This is 3-arm, multicenter study that will be conducted through the Pacific Pediatric Neuro-oncology Consortium (PNOC). This study will assess the safety and immune activity of a synthetic peptide vaccine specific for the H3.3.K27M epitope given in combination with poly-ICLC and the H3.3.K27M epitope given in combination with poly-ICLC and the PD-1 inhibitor, nivolumab, in HLA-A2 (02:01)+ children with newly diagnosed DIPG or other midline gliomas that are positive for H3.3K27M.
Name: K27M peptide
Name: Nivolumab
Description: Safety of the vaccine (Strata A and B) or vaccine in combination with nivolumab (Stratum C) will be assessed by monitoring for adverse events (AEs), scheduled laboratory assessments, vital signs, & physical examinations for subjects who receive the vaccination. The severity of toxicities will be graded according to the NCI CTCAE v5.0. AEs & clinically significant lab abnormalities (meeting Grade 3, 4, or 5 criteria according to CTCAE) will be summarized by maximum intensity & relationship to study drug(s). Grade 1 & 2 AEs will be summarized if related to study therapy. Descriptive statistics will be utilized to display the data on toxicity seen.
Measure: Number of Participants with Adverse Events related to treatment Time: 24 monthsDescription: OS12 will be the clinical efficacy primary endpoint for Stratum A. Any eligible subject that receives at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. For subjects who are still alive at 12 months, OS12 will be censored at the last contact date. OS will be estimated using the Kaplan-Meier method.
Measure: Overall survival (OS) at 12 months (OS12) Time: 36 monthsDescription: In subjects with evidence of progression that will undergo tissue collection as part of their standard of care, the tumor tissue will be analyzed for H3.3K27M expression status and infiltration of H3.3K27M specific T cells.
Measure: Assess H3.3K27M expression status and infiltration of H3.3K27M specific T cells Time: 36 monthsDescription: Archived tumor and normal DNA from each subject at time of initial diagnosis along with serial blood draw following therapy will be used for later studies to determine whether circulating tumor DNA (ctDNA) sequences in the subject's blood serve as biomarkers of tumor burden, response to therapy, or development of drug resistance.
Measure: Analyze circulating tumor DNA Time: 36 monthsDescription: A subject will be considered to have responded, if at any of post-vaccine time point against H3.3K27M antigen, the number of spots is double that at baseline, and there are at least 10 spots/20,000 cells, and if the number of the post-vaccine spots is at least three times the standard-deviation of the pre-vaccine value. This definition provides some protection against false positive response. We will correlate response with OS data. We will plot the time course of the magnitude of response and model it using a mixed-effects model approach.
Measure: Induction of the H3.3K27M epitope-specific cytotoxic T lymphocyte (CTL) response in post vaccine peripheral mononuclear cells (PBMC) in HLA-A2+ children with DIPG and other gliomas Time: 36 monthsDescription: Subjects in Stratum C will take age-appropriate surveys or complete questionnaires to assess treatment and disease impact on quality of life.
Measure: Assessment of Quality of Life and cognitive measures in HLA-A2 (02:01)+ children with H3.3K27M positive DIPG or other midline gliomas. Time: 48 monthsAllocation: Non-Randomized
Parallel Assignment
There is one SNP
OS12 will be the clinical efficacy primary endpoint for Stratum A. Any eligible subject that receives at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. --- K27M ---
Diffuse Intrinsic Pontine Glioma Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioma Subjects who are eligible will receive a specific peptide vaccine, along with a helper drug called poly-ICLC, in combination with nivolumab, every 3 weeks for the first 6 months of treatment. --- K27M ---