An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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,
      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.
    

Intervention name(s): Entinostat; Pembrolizumab
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles.
Other intervention name(s): Keytruda
Intervention MeSH terms: Pembrolizumab; Entinostat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: PD-1