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H3.3K27M-specific Peptide Vaccine and Poly ICLC with or without Nivolumab in Treating Patients with Newly Diagnosed HLA-A2 Positive, H3.3K27M Positive Diffuse Intrinsic Pontine Glioma or Other Newly Diagnosed Gliomas

Trial Status: Active

This pilot phase I trial studies the side effects of H3.3K27M-specific peptide vaccine and how well it works with poly ICLC in treating patients with newly diagnosed HLA-A2 positive, H3.3K27M positive diffuse intrinsic pontine glioma or other newly diagnosed glioma including spinal cord tumors. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Poly ICLC may boost the immune system. Nivolumab is designed to target a specific marker on cancer cells. It is believed that when the marker is targeted, the immune system works better to attack tumor cells. Giving H3.3K27M-specific peptide vaccine and poly ICLC with or without nivolumab may work better at treating HLA-A2 positive, H3.3K27M positive glioma.

Inclusion Criteria

  • Stratum A: Newly diagnosed children (3-21 years old) with DIPG who are positive for the H3.3K27M mutation (positive testing from a Clinical Laboratory Improvement Act [CLIA] laboratory or equivalent laboratory required) that underwent standard radiation therapy
  • Stratum B: Newly diagnosed children (3-21 years old) with diagnosis of midline glioma other than DIPG who are positive for the H3.3K27M mutation (positive testing from a CLIA laboratory or equivalent laboratory required) 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 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 4 mg/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
  • 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; 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
  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: * 3 to < 6 years: 0.8 (male and female) * 6 to < 10 years: 1 (male and female) * 10 to < 13 years: 1.2 (male and female) * 13 to < 16 years: 1.5 (male) 1.4 (female) * >= 16 years: 1.7 (male) 1.4 (female)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L
  • Serum albumin >= 2 g/dL
  • Serum lipase =< ULN at baseline
  • No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air
  • 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 human immunodeficiency virus (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)

California

San Diego
Rady Children's Hospital - San Diego
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: John Ross Crawford
Phone: 858-966-4939
University of California San Diego
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: John Ross Crawford
Phone: 858-966-4939
San Francisco
UCSF Medical Center-Mount Zion
Status: ACTIVE
Contact: Sabine Mueller
Phone: 877-827-3222

District of Columbia

Washington
Children's National Medical Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Lindsay Baker Kilburn
Phone: 202-476-5973

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Angela Jae Waanders
Phone: 312-227-4873

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Susan N. Chi
Phone: 617-632-2291
Massachusetts General Hospital Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: David H. Ebb
Phone: 614-726-2737

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Anne Elizabeth Bendel
Phone: 612-626-2778

Missouri

Saint Louis
Washington University School of Medicine
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Karen M. Gauvain
Phone: 314-286-2790

Ohio

Columbus
Nationwide Children's Hospital
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Mohamed Shebl AbdelBaki
Phone: 614-722-4087

Oregon

Portland
Oregon Health and Science University
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Kellie Jean Nazemi
Phone: 503-494-1543

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Jane E. Minturn
Phone: 267-426-5026

Tennessee

Memphis
Saint Jude Children's Research Hospital
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Amar Gajjar
Phone: 901-595-2615

Texas

Houston
Texas Children's Hospital
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Patricia Ann Baxter

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Nicholas Shawn Whipple
Phone: 801-662-4700

Washington

Seattle
Seattle Children's Hospital
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Sarah E. S. Leary
Phone: 206-667-7955

PRIMARY OBJECTIVES:

I. To assess the safety of repeated administration of the H3.3K27M-specific peptide vaccine (H3.3K27M epitope specific vaccine) in human leukocyte antigen (HLA)-A2 (02:01)+ children with H3.3K27M positive diffuse intrinsic pontine glioma (DIPGs). (Stratum A)

II. To determine the overall survival at 12 months (OS12) in HLA-A2+ children with DIPG that are being treated with repeated administration of the H3.3K27M peptide. (Stratum A)

III. To assess the safety of repeated administration of the H3.3K27M epitope specific vaccine in HLA-A2 (02:01)+ children with H3.3K27M positive midline gliomas other than DIPG, including spinal cord gliomas. (Stratum B)

IV. To assess the safety of repeated administration of the H3.3K27M epitope specific vaccine in combination with the PD-1 inhibitor nivolumab in HLA-A2 (02:01)+ children with H3.3K27M positive midline gliomas including DIPG and midline gliomas (excluding spinal cord tumors). (Stratum C)

EXPLORATORY OBJECTIVES:

I. Induction of the H3.3K27M epitope-specific cytotoxic T lymphocyte (CTL) response in post vaccine peripheral mononuclear cells (PBMC) in HLA-A2+ children with H3.3K27M positive gliomas other than DIPG. (Stratum A and B)

II. Assessment of H3.3K27M infiltrates in subjects with evidence of progression that undergo tissue collection as part of their standard of care. (Stratum A and B)

III. To archive tumor and normal deoxyribonucleic acid (DNA) from each subject at time of initial diagnosis along with serial blood draws following therapy to determine whether circulating tumor DNA (ctDNA) sequences in the patient’s blood serve as biomarkers of tumor burden, response to therapy, or development of drug resistance. (Stratum A and B)

IV. To determine the OS12 in HLA-A2 (02:01)+ children with H3.3K27 positive DIPGs and midline gliomas (excluding spinal cord tumors) that are treated with repeated administration of the H3.3K27M peptide and nivolumab. (Stratum C)

V. Induction of the H3.3K27M epitope-specific CTL response in post vaccine PBMCs in HLA-A2 (02:01)+ children with H3.3K27M positive gliomas including DIPG or other H3.3K27M positive midline gliomas, excluding spinal cord tumors. (Stratum C)

VI. To archive tumor and normal DNA from each subject at time of initial diagnosis along with serial blood draws following therapy 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. (Stratum C)

VII. To assess quality of life (QoL) and cognitive measures in HLA-A2 (02:01)+ children with H3.3K27M positive DIPG or other midline gliomas. (Stratum C)

OUTLINE: Patients are assigned to 1 of 2 stratum.

STRATUM A AND B: Beginning 2-8 weeks after completion of radiation therapy, patients receive H3.3K27M-specific peptide vaccine subcutaneously (SC), tetanus toxoid helper peptide SC, and poly ICLC intramuscularly (IM) on day 1. Treatment repeats every 3 weeks for up to 8 courses (week 21) in the absence of disease progression or unacceptable toxicity. Beginning week 30, patients with stable to improved disease may receive additional vaccines every 6 weeks thereafter for up to 2 years (96 weeks) in the absence of disease progression or unacceptable toxicity.

STRATUM C: Beginning 2-8 weeks after completion of radiation therapy, patients receive H3.3K27M-specific peptide vaccine SC, tetanus toxoid helper peptide SC, poly ICLC IM, and nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 8 courses (week 21) in the absence of disease progression or unacceptable toxicity. Patients with stable to improved disease may continue to receive nivolumab IV over 30 minutes every 3 weeks (beginning week 24) and additional vaccines every 6 weeks (beginning week 27) thereafter for up to 2 years (96 weeks) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for 24 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
UCSF Medical Center-Mount Zion

Principal Investigator
Sabine Mueller

  • Primary ID 150819
  • Secondary IDs NCI-2017-01830, 16-20574, PNOC 007
  • Clinicaltrials.gov ID NCT02960230