<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03765229</url>
  </required_header>
  <id_info>
    <org_study_id>LCCC1729</org_study_id>
    <nct_id>NCT03765229</nct_id>
  </id_info>
  <brief_title>An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma</brief_title>
  <official_title>Breaking Innate PD-1 Inhibitor (PD1i) Resistance Using Epigenetic Modifiers; Antitumor Efficacy and Correlative Analyses of Entinostat Plus Pembrolizumab in Non-Inflamed Metastatic Melanoma (MM)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNC Lineberger Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Syndax Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>UNC Lineberger Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cancers develop in two different ways. First, cancer cells can become invisible to the immune&#xD;
      system by stop having proteins on their surface that are required for the immune system to&#xD;
      recognize them. In this scenario, tumors do not attract any immune cells (e.g. white blood&#xD;
      cells) whatsoever or they do not attract specialized white blood cells against cancer cells,&#xD;
      called lymphocytes. White blood cells are the type of immune cells that attack foreign cells,&#xD;
      such as cancer cells or normal cells infected with viruses or bacteria. Second, cancer cells&#xD;
      can still grow side-to-side with white blood cells but are able to hide from them. As a&#xD;
      result, the white blood cells cannot find and attack the cancer cells. Different types of&#xD;
      cancers have different chance of having immune cells in the tumor. For example, the&#xD;
      possibility that immune cells are within skin melanomas is almost 50% whereas the possibility&#xD;
      in melanoma of the eye is only 10%.&#xD;
&#xD;
      As a result, the first goal of this study is to understand whether entinostat can make a&#xD;
      melanoma tumor more visible to the immune system. To see whether entinostat makes tumor more&#xD;
      visible to the immune system, participants will have a mandatory tumor biopsy 3 weeks after&#xD;
      starting entinostat therapy. Tumor tissue collected before and after participating in this&#xD;
      study will be compared to see if there are more immune cells in the tumor after receive&#xD;
      entinostat. The second goal of the study is to see if giving a combination of entinostat and&#xD;
      pembrolizumab can shrink melanoma tumors of patients who did not have immune cells in tumors&#xD;
      prior to treatment. The study will determine how many subjects cancer has become better or&#xD;
      not changed 6 months after subjects have started treatment on the study. We will also&#xD;
      determine what type of side effects occur in subjects receiving entinostat and pembrolizumab&#xD;
      to look at the safety of this combination.&#xD;
&#xD;
      The investigators will also look at any changes in the DNA of melanoma before the study&#xD;
      begins. As a result of these changes in DNA, there are often see differences in the proteins&#xD;
      that work to create other proteins. In addition, the study will look into how entinostat may&#xD;
      make melanoma cells more visible to the immune system by comparing proteins in tumors before&#xD;
      and after treatment. Finally, the study will see if this treatment changes the numbers and&#xD;
      types of immune cells that are found in the blood by comparing blood at different time points&#xD;
      while patients are on the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an exploratory (n=10-12 evaluable patients), open-label, single-arm, phase II study&#xD;
      in patients with 'non-inflamed' unresectable regional or distant metastatic melanomas&#xD;
      irrespective of prior treatment with PD-1/PD-L1 pathway inhibitors. The primary endpoint is&#xD;
      to assess the incidence of histopathologic conversion of non-inflamed melanomas from patients&#xD;
      with metastatic melanoma to 'inflamed' melanoma following single-agent entinostat &quot;priming&quot;&#xD;
      (entinostat monotherapy). More specifically, patients with metastatic melanomas that have no&#xD;
      evidence of tumor-infiltrating or tumor-associated lymphocytes (TIL/TAL), based on standard&#xD;
      hematoxylin and eosin (H&amp;E) staining of representative tumor sections (non-inflamed&#xD;
      melanomas) will receive weekly entinostat for 3 weeks in cycle 1 (entinostat monotherapy; 5mg&#xD;
      PO, qwk on D1, D8, D15 of cycle 1; cycle length = 21 days). Mandatory tumor tissue biopsies&#xD;
      will be performed in the end of cycle 1, beginning of cycle 2 (day 21±2 days), immediately&#xD;
      before treatment with concurrent entinostat (once weekly × 3) and pembrolizumab (200 mg&#xD;
      q3wks) in cycles 2-9 (see section 5.2.1 drug dosing schema). Correlative studies will be&#xD;
      performed at baseline and in the end of cycle 1, beginning of cycle 2 (day 21±2 days) to&#xD;
      assess whether: (a) 3 weeks of entinostat monotherapy converts TIL/TAL-absent melanomas to&#xD;
      TIL/TAL-present by histopathologic (H&amp;E stain) analysis, (b) 3 weeks of single-agent&#xD;
      entinostat induces changes in gene expression profiling by assessing distinct signatures as&#xD;
      defined by RNA-sequencing signatures (RNA-seq; 'immune-high', innate anti-PD-1 resistance&#xD;
      [IPRES], and epigenetic 1-3), (c) 3 weeks of single-agent entinostat induces changes in&#xD;
      histone-accessible DNA by performing formaldehyde-assisted isolation of regulatory elements&#xD;
      (FAIRE)4, (d) conversion of non-inflamed to inflamed melanomas by single-agent entinostat&#xD;
      and/or antitumor response to the entinostat-pembrolizumab combination is associated with a&#xD;
      baseline signature that consists of distinct somatic mutation gene profile, global histone&#xD;
      modification profile in melanoma tissue or peripheral blood mononuclear cells (PBMC), and/or&#xD;
      abundance of entinostat targets in melanoma cells (HDAC 1, 2, 3, and 11). Up to 12 evaluable&#xD;
      patients will be treated with entinostat plus pembrolizumab for up to 27 weeks (approximately&#xD;
      6 months) based on clinical benefit. Patients who continue to have clinical benefit at 27&#xD;
      weeks may continue therapy with pembrolizumab or any other PD-1/PD-L1 inhibitor, as per&#xD;
      standard of care.Secondary exploratory endpoints involve: (a) assessment of antitumor&#xD;
      response of entinostat administered concurrently with pembrolizumab at week 10 (or earlier if&#xD;
      patient progresses), based on response rate per Response Evaluation Criteria in Solid Tumors&#xD;
      version 1.1 (RECIST v1.1). (b) assessment of the progression-free survival (PFS) rate at 27&#xD;
      weeks (approximately 6 months) of the entinostat-pembrolizumab combination. (c) determine the&#xD;
      safety of the entinostat-pembrolizumab combination in patients with metastatic melanoma per&#xD;
      NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE). (d) assessment of other&#xD;
      exploratory biomarkers in tumor tissue and peripheral blood.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 22, 2019</start_date>
  <completion_date type="Actual">July 31, 2023</completion_date>
  <primary_completion_date type="Actual">December 31, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of conversion of non-inflamed to inflamed melanoma</measure>
    <time_frame>3 weeks after start of treatment</time_frame>
    <description>Assess the incidence of conversion (number of subjects who have changed) from non-inflamed Tumor-infiltrating lymphocyte / Tumor-associated lymphocyte (TIL/TAL) absent before treatment to TIL/TAL present after treatment by histopathologic analysis of Hematoxylin &amp; Eosin (H&amp;E)-stained tissue section from archived metastatic melanoma tumors.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>9 weeks</time_frame>
    <description>Radiographic response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST) Criteria for Complete Response (CR), disappearance of all target lesions or Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions. The Overall Response rate will be the percentage of subjects with CR or PR at 9 weeks after the start of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-Free Survival</measure>
    <time_frame>6 months</time_frame>
    <description>Progression Free Survival is measured as the rate of patients who are progression-free from the date of enrollment on study to the date of documented progression per RECIST 1.1. criteria or death. Per RECIST 1.1, Progressive Disease (PD), is a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events during the concurrent pembrolizumab-entinostat combination</measure>
    <time_frame>9 weeks</time_frame>
    <description>incidence of AEs that occur in subjects enroll who receive at least one dose of therapy will be reported based on the NCI Common Terminology Criteria for Adverse Events v5.0 (NCI-CTCAE v.5.0). The NCI-CTCAE is a descriptive terminology utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Single Arm: Entinostat + Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this trial will be administered entinostat, 5mg PO, once weekly (D1, D8, D15 of a 21-day cycle) starting on day 1 of study treatment. Pembrolizumab, 200 mg will be administered intravenously (IV) every 3 weeks and initiated at cycle 2 after the mandatory research tumor biopsy in the end of cycle 1, beginning of cycle 2 (day 21±2 days),. Combination therapy with both agents will continue if subject is receiving clinical benefit from therapy for up to 27 weeks (8 cycles of combination therapy or approximately 6 months). Study therapy will be discontinued for intolerable toxicity, disease progression or for other reasons at the discretion of the investigator.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Entinostat</intervention_name>
    <description>Oral drug 5 mg taken once weekly for up to nine 3-week (21 day) cycles. Take on an empty stomach i.e., at least 2 hours after a meal and at least 1 hour before the next meal. On days when entinostat is administered on the same day as pembrolizumab, entinostat should be taken before the pembrolizumab infusion.</description>
    <arm_group_label>Single Arm: Entinostat + Pembrolizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles.</description>
    <arm_group_label>Single Arm: Entinostat + Pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years at the time of consent.&#xD;
&#xD;
          -  Subject has provided informed consent and Health Insurance Portability and&#xD;
             Accountability Act (HIPAA) prior to initiation of any study-specific&#xD;
             activities/procedures.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.&#xD;
&#xD;
          -  Histologically confirmed metastatic (regional or distant) melanoma of any subtype&#xD;
             (cutaneous, mucosal, ocular).&#xD;
&#xD;
          -  American Joint Committee on Cancer (AJCC) stage unresectable III or stage IV disease&#xD;
             that is measurable by RECIST v1.1 criteria.&#xD;
&#xD;
          -  Must agree to undergo one on-treatment tumor biopsy on day 22 (±2 days) of the study.&#xD;
             Subjects for whom fresh samples cannot be safely provided (e.g., inaccessible tumor&#xD;
             for biopsy or has metastatic lung lesion(s) as the only site of metastatic disease)&#xD;
             will not be eligible for study participation.&#xD;
&#xD;
          -  Must have available archival tissue and subjects have consented to allow collection of&#xD;
             archived tumor blocks from previous surgeries confirming or treating unresectable&#xD;
             stage III or distant metastatic disease. If more than one archived tumor blocks are&#xD;
             available, two blocks have to be analyzed for the presence of Tumor-infiltrating&#xD;
             lymphocyte/Tumor-associated lymphocyte (TIL/TALS). Archived tumor tissues must fulfill&#xD;
             the following criteria based on two representative Hematoxylin &amp; Eosin (H&amp;E)-stained&#xD;
             tissue sections: (1) the tumor surface area must be at least 1cm (squared), (2) no&#xD;
             more than 20% of necrosis, (3) the ratio of viable tumor cells to tumor-associated&#xD;
             stroma should be at least 60/40, (4) if TILs are present based on H&amp;E stained&#xD;
             sections, they must be ≤ 1% of the total number of cells in the specimen; the amount&#xD;
             of tissue should be ≥ 1 cm2.&#xD;
&#xD;
        The study pathologists must sign off on the eligibility of archived tumor blocks before&#xD;
        study enrollment. If archival tissue is unavailable or insufficient, fresh biopsy should be&#xD;
        performed to confirm unresectable stage III or distant metastatic disease.&#xD;
&#xD;
          -  Previous treatment with immune checkpoint inhibitors and chemotherapies is allowed on&#xD;
             condition that the last treatment is at least 28 days prior to first dose of&#xD;
             entinostat. Previous treatment with targeted therapies (e.g. Mitogen-activated protein&#xD;
             kinase, MAPK inhibitors) is allowed on condition that the last treatment was&#xD;
             administered at least 15 days prior to first dose of entinostat).&#xD;
&#xD;
          -  Demonstrate adequate organ function as defined in the protocool table; all screening&#xD;
             labs to be obtained within 21 days prior to entinostat treatment.&#xD;
&#xD;
             *Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria&#xD;
             for study entry are allowed. Furthermore, changes in laboratory parameters during the&#xD;
             study should not be considered Adverse events (AEs) unless they meet criteria for dose&#xD;
             modification(s) of study medication outlined by the protocol in Section 5.3.1 and/or&#xD;
             worsen from baseline during therapy.&#xD;
&#xD;
          -  A female of childbearing potential must have a negative serum pregnancy test during&#xD;
             screening and a negative urine pregnancy test within 3 days prior to receiving the&#xD;
             first dose of study drug. If the screening serum test is done within 3 days prior to&#xD;
             receiving the first dose of study drug, a urine test is not required. A female of&#xD;
             childbearing potential must agree to use effective contraception during the study and&#xD;
             for 120 days after the last dose of study drug. A female of non-childbearing potential&#xD;
             defined as (by other than medical reasons):&#xD;
&#xD;
             -≥45 years of age and has not had menses for &gt;2 years,&#xD;
&#xD;
          -  Amenorrheic for &lt;2 years without a hysterectomy and oophorectomy and a&#xD;
             follicle-stimulating hormone value in the postmenopausal range upon pre-study&#xD;
             (screening) evaluation,&#xD;
&#xD;
          -  Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or&#xD;
             oophorectomy must be confirmed with medical records of the actual procedure or&#xD;
             confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of&#xD;
             the actual procedure; otherwise the patient must be willing to use 2 adequate barrier&#xD;
             methods throughout the study, starting with the screening visit through 120 days after&#xD;
             the last dose of entinostat,&#xD;
&#xD;
          -  If male, agrees to use an adequate method of contraception starting with the first&#xD;
             dose of study drug through 120 days after the last dose of entinostat,&#xD;
&#xD;
          -  See section 5.6.2 for information on acceptable methods of contraception.&#xD;
&#xD;
          -  Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy&#xD;
             to Grade ≤1 (except alopecia or neuropathy) by CTCAE v5.0. Exceptions are patients who&#xD;
             may have developed autoimmune-type side effects that require permanent hormonal&#xD;
             replacement from previous therapies.&#xD;
&#xD;
          -  If the patient underwent major surgery or radiation therapy, these procedures must&#xD;
             have occurred at least 15 days prior to the first dose of entinostat. In addition,&#xD;
             patients must have recovered from the toxicity and/or complications from the&#xD;
             intervention to Grade ≤1.&#xD;
&#xD;
          -  Subjects must be willing and able to comply with study procedures based on the&#xD;
             judgment of the investigator or protocol designee.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        All subjects meeting any of the exclusion criteria at baseline will be excluded from study.&#xD;
&#xD;
          -  Is receiving systemic steroid therapy or any other form of immunosuppressive therapy&#xD;
             for autoimmune side effects related to previous use of immunotherapies for melanoma.&#xD;
             Exceptions include episodic (up to 7 days) use of systemic steroids for common&#xD;
             conditions while on study treatment (e.g. Chronic obstructive pulmonary disease (COPD)&#xD;
             exacerbation, poison ivy), use of corticosteroids as replacement doses for adrenal or&#xD;
             pituitary insufficiency.&#xD;
&#xD;
          -  Has a known history of tuberculosis (Bacillus Tuberculosis) or human immunodeficiency&#xD;
             virus (HIV 1/2 antibodies).&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients. Allergy to benzamide or&#xD;
             inactive components of entinostat.&#xD;
&#xD;
          -  Has known history of biopsy-proven (non-infectious) pneumonitis that required systemic&#xD;
             steroids, or any evidence of current pneumonitis.&#xD;
&#xD;
          -  Conditions that would preclude adequate absorption of oral medications (malabsorption,&#xD;
             significant nausea and vomiting, resection of &gt;100-cm of proximal small bowel,&#xD;
             resection of &gt;200-cm of distant small bowel).&#xD;
&#xD;
          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator, including but&#xD;
             not limited to:&#xD;
&#xD;
             i. Myocardial infarction or arterial thromboembolic events within 6 months prior to&#xD;
             screening or severe or unstable angina, New York Heart Association (NYHA) Class III of&#xD;
             IV disease, or a QTc interval &gt; 470 msec,&#xD;
&#xD;
        ii. Uncontrolled hypertension (&gt;150/90 in more than 60% of recorded BP measurements taken&#xD;
        on 5 or more separate occasions, within 3 weeks of the first dose of entinostat; at least 3&#xD;
        recorded measurements required on each occasion) or diabetes mellitus (HbA1c &gt;9.0 within 15&#xD;
        days from first dose of entinostat),&#xD;
&#xD;
        iii. Active infection requiring systemic antibiotic therapy by the first day of entinostat&#xD;
        treatment,&#xD;
&#xD;
        iv. Known psychiatric or substance abuse disorders that would interfere with cooperation&#xD;
        with the requirements of the trial.&#xD;
&#xD;
          -  If female, is pregnant or breastfeeding, or, if male, expecting to conceive or father&#xD;
             children within the projected duration of the trial, starting with the pre-screening&#xD;
             or screening visit through 120 days after the last dose of trial treatment.&#xD;
&#xD;
          -  Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C&#xD;
             (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis&#xD;
             B virus (HBV) infection or resolved HBV infection (defined as the presence of&#xD;
             hepatitis B core antibody [HBc Ab] and absence of HBs Ag) are eligible. HBV DNA test&#xD;
             must be performed in these patients prior to study treatment if known history of viral&#xD;
             hepatitis. Patients positive for hepatitis C virus (HCV) antibody are eligible, only&#xD;
             if polymerase chain reaction is negative for HCV RNA.&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy. Note:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are&#xD;
             live-attenuated vaccines and are not allowed.&#xD;
&#xD;
          -  History of prior malignancy, with the exception of the following:&#xD;
&#xD;
               -  Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of&#xD;
                  the cervix,&#xD;
&#xD;
               -  Prior history of prostate cancer provided the patient is not undergoing active&#xD;
                  systemic treatment other than hormonal therapy and has documented PSA that is&#xD;
                  undetectable (&lt;0.2ng/mL),&#xD;
&#xD;
               -  Papillary thyroid cancer, even if patients may have just completed thyroidectomy&#xD;
                  within the last 2 years, have not received adjuvant radioactive iodine therapy,&#xD;
                  and were only recently diagnosed with asymptomatic papillary thyroid cancer and&#xD;
                  their surgery is pending,&#xD;
&#xD;
               -  Chronic lymphocytic leukemia (CLL) provided patient has isolated lymphocytosis&#xD;
                  (Rai stage 0) and does not require systemic treatment [for &quot;B&quot; symptoms,&#xD;
                  Richter's transformation, lymphocyte doubling time (&lt;6 months), lymphadenopathy&#xD;
                  or hepatosplenomegaly],&#xD;
&#xD;
               -  Lymphoma, hairy-cell leukemia, or myelodysplasia, provided that patient is not on&#xD;
                  active systemic treatment and is in complete remission, as evidenced by PET/CT&#xD;
                  scans and bone marrow biopsies for at least 3 months,&#xD;
&#xD;
               -  History of any other malignancy provided patient has completed therapy and is&#xD;
                  free of disease for ≥ 2 years. If patient had other malignancy within the last 2&#xD;
                  years from which he, or she, may have been completely cured by surgery alone, he&#xD;
                  may be considered to be enrolled on condition that the risk of development of&#xD;
                  distant metastatic disease based on the most recent AJCC staging system is less&#xD;
                  than 30%.&#xD;
&#xD;
          -  Has known active (i.e. previously untreated) parenchymal central nervous system (CNS)&#xD;
             metastases that are symptomatic, and/or more than one lesion with the largest diameter&#xD;
             being &gt; 5-mm and/or require antiepileptic drugs or systemic corticosteroids for&#xD;
             management of intracranial symptoms. Patients with carcinomatous meningitis are also&#xD;
             excluded. Exceptions are:&#xD;
&#xD;
               -  Subjects with previously treated brain metastases provided they are stable (i.e.&#xD;
                  without evidence of progression by brain Magnetic Resonance Imaging (MRI) or head&#xD;
                  CT with IV contrast) for at least 2 weeks prior to the first dose of entinostat.&#xD;
                  Any neurologic symptoms must have returned to baseline, and have no evidence of&#xD;
                  new or enlarging brain metastases, and are not using ongoing systemic&#xD;
                  corticosteroids for management of intracranial symptoms for at least 7 days prior&#xD;
                  to first dose of entinostat,&#xD;
&#xD;
               -  Patients with active (i.e. not treated with stereotactic radiosurgery), single,&#xD;
                  asymptomatic, up to 5-mm in largest diameter brain metastases (measured either by&#xD;
                  brain MRI with IV contrast or head CT with IV contrast measuring within 2 weeks&#xD;
                  prior to the first dose of entinostat).&#xD;
&#xD;
          -  Currently participating and receiving study therapy or has participated in a study of&#xD;
             an investigational agent and received study therapy or used an investigational device&#xD;
             within 4 weeks of the first dose of entinostat.&#xD;
&#xD;
          -  Subject is receiving prohibited medications or treatments as listed in section 5.5 of&#xD;
             the protocol that cannot be discontinued/replaced by an alternative therapy.&#xD;
&#xD;
          -  Prior treatment with Histone/deacetylase inhibitor (HDACi) for their melanoma.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stergios Moschos, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UNC Lineberger Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNC Lineberger Comprehensive Cancer Center</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://unclineberger.org/patientcare/clinical-trials/clinical-trials</url>
    <description>University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>November 15, 2018</study_first_submitted>
  <study_first_submitted_qc>December 3, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 5, 2018</study_first_posted>
  <last_update_submitted>September 14, 2023</last_update_submitted>
  <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>PD-1</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Entinostat</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03765229
org study id: LCCC1729
nct id: NCT03765229
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Cancers develop in two different ways. First, cancer cells can become invisible to the immune
      system by stop having proteins on their surface that are required for the immune system to
      recognize them. In this scenario, tumors do not attract any immune cells (e.g. white blood
      cells) whatsoever or they do not attract specialized white blood cells against cancer cells,
      called lymphocytes. White blood cells are the type of immune cells that attack foreign cells,
      such as cancer cells or normal cells infected with viruses or bacteria. Second, cancer cells
      can still grow side-to-side with white blood cells but are able to hide from them. As a
      result, the white blood cells cannot find and attack the cancer cells. Different types of
      cancers have different chance of having immune cells in the tumor. For example, the
      possibility that immune cells are within skin melanomas is almost 50% whereas the possibility
      in melanoma of the eye is only 10%.

      As a result, the first goal of this study is to understand whether entinostat can make a
      melanoma tumor more visible to the immune system. To see whether entinostat makes tumor more
      visible to the immune system, participants will have a mandatory tumor biopsy 3 weeks after
      starting entinostat therapy. Tumor tissue collected before and after participating in this
      study will be compared to see if there are more immune cells in the tumor after receive
      entinostat. The second goal of the study is to see if giving a combination of entinostat and
      pembrolizumab can shrink melanoma tumors of patients who did not have immune cells in tumors
      prior to treatment. The study will determine how many subjects cancer has become better or
      not changed 6 months after subjects have started treatment on the study. We will also
      determine what type of side effects occur in subjects receiving entinostat and pembrolizumab
      to look at the safety of this combination.

      The investigators will also look at any changes in the DNA of melanoma before the study
      begins. As a result of these changes in DNA, there are often see differences in the proteins
      that work to create other proteins. In addition, the study will look into how entinostat may
      make melanoma cells more visible to the immune system by comparing proteins in tumors before
      and after treatment. Finally, the study will see if this treatment changes the numbers and
      types of immune cells that are found in the blood by comparing blood at different time points
      while patients are on the study.
This is an exploratory (n=10-12 evaluable patients), open-label, single-arm, phase II study
      in patients with 'non-inflamed' unresectable regional or distant metastatic melanomas
      irrespective of prior treatment with PD-1/PD-L1 pathway inhibitors. The primary endpoint is
      to assess the incidence of histopathologic conversion of non-inflamed melanomas from patients
      with metastatic melanoma to 'inflamed' melanoma following single-agent entinostat "priming"
      (entinostat monotherapy). More specifically, patients with metastatic melanomas that have no
      evidence of tumor-infiltrating or tumor-associated lymphocytes (TIL/TAL), based on standard
      hematoxylin and eosin (H&E) staining of representative tumor sections (non-inflamed
      melanomas) will receive weekly entinostat for 3 weeks in cycle 1 (entinostat monotherapy; 5mg
      PO, qwk on D1, D8, D15 of cycle 1; cycle length = 21 days). Mandatory tumor tissue biopsies
      will be performed in the end of cycle 1, beginning of cycle 2 (day 21±2 days), immediately
      before treatment with concurrent entinostat (once weekly × 3) and pembrolizumab (200 mg
      q3wks) in cycles 2-9 (see section 5.2.1 drug dosing schema). Correlative studies will be
      performed at baseline and in the end of cycle 1, beginning of cycle 2 (day 21±2 days) to
      assess whether: (a) 3 weeks of entinostat monotherapy converts TIL/TAL-absent melanomas to
      TIL/TAL-present by histopathologic (H&E stain) analysis, (b) 3 weeks of single-agent
      entinostat induces changes in gene expression profiling by assessing distinct signatures as
      defined by RNA-sequencing signatures (RNA-seq; 'immune-high', innate anti-PD-1 resistance
      [IPRES], and epigenetic 1-3), (c) 3 weeks of single-agent entinostat induces changes in
      histone-accessible DNA by performing formaldehyde-assisted isolation of regulatory elements
      (FAIRE)4, (d) conversion of non-inflamed to inflamed melanomas by single-agent entinostat
      and/or antitumor response to the entinostat-pembrolizumab combination is associated with a
      baseline signature that consists of distinct somatic mutation gene profile, global histone
      modification profile in melanoma tissue or peripheral blood mononuclear cells (PBMC), and/or
      abundance of entinostat targets in melanoma cells (HDAC 1, 2, 3, and 11). Up to 12 evaluable
      patients will be treated with entinostat plus pembrolizumab for up to 27 weeks (approximately
      6 months) based on clinical benefit. Patients who continue to have clinical benefit at 27
      weeks may continue therapy with pembrolizumab or any other PD-1/PD-L1 inhibitor, as per
      standard of care.Secondary exploratory endpoints involve: (a) assessment of antitumor
      response of entinostat administered concurrently with pembrolizumab at week 10 (or earlier if
      patient progresses), based on response rate per Response Evaluation Criteria in Solid Tumors
      version 1.1 (RECIST v1.1). (b) assessment of the progression-free survival (PFS) rate at 27
      weeks (approximately 6 months) of the entinostat-pembrolizumab combination. (c) determine the
      safety of the entinostat-pembrolizumab combination in patients with metastatic melanoma per
      NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE). (d) assessment of other
      exploratory biomarkers in tumor tissue and peripheral blood.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of conversion of non-inflamed to inflamed melanoma
time frame: 3 weeks after start of treatment
description: Assess the incidence of conversion (number of subjects who have changed) from non-inflamed Tumor-infiltrating lymphocyte / Tumor-associated lymphocyte (TIL/TAL) absent before treatment to TIL/TAL present after treatment by histopathologic analysis of Hematoxylin & Eosin (H&E)-stained tissue section from archived metastatic melanoma tumors.
measure: Overall Response Rate
time frame: 9 weeks
description: Radiographic response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST) Criteria for Complete Response (CR), disappearance of all target lesions or Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. The Overall Response rate will be the percentage of subjects with CR or PR at 9 weeks after the start of treatment.
measure: Progression-Free Survival
time frame: 6 months
description: Progression Free Survival is measured as the rate of patients who are progression-free from the date of enrollment on study to the date of documented progression per RECIST 1.1. criteria or death. Per RECIST 1.1, Progressive Disease (PD), is a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
measure: Incidence of adverse events during the concurrent pembrolizumab-entinostat combination
time frame: 9 weeks
description: incidence of AEs that occur in subjects enroll who receive at least one dose of therapy will be reported based on the NCI Common Terminology Criteria for Adverse Events v5.0 (NCI-CTCAE v.5.0). The NCI-CTCAE is a descriptive terminology utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
arm group label: Single Arm: Entinostat + Pembrolizumab
arm group type: Experimental
description: Subjects in this trial will be administered entinostat, 5mg PO, once weekly (D1, D8, D15 of a 21-day cycle) starting on day 1 of study treatment. Pembrolizumab, 200 mg will be administered intravenously (IV) every 3 weeks and initiated at cycle 2 after the mandatory research tumor biopsy in the end of cycle 1, beginning of cycle 2 (day 21±2 days),. Combination therapy with both agents will continue if subject is receiving clinical benefit from therapy for up to 27 weeks (8 cycles of combination therapy or approximately 6 months). Study therapy will be discontinued for intolerable toxicity, disease progression or for other reasons at the discretion of the investigator.
intervention type: Drug
intervention name: Entinostat
description: Oral drug 5 mg taken once weekly for up to nine 3-week (21 day) cycles. Take on an empty stomach i.e., at least 2 hours after a meal and at least 1 hour before the next meal. On days when entinostat is administered on the same day as pembrolizumab, entinostat should be taken before the pembrolizumab infusion.
arm group label: Single Arm: Entinostat + Pembrolizumab
intervention type: Drug
intervention name: Pembrolizumab
description: 200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles.
arm group label: Single Arm: Entinostat + Pembrolizumab
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Stergios Moschos, MD
role: Principal Investigator
affiliation: UNC Lineberger Comprehensive Cancer Center
facility: 
country: United States
url: http://unclineberger.org/patientcare/clinical-trials/clinical-trials
description: University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Pembrolizumab
mesh term: Entinostat