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NCT02780804

Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

Completed Phase 1 Results posted Last updated 17 October 2023
What this trial tests

Phase 1 trial testing Entinostat in Brain Stem Neoplasm in 21 participants. Completed in 30 September 2021.

Timeline
6 January 2017
Primary endpoint
30 June 2021
30 September 2021

Quick facts

Lead sponsorNational Cancer Institute (NCI)
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment21
Start date6 January 2017
Primary completion30 June 2021
Estimated completion30 September 2021
Sites21 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 12 Months to 21, any sex, with Brain Stem Neoplasm or Pineal Region Neoplasm. 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.

Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (R2PD) of Entinostat Primary · Up to 28 days

The MTD/RP2D will be defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity during cycle 1 of therapy among 6 toxicity-evaluable patients. The frequency of cycle 1 dose limiting toxicities will be summarized by dose level among patients in the dose escalation part of the study.

GroupValue95% CI
Treatment (Entinostat)4
Frequency of Adverse Events for Entinostat Primary · Up to 28 days

The frequency of patients with at least one Grade 3 or greater adverse event that are at least possibly attributable to entinostat during cycle 1 will be summarized by study part, dose level.

GroupValue95% CI
Stratum 1 With 3 mg/m²5
Stratum 1 With 4 mg/m²7
PK Part With 4 mg/m²5
Half-life of Entinostat Primary · Plasma concentrations were measured at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

The median (min, max) Half-Life of entinostat stratified by study part and dose level. The half-life (t1/2) was calculated using the equation t1/2 = 0.693/λz, where the terminal elimination rate constant (λz) was determined from a least-squares regression of the log-transformed plasma concentration vs. time data for the last 3 - 4 time points.

GroupValue95% CI
Stratum 1 With 3 mg/m²50.9627.38 – 103.66
Stratum 1 With 4 mg/m²46.0440.51 – 81.32
PK Part With 4 mg/m²44.2329.86 – 103.74
Peak Plasma Concentration of Entinostat: C-Max Primary · Up to 96 hours

The median (min, max) of the peak plasma concentration of entinostat stratified by study part, dose level. Time points were assessed at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

GroupValue95% CI
Stratum 1 With 3 mg/m²54.45.19 – 136.00
Stratum 1 With 4 mg/m²61.514.00 – 107.00
PK Part With 4 mg/m²23.819.10 – 293.00
Total Area Under the Plasma Concentration Curve of Entinostat: AUC Primary · Up to 96 hours

The median (min, max) of the total area under the plasma concentration curve of entinostat stratified by study part, dose level. Time points were assessed at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

GroupValue95% CI
Stratum 1 With 3 mg/m²755252 – 1320
Stratum 1 With 4 mg/m²1111816 – 1910
PK Part With 4 mg/m²11471074 – 2349
Time to Reach Maximum Plasma Concentration of Entinostat: T-Max Primary · Up to 96 hours

The median (min, max) of the time to reach maximum plasma concentration of entinostat stratified by study part, dose level. Time points were assessed at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

GroupValue95% CI
Stratum 1 With 3 mg/m²1.010.53 – 6.00
Stratum 1 With 4 mg/m²0.590.50 – 24.55
PK Part With 4 mg/m²10.50 – 24.08
Antitumor Activity of Entinostat Secondary · Up to 4 years 9 months

Frequency of response to entinostat per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and/or assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, stratified by study part and dose

GroupValue95% CI
Stratum 1 With 3 mg/m²0
Stratum 1 With 4 mg/m²0
PK Part With 4 mg/m²0

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 4 years 9 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Stratum 1 With 3 mg/m²
Serious: 5/6 (83%)
Deaths: 1/6
Stratum 1 With 4 mg/m²
Serious: 7/9 (78%)
Deaths: 0/9
PK Part With 4 mg/m²
Serious: 5/6 (83%)
Deaths: 2/6

Serious adverse events (62 terms)

ReactionSystemStratum 1 With 3 mg/m²Stratum 1 With 4 mg/m²PK Part With 4 mg/m²
Neutrophil count decreasedInvestigations
HeadacheNervous system disorders
HydrocephalusNervous system disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Lymphocyte count decreasedInvestigations
Abdominal painGastrointestinal disorders
Abducens nerve disorderNervous system disorders
AcidosisMetabolism and nutrition disorders
AgitationPsychiatric disorders
Alanine aminotransferase increasedInvestigations
Anal hemorrhageGastrointestinal disorders
AnemiaBlood and lymphatic system disorders
AscitesGastrointestinal disorders
Aspartate aminotransferase increasedInvestigations
AspirationRespiratory, thoracic and mediastinal disorders
AtaxiaNervous system disorders
Back painMusculoskeletal and connective tissue disorders
ConfusionPsychiatric disorders
Death NOSGeneral disorders
DeliriumPsychiatric disorders
DelusionsPsychiatric disorders
Depressed level of consciousnessNervous system disorders
DepressionPsychiatric disorders
DiarrheaGastrointestinal disorders
DysarthriaNervous system disorders
Other adverse events (247 terms — click to expand)

ReactionSystemStratum 1 With 3 mg/m²Stratum 1 With 4 mg/m²PK Part With 4 mg/m²
Aspartate aminotransferase increasedInvestigations
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
FatigueGeneral disorders
HyperglycemiaMetabolism and nutrition disorders
Platelet count decreasedInvestigations
White blood cell decreasedInvestigations
DiarrheaGastrointestinal disorders
HeadacheNervous system disorders
HypoalbuminemiaMetabolism and nutrition disorders
HypophosphatemiaMetabolism and nutrition disorders
AnemiaBlood and lymphatic system disorders
AnorexiaMetabolism and nutrition disorders
AnxietyPsychiatric disorders
ConstipationGastrointestinal disorders
HypermagnesemiaMetabolism and nutrition disorders
HypertensionVascular disorders
Lymphocyte count decreasedInvestigations
Neutrophil count decreasedInvestigations
Peripheral sensory neuropathyNervous system disorders
Sinus tachycardiaCardiac disorders
Alkaline phosphatase increasedInvestigations
Back painMusculoskeletal and connective tissue disorders
Blood bilirubin increasedInvestigations
Blurred visionEye disorders
Creatinine increasedInvestigations
DizzinessNervous system disorders
Facial nerve disorderNervous system disorders
FeverGeneral disorders
Gait disturbanceGeneral disorders
Hemoglobin increasedInvestigations
HyperkalemiaMetabolism and nutrition disorders
HypocalcemiaMetabolism and nutrition disorders
HypokalemiaMetabolism and nutrition disorders
HyponatremiaMetabolism and nutrition disorders
HypotensionVascular disorders
InsomniaPsychiatric disorders
Memory impairmentNervous system disorders
MyalgiaMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Neutrophil count decreased, Headache, Hydrocephalus, Hypoxia, Lymphocyte count decreased, Abdominal pain, Abducens nerve disorder, Acidosis.

Data from ClinicalTrials.gov NCT02780804 adverse events section.

Sponsor's own description

This phase I trial studies the side effects and best dose of entinostat in treating pediatric patients with solid tumors that have come back or have not responded to treatment. Entinostat may block some of the enzymes needed for cell division and it may help to kill tumor cells.

Publications & conference data

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

  1. 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
  2. Current and Future Treatment Strategies for Rhabdomyosarcoma.
    Chen C, Dorado Garcia H, Scheer M, Henssen AG. · · 2019 · cited 131× · PMID 31921698 · DOI 10.3389/fonc.2019.01458
  3. Chemical genomics reveals histone deacetylases are required for core regulatory transcription.
    Gryder BE, Wu L, Woldemichael GM, Pomella S, et al · · 2019 · cited 127× · PMID 31285436 · DOI 10.1038/s41467-019-11046-7
  4. Insights into pediatric rhabdomyosarcoma research: Challenges and goals.
    Yohe ME, Heske CM, Stewart E, Adamson PC, et al · · 2019 · cited 65× · PMID 31222885 · DOI 10.1002/pbc.27869
  5. Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis.
    Schmidt O, Nehls N, Prexler C, von Heyking K, et al · · 2021 · cited 35× · PMID 34654445 · DOI 10.1186/s13046-021-02125-z
  6. A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN).
    Bukowinski A, Chang B, Reid JM, Liu X, et al · · 2021 · cited 34× · PMID 33438318 · DOI 10.1002/pbc.28892
  7. Epigenetic regulation in medulloblastoma.
    Yi J, Wu J. · · 2018 · cited 24× · PMID 29269116 · DOI 10.1016/j.mcn.2017.09.003
  8. Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.
    Wu T, Zhao Y, Zhang X, Wang Y, et al · · 2025 · cited 23× · PMID 40703012 · DOI 10.1002/cac2.70048

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