocrine
system and other organs and comprise a heterogeneous group of neoplasms. Because NETs can
arise in a broad spectrum of locations they are associated with a broad range of symptoms
that may be caused by mass effects and/or by the production of hormones or biogenic amines.
Most recently, entinostat has been shown to down-regulate the number and function of two key
immunosuppressive cells, myeloid derived suppressor cells (MDSCs) and regulatory T-cells
(Tregs), in the tumor microenvironment thereby enhancing the activity of immune checkpoint
inhibition. To date, entinostat has been investigated alone or in combination in >900
patients with cancer in clinical studies, including >600 patients with solid tumors.
Entinostat as a single agent has been studied in metastatic melanoma and in combination has
been studied in metastatic non-small cell lung cancer (NSCLC), breast cancer, renal cell
cancer, and colon cancer.
1. Pathologically confirmed stage intravenous (IV) unresectable relapsed, or unresectable
refractory abdominal neuroendocrine tumor from the last biopsy available which may be
the initial diagnostic biopsy.
Relapsed disease is defined as progressive disease following systematic therapy with
lanreotide or equivalent and either Sunitinib or everolimus or both. Refractory
disease is defined as disease not responding to or having progressed within 1 month of
the last dose of most recent systemic therapy to include lanreotide or an analog and
either sunitinib or everolimus. (Note, small cell carcinoma and large cell
undifferentiated neuroendocrine tumors will be excluded from this trial).
2. Eligibility for stage 2 of the study, if the extension stage is opened, will be
determined by ribonucleic acid-sequencing (RNA-seq) analysis and master regulator
profile of a single fresh needle biopsy specimen obtained during study screening.
3. Documented disease that is radiographically measurable.
4. Last dose of prior therapy must be > 21 days before the first dose of study drug
administration. There is no upper limit to number of prior therapies. However, the
patient must have recovered from acute toxicities from the most recent therapy to
grade 1 or less.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (must be done
within 7 days prior to study drug administration).
6. Age 18 years or older
7. Total Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) and aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) < 2.5 x ULN (results within 7 days before
study drug administration), ≤5×ULN for patients with liver metastases.
8. Serum creatinine ≤ 1.5 x ULN (results within 7 days before study drug administration)
9. Absolute neutrophil counts of ≥ 1500/μL (without growth factor support), platelet
counts ≥100,000/μL (without transfusion support); and hemoglobin ≥9 g/dL results
within 7 days before study drug administration.
10. Patients or their legal representative must be able to read, understand, and sign a
written informed consent
11. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5×ULN unless patient
is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT)
is within therapeutic range of intended use of anticoagulants and activated partial
Thromboplastin Time (aPTT) ≤1.5×ULN unless patient is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of anticoagulants
12. If a female of childbearing potential, has a negative serum blood pregnancy test
during screening and a negative urine pregnancy test within 3 days prior to receiving
the 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. Note: Women
of childbearing potential (WoCP) are any women between menarche and menopause who have
not been permanently or surgically sterilized and are capable of procreation.
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or
bilateral salpingectomy but excludes bilateral tubal occlusion. WoCP include non-women
who have experienced menopause onset < 12 months prior to enrollment.
13. If a female of childbearing potential, willing to use 2 methods of birth control or
willing to abstain from heterosexual activity for the course of the study through 120
days after the last dose of study drug.
14. If male, agrees to use an adequate method of contraception starting with the first
dose of study drug through 120 days after the last dose of study drug.
Patients fulfilling any of the following criteria will not be admitted into the study:
1. Patients with another active cancer (excluding basal cell carcinoma or cervical
intraepithelial neoplasia (Cervical Intraepithelial Neoplasia (CIN) / cervical
carcinoma in situ) or melanoma in situ)). Prior history of other cancer is allowed, as
long as there is no active disease within the prior 5 years.
2. Pregnant or lactating women. Women of child-bearing potential (WOCBP) must have a
negative serum pregnancy test documented within 3 days prior to start of study drug.
3. Patients with uncontrolled intercurrent illness, active or uncontrolled infections, or
a fever >38.5°C that has not been evaluated for infection up to the day of initial
dosing. Patients with documented history of tumor fever are accepted provided acute or
chronic infection has been excluded as possible cause of the fever.
4. Patients who have been treated with any investigational drug within 28 days prior to
the first dose of study medication, or who are receiving concurrent treatment with
other experimental drugs or anti-cancer therapy.
5. Prior treatment with histone deacetylase (HDAC) inhibitors (e.g. valproic acid,
Zolinza® (SAHA), romidepsin (Istodax®).
6. History of pericarditis or pericardial effusion that had required medical or surgical
intervention in the last 6 months, or myocardial infarction or arterial thromboembolic
events within 6 months, or experiencing severe or unstable angina, or New York Heart
Association (NYHA) Class III or IV disease, or a corrected QT (QTc) interval >0.47
7. Known human immunodeficiency virus (HIV) or a history of active Hepatitis B or C as
evidenced by laboratory abnormalities in addition to positive serology. Testing is not
required for patients not suspected of having these conditions
8. Any condition (e.g., known or suspected poor compliance, psychological instability,
geographical location, etc) that, in the judgment of the investigator, may affect the
patient's ability to sign the informed consent and comply with study procedures
9. Any condition that will put the patient at undue risk or discomfort as a result of
adherence to study procedures
10. Presence or history of brain metastases.
11. Uncontrolled hypertension or diabetes mellitus
12. 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.
13. Allergy to benzamide or inactive components of entinostat.
14. Patients may not be taking any corticosteroid for any reason while on study and all
corticosteroids must be stopped two weeks prior to initiation of study drug.