Clinical Trials /

An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma

NCT03765229

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1729
  • NCT ID: NCT03765229

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
EntinostatSingle Arm: Entinostat + Pembrolizumab
PembrolizumabKeytrudaSingle Arm: Entinostat + Pembrolizumab

Purpose

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
      [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 9 (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.
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm: Entinostat + PembrolizumabExperimentalSubjects 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.
  • Entinostat
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years at the time of consent.

          -  Subject has provided informed consent and Health Insurance Portability and
             Accountability Act (HIPAA) prior to initiation of any study-specific
             activities/procedures.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.

          -  Histologically confirmed metastatic (regional or distant) melanoma of any subtype
             (cutaneous, mucosal, ocular).

          -  American Joint Committee on Cancer (AJCC) stage unresectable III or stage IV disease
             that is measurable by RECIST v1.1 criteria.

          -  Must agree to undergo one on-treatment tumor biopsy on day 22 (±2 days) of the study.
             Subjects for whom fresh samples cannot be safely provided (e.g., inaccessible tumor
             for biopsy or has metastatic lung lesion(s) as the only site of metastatic disease)
             will not be eligible for study participation.

          -  Must have available archival tissue and subjects have consented to allow collection of
             archived tumor blocks from previous surgeries confirming or treating unresectable
             stage III or distant metastatic disease. If more than one archived tumor blocks are
             available, two blocks have to be analyzed for the presence of Tumor-infiltrating
             lymphocyte/Tumor-associated lymphocyte (TIL/TALS). Archived tumor tissues must fulfill
             the following criteria based on two representative Hematoxylin & Eosin (H&E)-stained
             tissue sections: (1) the tumor surface area must be at least 1cm2, (2) no more than
             20% of necrosis, (3) the ratio of viable tumor cells to tumor-associated stroma should
             be at least 60/40, (4) absolutely no TIL/TAL. Dr. Paula Googe, study pathologist, must
             sign off on the eligibility of archived tumor blocks before study enrollment. If
             archival tissue is unavailable or insufficient, fresh biopsy should be performed to
             confirm unresectable stage III or distant metastatic disease.

          -  Previous treatment with immune checkpoint inhibitors and chemotherapies is allowed on
             condition that the last treatment is at least 28 days prior to first dose of
             entinostat. Previous treatment with targeted therapies (e.g. Mitogen-activated protein
             kinase, MAPK inhibitors) is allowed on condition that the last treatment was
             administered at least 15 days prior to first dose of entinostat).

          -  Demonstrate adequate organ function as defined in the table below; all screening labs
             to be obtained within 21 days prior to entinostat treatment.

             *Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria
             for study entry are allowed. Furthermore, changes in laboratory parameters during the
             study should not be considered Adverse events (AEs) unless they meet criteria for dose
             modification(s) of study medication outlined by the protocol in Section 5.3.1 and/or
             worsen from baseline during therapy.

          -  A female of childbearing potential must have a negative serum 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. A female of
             childbearing potential must agree to use effective contraception during the study and
             for 120 days after the last dose of study drug. A female of non-childbearing potential
             defined as (by other than medical reasons):

             -≥45 years of age and has not had menses for >2 years,

          -  Amenorrheic for <2 years without a hysterectomy and oophorectomy and a
             follicle-stimulating hormone value in the postmenopausal range upon pre-study
             (screening) evaluation,

          -  Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or
             oophorectomy must be confirmed with medical records of the actual procedure or
             confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of
             the actual procedure; otherwise the patient must be willing to use 2 adequate barrier
             methods throughout the study, starting with the screening visit through 120 days after
             the last dose of entinostat,

          -  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 entinostat,

          -  See section 5.6.2 for information on acceptable methods of contraception.

          -  Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy
             to Grade ≤1 (except alopecia or neuropathy) by CTCAE v5.0. Exceptions are patients who
             may have developed autoimmune-type side effects that require permanent hormonal
             replacement from previous therapies.

          -  If the patient underwent major surgery or radiation therapy, these procedures must
             have occurred at least 15 days prior to the first dose of entinostat. In addition,
             patients must have recovered from the toxicity and/or complications from the
             intervention.

          -  Subjects must be willing and able to comply with study procedures based on the
             judgement of the investigator or protocol designee.

        Exclusion Criteria:

        All subjects meeting any of the exclusion criteria at baseline will be excluded from study.

        -Is receiving systemic steroid therapy or any other form of immunosuppressive therapy for
        autoimmune side effects related to previous use of immunotherapies for melanoma. Exceptions
        include episodic (up to 7 days) use of systemic steroids for common conditions while on
        study treatment (e.g. Chronic obstructive pulmonary disease (COPD) exacerbation, poison
        ivy), use of corticosteroids as replacement doses for adrenal or pituitary insufficiency.

        Has a known history of tuberculosis (Bacillus Tuberculosis) or human immunodeficiency virus
        (HIV 1/2 antibodies).

        Hypersensitivity to pembrolizumab or any of its excipients. Allergy to benzamide or
        inactive components of entinostat.

        Has known history of biopsy-proven (non-infectious) pneumonitis that required systemic
        steroids, or any evidence of current pneumonitis.

        Conditions that would preclude adequate absorption of oral medications (malabsorption,
        significant nausea and vomiting, resection of >100-cm of proximal small bowel, resection of
        >200-cm of distant small bowel).

        Has a history or current evidence of any condition, therapy, or laboratory abnormality that
        might confound the results of the trial, interfere with the subject's participation for the
        full duration of the trial, or is not in the best interest of the subject to participate,
        in the opinion of the treating investigator, including but not limited to:

        i. Myocardial infarction or arterial thromboembolic events within 6 months prior to
        screening or severe or unstable angina, New York Heart Association (NYHA) Class III of IV
        disease, or a QTc interval > 470 msec,

        ii. Uncontrolled hypertension (>150/90 in more than 60% of recorded BP measurements taken
        on 5 or more separate occasions, within 3 weeks of the first dose of entinostat; at least 3
        recorded measurements required on each occasion) or diabetes mellitus (HbA1c >9.0 within 15
        days from first dose of entinostat),

        iii. Active infection requiring systemic antibiotic therapy by the first day of entinostat
        treatment,

        iv. Known psychiatric or substance abuse disorders that would interfere with cooperation
        with the requirements of the trial.

        If female, is pregnant or breastfeeding, or, if male, expecting to conceive or father
        children within the projected duration of the trial, starting with the pre-screening or
        screening visit through 120 days after the last dose of trial treatment.

        Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g.,
        hepatitis C virus ribonucleic acid [qualitative]). Patients 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 HBs Ag) are eligible. HBV DNA test must be performed in
        these patients prior to study treatment if known history of viral hepatitis. Patients
        positive for hepatitis C virus (HCV) antibody are eligible, only if polymerase chain
        reaction is negative for HCV RNA.

        Has received a live vaccine within 30 days of 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.

        History of prior malignancy, with the exception of the following:

          -  Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the
             cervix,

          -  Prior history of prostate cancer provided the patient is not undergoing active
             systemic treatment other than hormonal therapy and has documented PSA that is
             undetectable (<0.2ng/mL),

          -  Papillary thyroid cancer, even if patients may have just completed thyroidectomy
             within the last 2 years, have not received adjuvant radioactive iodine therapy, and
             were only recently diagnosed with asymptomatic papillary thyroid cancer and their
             surgery is pending,

          -  Chronic lymphocytic leukemia (CLL) provided patient has isolated lymphocytosis (Rai
             stage 0) and does not require systemic treatment [for "B" symptoms, Richter's
             transformation, lymphocyte doubling time (<6 months), lymphadenopathy or
             hepatosplenomegaly],

          -  Lymphoma, hairy-cell leukemia, or myelodysplasia, provided that patient is not on
             active systemic treatment and is in complete remission, as evidenced by PET/CT scans
             and bone marrow biopsies for at least 3 months,

          -  History of any other malignancy provided patient has completed therapy and is free of
             disease for ≥ 2 years. If patient had other malignancy within the last 2 years from
             which he, or she, may have been completely cured by surgery alone, he may be
             considered to be enrolled on condition that the risk of development of distant
             metastatic disease based on the most recent AJCC staging system is less than 30%.

        Has known active (i.e. previously untreated) parenchymal central nervous system (CNS)
        metastases that are symptomatic, and/or more than one lesion with the largest diameter
        being > 5-mm and/or require antiepileptic drugs or systemic corticosteroids for management
        of intracranial symptoms. Patients with carcinomatous meningitis are also excluded.
        Exceptions are:

          -  Subjects with previously treated brain metastases provided they are stable (i.e.
             without evidence of progression by brain Magnetic Resonance Imaging (MRI) or head CT
             with IV contrast) for at least 2 weeks prior to the first dose of entinostat. Any
             neurologic symptoms must have returned to baseline, and have no evidence of new or
             enlarging brain metastases, and are not using ongoing systemic corticosteroids for
             management of intracranial symptoms for at least 7 days prior to first dose of
             entinostat,

          -  Patients with active (i.e. not treated with stereotactic radiosurgery), single,
             asymptomatic, up to 5-mm in largest diameter brain metastases (measured either by
             brain MRI with IV contrast or head CT with IV contrast measuring within 2 weeks prior
             to the first dose of entinostat).

        Currently participating and receiving study therapy or has participated in a study of an
        investigational agent and received study therapy or used an investigational device within 4
        weeks of the first dose of entinostat.

        Subject is receiving prohibited medications or treatments as listed in section 5.5 of the
        protocol that cannot be discontinued/replaced by an alternative therapy.

        Prior treatment with Histone/deacetylase inhibitor (HDACi) for their melanoma.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of conversion of non-inflamed to inflamed melanoma
Time Frame:3 weeks after start of treatment
Safety Issue:
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.

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:9 weeks
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • PD-1

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