An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma
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|ClinicalTrials.gov Identifier: NCT03765229|
Recruitment Status : Recruiting
First Posted : December 5, 2018
Last Update Posted : April 16, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Melanoma||Drug: Entinostat Drug: Pembrolizumab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||14 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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)|
|Actual Study Start Date :||March 22, 2019|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||June 2023|
Experimental: Single Arm: Entinostat + Pembrolizumab
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.
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 Name: Keytruda
- Incidence of conversion of non-inflamed to inflamed melanoma [ Time Frame: 3 weeks after start of treatment ]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.
- Overall Response Rate [ Time Frame: 9 weeks ]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.
- Progression-Free Survival [ Time Frame: 6 months ]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.
- Incidence of adverse events during the concurrent pembrolizumab-entinostat combination [ Time Frame: 9 weeks ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03765229
|Contact: Diana Wallackemail@example.com|
|Contact: Deeanna Bouchardfirstname.lastname@example.org|
|United States, North Carolina|
|UNC Lineberger Comprehensive Cancer Center||Recruiting|
|Chapel Hill, North Carolina, United States, 27599|
|Contact: Diana Wallack 984-974-8652 email@example.com|
|Principal Investigator:||Stergios Moschos, MD||UNC Lineberger Comprehensive Cancer Center|