Clinical Trials /

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

NCT02960230

Description:

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.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Midline Glioma, H3 K27M-Mutant
  • Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: H3.3K27M Peptide Vaccine With Nivolumab for Children With Newly Diagnosed DIPG and Other Gliomas
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PNOC 007
  • SECONDARY ID: 150819
  • SECONDARY ID: NCI-2017-01830
  • SECONDARY ID: CA209-8TX
  • NCT ID: NCT02960230

Conditions

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

Interventions

DrugSynonymsArms
K27M peptideStratum A: Newly Diagnosed DIPG
NivolumabStratum C: Newly Diagnosed DIPG or other Midline Glioma

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Stratum A: Newly Diagnosed DIPGExperimentalNewly 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.
  • K27M peptide
Stratum B: Newly Diagnosed Glioma (non-DIPG)ExperimentalNewly 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.
  • K27M peptide
Stratum C: Newly Diagnosed DIPG or other Midline GliomaExperimentalNewly diagnosed children with DIPG or other midline gliomas (excluding 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.
  • K27M peptide
  • Nivolumab

Eligibility Criteria

        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).
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Adverse Events related to treatment
Time Frame:24 months
Safety Issue:
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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Trial Keywords

  • peptide vaccine
  • immunotherapy
  • DIPG
  • vaccine
  • nivolumab

Last Updated

March 18, 2020