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

Primary Purpose

Diffuse Intrinsic Pontine Glioma

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Histone H3.3-K27M Neoantigen Vaccine Therapy
Sponsored by
Yang Zhang
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Intrinsic Pontine Glioma

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Beijing Tiantan Hospital, Capital Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Open surgical biopsy

Stereotactic biopsy

Arm Description

A total of 15 subjects with open surgical biopsy indications will receive microsurgical resection, followed by conformal radiotherapy and administration of the researched vaccine.

A total of 15 subjects without open surgical biopsy indications will receive stereotactic biopsy, followed by conformal radiotherapy and administration of the researched vaccine.

Outcomes

Primary Outcome Measures

Safety of histone H3.3-K27M neoantigen vaccine in treating newly diagnosed DIPGs
AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
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
One-year survival rate

Secondary Outcome Measures

Maximum Tolerated Dose of H3.3-K27M neoantigen vaccine to treat DIPGs
">= 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.
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
two-year survival rate
Median Progression-free survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine
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)
Median Overall survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine
overall survival time: the time from operation/biopsy to death.
Immunological effectiveness of H3.3-K27M neoantigen vaccine for the treatment of DIPG patients
Immunological effectiveness is measured by an IFN-γ ELISPOT assay as number of spot-forming cells in one million peripheral blood mononuclear cells.

Full Information

First Posted
February 3, 2021
Last Updated
July 25, 2023
Sponsor
Yang Zhang
Collaborators
TCRCure Biopharma Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04749641
Brief Title
Neoantigen Vaccine Therapy Against H3.3-K27M Diffuse Intrinsic Pontine Glioma
Acronym
ENACTING
Official Title
Enhanced Histone H3.3-K27M Neoantigen Vaccine Therapy Against Diffuse Intrinsic Pontine Glioma (ENACTING)- A Phase I Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 8, 2021 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
December 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Yang Zhang
Collaborators
TCRCure Biopharma Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Intrinsic Pontine Glioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Open surgical biopsy
Arm Type
Experimental
Arm Description
A total of 15 subjects with open surgical biopsy indications will receive microsurgical resection, followed by conformal radiotherapy and administration of the researched vaccine.
Arm Title
Stereotactic biopsy
Arm Type
Experimental
Arm Description
A total of 15 subjects without open surgical biopsy indications will receive stereotactic biopsy, followed by conformal radiotherapy and administration of the researched vaccine.
Intervention Type
Biological
Intervention Name(s)
Histone H3.3-K27M Neoantigen Vaccine Therapy
Intervention Description
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.
Primary Outcome Measure Information:
Title
Safety of histone H3.3-K27M neoantigen vaccine in treating newly diagnosed DIPGs
Description
AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time Frame
All the Adverse events (AEs) were recorded until 24 weeks after the last shot
Title
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
Description
One-year survival rate
Time Frame
One year after surgery or biopsy
Secondary Outcome Measure Information:
Title
Maximum Tolerated Dose of H3.3-K27M neoantigen vaccine to treat DIPGs
Description
">= 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.
Time Frame
DLTs were monitored at timepoints of every vaccine shot until the 28th day after the first injection
Title
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
Description
two-year survival rate
Time Frame
two years after surgery or biopsy
Title
Median Progression-free survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine
Description
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)
Time Frame
start 4 weeks after the first shot and every 8 weeks until disease progression
Title
Median Overall survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine
Description
overall survival time: the time from operation/biopsy to death.
Time Frame
start 4 weeks after the first shot and every 8 weeks until death
Title
Immunological effectiveness of H3.3-K27M neoantigen vaccine for the treatment of DIPG patients
Description
Immunological effectiveness is measured by an IFN-γ ELISPOT assay as number of spot-forming cells in one million peripheral blood mononuclear cells.
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: A. First entry criteria Age ≥ 5 years old; Newly-diagnosed patients with DIPG appearance on MRI image; HLA-A2 subtype; The expected survival time exceeds 24 weeks; 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: With past medical history of malignant tumors (except being asymptomatic for more than 3 years); History of allergy to chemotherapeutics or radiosensitizers for the treatment of cancer in central nervous system and head/neck; History of allergy to the vaccine and its ingredients; Comorbidity with HIV infection and/or acute phase of hepatitis B/C; Any progressive diseases that hinder participation in the trial; With unstable cardiovascular diseases such as coronary heart disease, angina pectoris, myocardial infarction, arrhythmia et.al.; History of uncontrolled mental illnesses; Inability to comprehend or sign informed consent form or abide by the research procedures; Other conditions believed to hinder participation in this trial at investigator' discretion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yang Zhang, M.D. & Ph.D.
Phone
+861059976516
Email
zhangyang8025@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Liwei Zhang, M.D.
Organizational Affiliation
Beijing Tiantan Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beijing Tiantan Hospital, Capital Medical University
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100070
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yang Zhang, Dr.
Phone
+861059976516
Email
zhangyang8025@163.com

12. IPD Sharing Statement

Plan to Share IPD
No

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

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