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NCT03765229

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

Completed Phase 2 Results posted Last updated 10 January 2024
What this trial tests

Phase 2 trial testing Entinostat in Melanoma in 11 participants. Completed in 31 July 2023.

Timeline
22 March 2019
Primary endpoint
31 December 2022
31 July 2023

Quick facts

Lead sponsorUNC Lineberger Comprehensive Cancer Center
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment11
Start date22 March 2019
Primary completion31 December 2022
Estimated completion31 July 2023
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

UNC Lineberger Comprehensive Cancer Center — full company profile →

Who can join

Adults 18 to 99, any sex, with Melanoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Conversions of Non-inflamed to Inflamed Melanoma Primary · 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).

Tumor-infiltrating lymphocyte increased
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab3
Tumor-infiltrating lymphocyte not increased
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab7
Overall Response Rate Secondary · 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.

Complete Response or Partial Response
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab3
Stable Disease or Progression
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab8
Progression-Free Survival Secondary · 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.

Alive with no evidence of disease
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab1
Alive with disease
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab3
Died from disease
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab7
Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination Secondary · 9 weeks

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

fatigue
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab11
nausea
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab6
vomiting
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab3
diarrhea
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab7
anorexia
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab3
musculoskeletal pain
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab5
cytopenia
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab2
anemia
GroupValue95% CI
Single Arm: Entinostat + Pembrolizumab8

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 90 days.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Single Arm: Entinostat + Pembrolizumab
Serious: 5/11 (45%)
Deaths: 7/11

Serious adverse events (15 terms)

ReactionSystemSingle Arm: Entinostat + P…
DehydrationMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
AnemiaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
General disorders and administration site conditions - Other, specifyGastrointestinal disorders
fatigueGeneral disorders
Hepatic painHepatobiliary disorders
Urinary tract infectionInfections and infestations
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specifyNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor painMusculoskeletal and connective tissue disorders
EncephalopathyNervous system disorders
SeizureNervous system disorders
HallucinationsPsychiatric disorders
Acute kidney injuryRenal and urinary disorders
HematomaVascular disorders
Other adverse events (105 terms — click to expand)

ReactionSystemSingle Arm: Entinostat + P…
FatigueGeneral disorders
Lymphocyte count decreasedInvestigations
HypoalbuminemiaMetabolism and nutrition disorders
Alkaline phosphatase increasedInvestigations
ArthralgiaMusculoskeletal and connective tissue disorders
AnemiaBlood and lymphatic system disorders
DiarrheaGastrointestinal disorders
HyponatremiaMetabolism and nutrition disorders
HypophosphatemiaMetabolism and nutrition disorders
Skin and subcutaneous tissue disorders - Other, specifySkin and subcutaneous tissue disorders
NauseaGastrointestinal disorders
Creatinine increasedInvestigations
Platelet count decreasedInvestigations
Tumor painNeoplasms benign, malignant and unspecified (incl cysts and polyps)
HypertensionVascular disorders
Aspartate aminotransferase increasedInvestigations
Blood lactate dehydrogenase increasedInvestigations
Neutrophil count decreasedInvestigations
White blood cell decreasedInvestigations
DehydrationMetabolism and nutrition disorders
InsomniaPsychiatric disorders
ConstipationGastrointestinal disorders
Edema limbsGastrointestinal disorders
AnxietyPsychiatric disorders
DepressionPsychiatric disorders
HypothyroidismEndocrine disorders
Abdominal painGastrointestinal disorders
VomitingGastrointestinal disorders
PainGeneral disorders
BruisingInjury, poisoning and procedural complications
AnorexiaMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
Generalized muscle weaknessMusculoskeletal and connective tissue disorders
Dry skinSkin and subcutaneous tissue disorders
Skin hypopigmentationSkin and subcutaneous tissue disorders
EosinophiliaBlood and lymphatic system disorders
Atrial fibrillationCardiac disorders
Sinus bradycardiaCardiac disorders
Blurred visionEye disorders
Dry mouthGastrointestinal disorders

Most-reported serious reactions: Dehydration, Back pain, Anemia, Nausea, General disorders and administration site conditions - Other, specify, fatigue, Hepatic pain, Urinary tract infection.

Data from ClinicalTrials.gov NCT03765229 adverse events section.

Sponsor's own 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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
    Cheng Y, He C, Wang M, Ma X, et al · · 2019 · cited 760× · PMID 31871779 · DOI 10.1038/s41392-019-0095-0
  2. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets.
    Yang J, Xu J, Wang W, Zhang B, et al · · 2023 · cited 251× · PMID 37217462 · DOI 10.1038/s41392-023-01480-x
  3. Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker.
    Wang Z, Wu X. · · 2020 · cited 147× · PMID 32875727 · DOI 10.1002/cam4.3410
  4. Epigenetics-targeted drugs: current paradigms and future challenges.
    Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
  5. Combining epigenetic and immune therapy to overcome cancer resistance.
    Gomez S, Tabernacki T, Kobyra J, Roberts P, et al · · 2020 · cited 130× · PMID 31877341 · DOI 10.1016/j.semcancer.2019.12.019
  6. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer.
    Zeng Z, Fu M, Hu Y, Wei Y, et al · · 2023 · cited 93× · PMID 37853437 · DOI 10.1186/s12943-023-01877-w
  7. Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors.
    Perrier A, Didelot A, Laurent-Puig P, Blons H, et al · · 2020 · cited 78× · PMID 32708698 · DOI 10.3390/biom10071061
  8. BRAF Gene and Melanoma: Back to the Future.
    Ottaviano M, Giunta EF, Tortora M, Curvietto M, et al · · 2021 · cited 75× · PMID 33801689 · DOI 10.3390/ijms22073474

Verify or expand the search:

Other trials of Entinostat

Trials testing the same drug.

Other recruiting trials for Melanoma

Currently open trials in the same condition.

Other UNC Lineberger Comprehensive Cancer Center trials

Trials by the same sponsor.

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT03765229.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing