Clinical Trials /

Entinostat Neuroendocrine (NE) Tumor

NCT03211988

Description:

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.

Related Conditions:
  • Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Entinostat Neuroendocrine (NE) Tumor
  • Official Title: A Phase 2 Single-Arm Multicenter Study of Entinostat in Patients With Relapsed or Refractory Abdominal Neuroendocrine (NE) Tumors

Clinical Trial IDs

  • ORG STUDY ID: AAAR1117
  • NCT ID: NCT03211988

Conditions

  • Neuroendocrine Tumors

Interventions

DrugSynonymsArms
EntinostatSNDX-275, MS-275Entinostat

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
EntinostatOtherEligible patients will be enrolled according to Simon's two-stage design. The dose of Entinostat is 5 mg (one tablet) orally, once every week in a 28 day cycle.
  • Entinostat

Eligibility Criteria

        Inclusion Criteria:

          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.

        Exclusion Criteria:

        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
             seconds

          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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to Two Years
Safety Issue:
Description:Percentage of patients who experience a tumor size reduction from the time of initial response to tumor progression.

Secondary Outcome Measures

Measure:Duration of Progression-Free Survival (PFS)
Time Frame:Up to Two Years
Safety Issue:
Description:Time from study enrollment until disease progression or death.
Measure:Duration of Overall Survival (OS)
Time Frame:Up to Two Years
Safety Issue:
Description:The length of time from either the date of diagnosis or start of treatment that years patients diagnosed with the disease are still alive.
Measure:Duration of Response for Patients who Achieve Complete Response (CR) or Partial Response (PR)
Time Frame:Up to Two Years
Safety Issue:
Description:Time from documentation of tumor response to disease progression.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Antonio Fojo

Trial Keywords

  • abdominal
  • neuroendocrine tumor
  • columbia
  • relapsed
  • refractory

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