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

 -  Stratum A:

 • Newly diagnosed children (3-21 years old) with DIPG who are positive for the
 H3.3K27M mutation (positive testing in 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 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
 (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.

 o Stratum A: Radiation therapy must have started within 4 weeks of diagnosis by
 imaging or surgery, whichever is later.

 o Stratum B: For subjects undergoing surgery for more extensive resection, radiation
 therapy should be started within 4-6 weeks from surgery.

 o 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.

 -  H3.3K27 mutation must have been confirmed in the tumor tissue in a CLIA or equivalent
 approved laboratory.

 -  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) ≥ 70mL/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 CDC.

 Adequate Liver Function Defined as:

 -  Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for
 age and

 -  SGPT (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 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).