Phase 2
Completed N=11
An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma
Source: ClinicalTrials.gov NCT03765229 ↗Enrolled (actual)
11
Serious AEs
45.5%
Results posted
Jan 2024
Primary outcomePrimary: Number of Conversions of Non-inflamed to Inflamed Melanoma — 3; 7 Participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Conversions of Non-inflamed to Inflamed Melanoma |
3; 7 | — |
| SECONDARY Overall Response Rate |
3; 8 | — |
| SECONDARY Progression-Free Survival |
1; 3; 7 | — |
| SECONDARY Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination |
11; 6; 3; 7; 3; 5 | — |
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 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 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 thromboembol
Data sourced from ClinicalTrials.gov (NCT03765229). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.