MelanomaPhase 2NCT03765229
An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma
A Phase 2 study testing Entinostat and Pembrolizumab in people with Melanoma, run by UNC Lineberger Comprehensive Cancer Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Melanoma
- What is being tested?
- Entinostat and Pembrolizumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteUnited States
- Study dates
- 22 Mar 2019to 31 Jul 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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 1cm (squared), (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) if TILs are present based on H\&E stained sections, they must be ≤ 1% of the total number of cells in the specimen; the amount of tissue should be ≥ 1 cm2.
- The study pathologists 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 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 protocol table; 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 to Grade ≤1.
- Subjects must be willing and able to comply with study procedures based on the judgment of the investigator or protocol designee.
Who cannot join
- 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).
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- 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:
- 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 QT corrected for heart rate interval > 470 msec,
- 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),
- Active infection requiring systemic antibiotic therapy by the first day of entinostat treatment,
- 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 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 prostate-specific antigen 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 positron emission tomography/computerized tomography (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.
Trial locations and contacts
1 site in 1 country.
United States1 site
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
About this study
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)
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.
Read the 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.
- Conditions
- Melanoma
- Being tested
- Entinostat, Pembrolizumab
- Keywords
- PD-1
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EntinostatDrug
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.
PembrolizumabDrug
Also called Keytruda
200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles.
| Study group | Role | What they receive |
|---|---|---|
| Single Arm: Entinostat + Pembrolizumab | Experimental | 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. Receives: Drug: Entinostat; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Conversions of Non-inflamed to Inflamed Melanoma
Number of subjects with conversion from non-inflamed Tumor-infiltrating lymphocyte / Tumor-associated lymphocyte (TIL/TAL) absent before treatment to TIL/TAL present after treatment was assessed by histopathologic analysis. Representative 5-micron thick formalin fixed paraffin embedded sections collected from baseline and on-treatment (entinostat-alone, day 21 of the trial) were stained with hematoxylin and eosin on day 21 (on-treatment biopsy).
Measured: 3 weeks after start of treatment
Secondary outcomes (3)
Overall Response Rate
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.
Measured: 9 weeks
Progression-Free Survival
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.
Measured: 6 months
Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination
Type of AEs that occur in subjects enrolled 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.
Measured: 9 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2018
- Study start22 Mar 2019
- Primary completion31 Dec 2022
- Study completion31 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by UNC Lineberger Comprehensive Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- UNC Lineberger Comprehensive Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- Syndax Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Stergios Moschos, MD, Principal investigator, UNC Lineberger Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03765229
- Sponsor's protocol ID
- LCCC1729
- Status last verified
- Dec 2023
- First submitted
- 15 Nov 2018
- Last updated
- 10 Jan 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03765229
- Acronym / sponsor ID
- LCCC1729
- Conditions
- Melanoma
- Keywords
- PD-1
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- UNC Lineberger Comprehensive Cancer CenterUniversity, hospital or other
- Collaborators
- Syndax Pharmaceuticals
- Study start
- 22 Mar 2019 (actual)
- Primary completion
- 31 Dec 2022 (actual)
- Study completion
- 31 Jul 2023 (actual)
- First posted
- 5 Dec 2018 (actual)
- Results
- Posted 10 Jan 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Arm: Entinostat + Pembrolizumab | Experimental | Drug: Entinostat, Drug: PembrolizumabSubjects 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. |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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.
Key exclusion criteria (27 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EntinostatOral 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. | Drug | Single Arm: Entinostat + Pembrolizumab |
| PembrolizumabAlso: Keytruda200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles. | Drug | Single Arm: Entinostat + Pembrolizumab |
Primary outcome
Number of Conversions of Non-inflamed to Inflamed Melanoma
Time frame: 3 weeks after start of treatment
Number of subjects with conversion from non-inflamed Tumor-infiltrating lymphocyte / Tumor-associated lymphocyte (TIL/TAL) absent before treatment to TIL/TAL present after treatment was assessed by histopathologic analysis. Representative 5-micron thick formalin fixed paraffin embedded sections collected from baseline and on-treatment (entinostat-alone, day 21 of the trial) were stained with hematoxylin and eosin on day 21 (on-treatment biopsy).
3 secondary outcomes
Overall Response Rate
Time frame: 9 weeks
Progression-Free Survival
Time frame: 6 months
Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination
Time frame: 9 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jan 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- University of North Carolina Lineberger Comprehensive Cancer Center Clinical TrialsLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stergios Moschos, MD principal investigator
UNC Lineberger Comprehensive Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Entinostat and Pembrolizumab in people with Melanoma, run by UNC Lineberger Comprehensive Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Conversions of Non-inflamed to Inflamed Melanoma (time frame: 3 weeks after start of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jan 2024.