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Neoantigen Vaccine Therapy Against H3.3-K27M Diffuse Intrinsic Pontine Glioma (ENACTING)

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ClinicalTrials.gov Identifier: NCT04749641
Recruitment Status : Recruiting
First Posted : February 11, 2021
Last Update Posted : July 20, 2022
Sponsor:
Collaborator:
TCRCure Biopharma Ltd.
Information provided by (Responsible Party):
Yang Zhang, Beijing Tiantan Hospital

Study Description
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Brief Summary:
Diffuse intrinsic pontine gliomas (DIPGs), which diffusely occupy the pons of brainstem, are the deadliest primary brain cancer in children. Biopsy for pathology plus radiotherapy remains the current standard-of-care treatment that is minimal effective. Thus, the median overall survival after diagnosis is just 10 months. Recent studies have identified a lysine 27-to-methionine (K27M) somatic mutation at histone H3 variant (H3.3), as a feature mutation in DIPGs. Several preclinical studies have already demonstrated H3.3-K27M as a promising target for immunotherapy. The researched vaccine is a cancer-treatment vaccine containing an H3.3-K27M targeted neoantigen peptide, that can be taken up by antigen-presenting cells (APCs). APCs can present the peptide with the major histocompatibility complex (MHC) molecules on cell surface, thereby activating neoantigen-specific T cells and triggering corresponding cytotoxic T cell immune responses to eliminate H3.3-K27M-expressing DIPG cells. The main goal of this study is investigating the safety and preliminary efficacy of the vaccine in treating newly-diagnosed DIPGs when the vaccine is administered in combination with the standard-of-care treatment.

Condition or disease Intervention/treatment Phase
Diffuse Intrinsic Pontine Glioma Biological: Histone H3.3-K27M Neoantigen Vaccine Therapy Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Enhanced Histone H3.3-K27M Neoantigen Vaccine Therapy Against Diffuse Intrinsic Pontine Glioma (ENACTING)- A Phase I Clinical Trial
Actual Study Start Date : March 8, 2021
Estimated Primary Completion Date : March 31, 2023
Estimated Study Completion Date : April 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy Vaccines

Arms and Interventions
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Arm Intervention/treatment
Experimental: Open surgical biopsy
A total of 15 subjects with open surgical biopsy indications will receive microsurgical resection, followed by conformal radiotherapy and administration of the researched vaccine.
 Biological: Histone H3.3-K27M Neoantigen Vaccine Therapy
The researched vaccine, containing H3.3-K27M-targeting neoantigen peptides and poly ICLC, will be administered through subcutaneous injection into DIPG patients after they complete surgical/stereotactic biopsy and conformal radiotherapy. The day of first vaccine injection is defined as D1 (day 1), and then the injections will be administered on D3, D15, Day 29, Day 57, Day 85 and one injection every 8 weeks thereafter. In order to determine the Maximum Tolerated Dose (MTD) of the vaccine, a "6+3" dose escalation design is applied. There are three doses for the vaccine. Dose 1: 0.5mg peptide + Poly ICLC; Dose 2: 1mg peptide + Poly ICLC; Dose 3: 2mg peptide + Poly ICLC.
Experimental: Stereotactic biopsy
A total of 15 subjects without open surgical biopsy indications will receive stereotactic biopsy, followed by conformal radiotherapy and administration of the researched vaccine.
 Biological: Histone H3.3-K27M Neoantigen Vaccine Therapy
The researched vaccine, containing H3.3-K27M-targeting neoantigen peptides and poly ICLC, will be administered through subcutaneous injection into DIPG patients after they complete surgical/stereotactic biopsy and conformal radiotherapy. The day of first vaccine injection is defined as D1 (day 1), and then the injections will be administered on D3, D15, Day 29, Day 57, Day 85 and one injection every 8 weeks thereafter. In order to determine the Maximum Tolerated Dose (MTD) of the vaccine, a "6+3" dose escalation design is applied. There are three doses for the vaccine. Dose 1: 0.5mg peptide + Poly ICLC; Dose 2: 1mg peptide + Poly ICLC; Dose 3: 2mg peptide + Poly ICLC.


Outcome Measures
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Primary Outcome Measures :
  1. Safety of histone H3.3-K27M neoantigen vaccine in treating newly diagnosed DIPGs [ Time Frame: All the Adverse events (AEs) were recorded until 24 weeks after the last shot ]
    AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  2. Rate of the patients who survive for more than one year after surgery/biopsy in all the DIPG patients who receive H3.3-K27M neoantigen vaccine [ Time Frame: One year after surgery or biopsy ]
    One-year survival rate


Secondary Outcome Measures :
  1. Maximum Tolerated Dose of H3.3-K27M neoantigen vaccine to treat DIPGs [ Time Frame: DLTs were monitored at timepoints of every vaccine shot until the 28th day after the first injection ]
    ">= Grade 3 " vaccine related AEs are defined as DLTs. In order to determine the Maximum Tolerated Dose (MTD) of the vaccine, a "6+3" dose escalation design is applied.

  2. Rate of the patients who survive for more than two years after surgery/biopsy in all the DIPG patients who receive H3.3-K27M neoantigen vaccine [ Time Frame: two years after surgery or biopsy ]
    two-year survival rate

  3. Median Progression-free survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine [ Time Frame: start 4 weeks after the first shot and every 8 weeks until disease progression ]
    Progression-free survival time: the time from operation/biopsy to progression (when shows signs or symptoms of the growth or the spreading of a tumor)

  4. Median Overall survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine [ Time Frame: start 4 weeks after the first shot and every 8 weeks until death ]
    overall survival time: the time from operation/biopsy to death.

  5. Immunological effectiveness of H3.3-K27M neoantigen vaccine for the treatment of DIPG patients [ Time Frame: baseline 1: pre-radiotherapy; baseline 2: immediately after completing radiotherapy; Day 15, Day 57, Day 85 and every 8 weeks thereafter until up to 2 years after the first shot. ]
    Immunological effectiveness is measured by an IFN-γ ELISPOT assay as number of spot-forming cells in one million peripheral blood mononuclear cells.


Eligibility Criteria
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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

A. First entry criteria

  1. Age ≥ 5 years old;
  2. Newly-diagnosed patients with DIPG appearance on MRI image;
  3. HLA-A2 subtype;
  4. The expected survival time exceeds 24 weeks;
  5. The KPS score is greater than 50; B. Second entry criteria

1. The KPS score is greater than 50; 2. DIPG is diagnosed histologically on tumor tissue obtained by biopsy or surgical resection; 3. H3.3K27M mutation is detected on tumor tissue obtained by biopsy or surgical resection ; 4. Adequate organ functions that meet the following criteria: The absolute number of neutrophils: ≥1500/mm3 Platelet count: ≥75000/uL Hemoglobin: ≥80 g/L Creatinine≤1.5×ULN Bilirubin≤1.5×ULN ALT≤3×ULN AST≤3×ULN 5. Ability to comprehend and sign an informed consent form.

Exclusion Criteria:

  1. With past medical history of malignant tumors (except being asymptomatic for more than 3 years);
  2. History of allergy to chemotherapeutics or radiosensitizers for the treatment of cancer in central nervous system and head/neck;
  3. History of allergy to the vaccine and its ingredients;
  4. Comorbidity with HIV infection and/or acute phase of hepatitis B/C;
  5. Any progressive diseases that hinder participation in the trial;
  6. With unstable cardiovascular diseases such as coronary heart disease, angina pectoris, myocardial infarction, arrhythmia et.al.;
  7. History of uncontrolled mental illnesses;
  8. Inability to comprehend or sign informed consent form or abide by the research procedures;
  9. Other conditions believed to hinder participation in this trial at investigator' discretion.
Contacts and Locations
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Information from the National Library of Medicine

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): NCT04749641


Contacts
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Contact: Yang Zhang, M.D. & Ph.D. +861059976516 zhangyang8025@163.com

Locations
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China, Beijing
Beijing Tiantan Hospital, Capital Medical University Recruiting
Beijing, Beijing, China, 100070
Contact: Yang Zhang, Dr.    +861059976516    zhangyang8025@163.com   
Sponsors and Collaborators
Yang Zhang
TCRCure Biopharma Ltd.
Investigators
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Principal Investigator: Liwei Zhang, M.D. Beijing Tiantan Hospital
More Information
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Responsible Party: Yang Zhang, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing,100070 P.R.China, Beijing Tiantan Hospital
ClinicalTrials.gov Identifier: NCT04749641    
Other Study ID Numbers: KY 2019-126-01
First Posted: February 11, 2021    Key Record Dates
Last Update Posted: July 20, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Diffuse Intrinsic Pontine Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Brain Stem Neoplasms
Infratentorial Neoplasms
 Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs