H3.3K27M Peptide Vaccine With Nivolumab for Children With Newly Diagnosed DIPG and Other Gliomas

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Subjects will be monitored routinely by laboratory assessments, physical evaluation, vital signs, and MRI. Subjects who tolerate therapy well and have stable or improved disease after 6 months of treatment can continue to receive treatment, nivolumab continuing every 3 weeks but vaccine and poly-ICLC now every 6 weeks, for a total of 96 weeks of treatment.

Official Title
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H3.3K27M Specific Peptide Vaccine Combined With Poly-ICLC With and Without PD-1 Inhibition Using Nivolumab for the Treatment of Newly Diagnosed HLA-A2 (02:01)+ H3.3K27M Positive Diffuse Intrinsic Pontine Glioma (DIPG) and Newly Diagnosed HLA-A2 (02:01)+ H3.3K27M Positive Gliomas

Conditions
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Diffuse Intrinsic Pontine Glioma, Glioma, Diffuse Midline Glioma, H3 K27M-Mutant

Intervention / Treatment
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* Biological: K27M peptide
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stratum A: • Newly diagnosed children (3-21 years old) with DIPG who are positive for the H3.3K27M mutation (positive testing in Clinical Laboratory Improvement Amendments (CLIA) laboratory) that underwent standard radiation therapy. Stratum B: • Newly diagnosed children (3-21 years old) with diagnosis of glioma other than DIPG who are positive for the H3.3K27M mutation (positive testing in CLIA laboratory) including spinal cord gliomas that underwent standard radiation therapy. Stratum C: Newly diagnosed children 3-21 years of age with diagnosis of DIPG or midline glioma other than DIPG (excluding primary spinal cord gliomas) who are positive for the H3.3K27M mutation (positive testing from a CLIA or equivalent laboratory required), that underwent standard radiation therapy. The following eligibility criteria apply to strata A, B and C: The patient must test positive for HLA-A*02:01 (positive testing from a CLIA or equivalent laboratory required; only the HLA A*02:01 subtype is eligible; other subtypes are excluded) The patient must be either off systemic steroids or be on stable dose of dexamethasone or equivalent (max 0.1 mg/kg/day; maximum 4mg/day) at time of enrollment. Patients must not have received any prior chemotherapy, immunotherapy or bone marrow transplant for the treatment of their tumor. Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m^2/dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Patients must have undergone radiation therapy and surgery as part of their standard of care. Stratum A: Radiation therapy must have started within 4 weeks of diagnosis by imaging or surgery, whichever is later. Stratum B: For subjects undergoing surgery for more extensive resection, radiation therapy should be started within 4-6 weeks from surgery. Stratum C: Radiation therapy must have started within 4 weeks of diagnosis by imaging or surgery, whichever is later. For subjects undergoing surgery for more extensive resection, radiation therapy should be started within 4-6 weeks from surgery. Karnofsky ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years of age (See Appendix A). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. The patient must have adequate organ function defined as Adequate Bone Marrow Function Defined as: Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). Adequate Renal Function Defined as: Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2 or A serum creatinine based on age/gender as follows: Age Maximum Serum Creatinine (mg/dL) Male Female 3 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Center for Disease Control (CDC). Adequate Liver Function Defined as: Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age and serum glutamic-pyruvic transaminase (SGPT)/ alanine aminotransferase (ALT) ≤ 110 U/L and Serum albumin ≥ 2 g/dL. Adequate Pancreatic Function Defined as: • Serum lipase ≤ ULN at baseline. Adequate Pulmonary Function Defined as: • No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air. Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if seizure disorder is well controlled. The effects of the H3.3K27M vaccine and nivolumab on the developing human fetus are unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation. Ability to understand a written informed consent document, and the willingness to sign it. Assent will be obtained when appropriate based on the subjects age. Exclusion Criteria: Investigational Drugs Patients who are currently receiving another investigational drug are not eligible. Prior treatment with another investigational drug. Anti-cancer Agents Patients who are currently receiving other anti-cancer agents are not eligible. Prior treatment with other anti-cancer agents. Patients who have received a live / attenuated vaccine within 30 days of first treatment. Patients with evidence of disseminated or leptomeningeal disease. Patients with a known disorder that affects their immune system, such as HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible. Note: Patients that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair. Patients with a ≥ Grade 2 hypothyroidism due to history of autoimmunity are not eligible. (Note: Hypothyroidism due to previous irradiation or thyroidectomy will not impact eligibility). Patients who have received prior solid organ or bone marrow transplantation are not eligible. Patients with uncontrolled infection. Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated).

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum A: Newly Diagnosed DIPG<br>Newly diagnosed children with diffuse intrinsic pontine glioma who are positive for HLA-A2 and the H3.3K27M mutation that underwent radiation therapy will receive the specific H3.3K27M peptide vaccine, combined with the tetanus toxoid (TT) peptide, emulsified in Montanide. Poly-ICLC, which is a synthetic nucleic acid, will be given concurrently to improve the therapeutic effects of the vaccine. Vaccine will be given every 3 weeks for the first 24 weeks, then if there is stable or improved disease, will be given every 6 weeks for a total treatment period of 96 weeks. | Biological: K27M peptide<br>* K27M peptide vaccine, combined with Tetanus Toxoid peptide, emulsified in montanide. Poly-ICLC will be given concurrently<br>|
| Experimental: Stratum B: Newly Diagnosed Glioma (non-DIPG)<br>Newly diagnosed children with gliomas other than DIPG who are positive for HLA-A2 and the H3.3K27M mutation that underwent radiation therapy will receive the specific H3.3K27M peptide vaccine, combined with the tetanus toxoid peptide, emulsified in Montanide. Poly-ICLC, which is a synthetic nucleic acid, will be given concurrently to improve the therapeutic effects of the vaccine. Vaccine will be given every 3 weeks for the first 24 weeks, then if there is stable or improved disease, will be given every 6 weeks for a total treatment period of 96 weeks. | Biological: K27M peptide<br>* K27M peptide vaccine, combined with Tetanus Toxoid peptide, emulsified in montanide. Poly-ICLC will be given concurrently<br>|
| Experimental: Stratum C: Newly Diagnosed DIPG or other Midline Glioma<br>Newly diagnosed children with DIPG or other midline gliomas (excluding primary spinal cord tumors) who are positive for HLA-A2 (02:01) and the H3.3K27M mutation that underwent radiation therapy will receive the specific H3.3K27M peptide vaccine, combined with the tetanus toxoid peptide, emulsified in Montanide. Poly-ICLC, which is a synthetic nucleic acid, will be given concurrently to improve the therapeutic effects of the vaccine. Nivolumab will also be given via IV. Vaccine will be given every 3 weeks for the first 24 weeks, then if there is stable or improved disease, will be given every 6 weeks for a total treatment period of 96 weeks. Nivolumab will continue to be given every 3 weeks throughout all of treatment. | Biological: K27M peptide<br>* K27M peptide vaccine, combined with Tetanus Toxoid peptide, emulsified in montanide. Poly-ICLC will be given concurrently<br>Drug: Nivolumab<br>* anti-PD1 monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events related to treatment | 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. | 24 months | 
| Overall survival (OS) at 12 months (OS12) | 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. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peptide vaccine, immunotherapy, DIPG, vaccine, nivolumab