Clinical trial NCT04749641: Neoantigen Vaccine Therapy Against H3.3-K27M Diffuse Intrinsic Pontine Glioma
Official title: Enhanced Histone H3.3-K27M Neoantigen Vaccine Therapy Against Diffuse Intrinsic Pontine Glioma (ENACTING)- A Phase I Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diffuse Intrinsic Pontine Glioma
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: TCRCure Biopharma Ltd.
First posted: 2021-02-11
Enrollment: 16
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Safety of histone H3.3-K27M neoantigen vaccine in treating newly diagnosed DIPGs
timeFrame: All the Adverse events (AEs) were recorded until 24 weeks after the last shot
measure: 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
timeFrame: One year after surgery or biopsy
Secondary outcomes:
measure: Maximum Tolerated Dose of H3.3-K27M neoantigen vaccine to treat DIPGs
timeFrame: DLTs were monitored at timepoints of every vaccine shot until the 28th day after the first injection
measure: 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
timeFrame: two years after surgery or biopsy
measure: Median Progression-free survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine
timeFrame: start 4 weeks after the first shot and every 8 weeks until disease progression
measure: Median Overall survival time of the DIPG patients who receive H3.3-K27M neoantigen vaccine
timeFrame: start 4 weeks after the first shot and every 8 weeks until death
measure: Immunological effectiveness of H3.3-K27M neoantigen vaccine for the treatment of DIPG patients
timeFrame: 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.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital, Capital Medical University
state: Beijing
Study officials:
affiliation: Beijing Tiantan Hospital
name: Liwei Zhang, M.D.
role: PRINCIPAL_INVESTIGATOR
References: