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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

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

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.

Sites / Locations

Beijing Tiantan Hospital, Capital Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

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

NCT ID

NCT04749641

First Posted

February 3, 2021

Last Updated

July 25, 2023

Sponsor

Yang Zhang

Collaborators

TCRCure Biopharma Ltd.

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

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

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

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

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

zhangyang8025@163.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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