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

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ClinicalTrials.gov Identifier: NCT02960230
Recruitment Status : Recruiting
First Posted : November 9, 2016
Last Update Posted : March 11, 2021
Sponsor:
Collaborators:
The V Foundation for Cancer Research
Pacific Pediatric Neuro-Oncology Consortium
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sabine Mueller, MD, PhD, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE November 2, 2016
First Posted Date  ICMJE November 9, 2016
Last Update Posted Date March 11, 2021
Actual Study Start Date  ICMJE November 18, 2016
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2020)
  • Number of Participants with Adverse Events related to treatment [ Time Frame: 24 months ]
    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.
  • Overall survival (OS) at 12 months (OS12) [ Time Frame: 36 months ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 8, 2016)
  • Number of Participants with Adverse Events related to treatment [ Time Frame: 24 months ]
    Safety of the vaccine 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 v4.0. 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.
  • Overall survival (OS) at 12 months (OS12) [ Time Frame: 36 months ]
    OS12 will be the clinical efficacy primary endpoint. 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.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2016)
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 Frame: 36 months ]
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.
Current Other Pre-specified Outcome Measures
 (submitted: March 18, 2020)
  • Assess H3.3K27M expression status and infiltration of H3.3K27M specific T cells [ Time Frame: 36 months ]
    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.
  • Analyze circulating tumor DNA [ Time Frame: 36 months ]
    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.
  • 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 Frame: 36 months ]
    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.
  • Assessment of Quality of Life and cognitive measures in HLA-A2 (02:01)+ children with H3.3K27M positive DIPG or other midline gliomas. [ Time Frame: 48 months ]
    Subjects in Stratum C will take age-appropriate surveys or complete questionnaires to assess treatment and disease impact on quality of life.
Original Other Pre-specified Outcome Measures
 (submitted: November 8, 2016)
  • Assess H3.3K27M expression status and infiltration of H3.3K27M specific T cells [ Time Frame: 36 months ]
    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.
  • Analyze circulating tumor DNA [ Time Frame: 36 months ]
    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.
 
Descriptive Information
Brief Title  ICMJE H3.3K27M Peptide Vaccine With Nivolumab for Children With Newly Diagnosed DIPG and Other Gliomas
Official Title  ICMJE 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
Brief Summary

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Diffuse Intrinsic Pontine Glioma
  • Glioma
  • Diffuse Midline Glioma, H3 K27M-Mutant
Intervention  ICMJE
  • Biological: K27M peptide
    K27M peptide vaccine, combined with Tetanus Toxoid peptide, emulsified in montanide. Poly-ICLC will be given concurrently
  • Drug: Nivolumab
    anti-PD1 monoclonal antibody
Study Arms  ICMJE
  • Experimental: Stratum A: Newly Diagnosed DIPG
    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.
    Intervention: Biological: K27M peptide
  • Experimental: Stratum B: Newly Diagnosed Glioma (non-DIPG)
    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.
    Intervention: Biological: K27M peptide
  • Experimental: Stratum C: Newly Diagnosed DIPG or other Midline Glioma
    Newly 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.
    Interventions:
    • Biological: K27M peptide
    • Drug: Nivolumab
Publications * Mueller S, Taitt JM, Villanueva-Meyer JE, Bonner ER, Nejo T, Lulla RR, Goldman S, Banerjee A, Chi SN, Whipple NS, Crawford JR, Gauvain K, Nazemi KJ, Watchmaker PB, Almeida ND, Okada K, Salazar AM, Gilbert RD, Nazarian J, Molinaro AM, Butterfield LH, Prados MD, Okada H. Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. J Clin Invest. 2020 Dec 1;130(12):6325-6337. doi: 10.1172/JCI140378.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 18, 2020)
49
Original Estimated Enrollment  ICMJE
 (submitted: November 8, 2016)
29
Estimated Study Completion Date  ICMJE January 1, 2023
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sabine Mueller, MD, PhD, MAS 877-827-3222 cancertrials@ucsf.edu
Contact: Rosemarie Dehesa rosemarie.dehesa@ucsf.edu
Listed Location Countries  ICMJE Switzerland,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02960230
Other Study ID Numbers  ICMJE PNOC 007
150819 ( Other Identifier: University of California, San Francisco )
NCI-2017-01830 ( Other Identifier: Clinical Trials Reporting Program (CTRP) )
CA209-8TX ( Other Identifier: Bristol-Meyers Squibb )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sabine Mueller, MD, PhD, University of California, San Francisco
Study Sponsor  ICMJE Sabine Mueller, MD, PhD
Collaborators  ICMJE
  • The V Foundation for Cancer Research
  • Pacific Pediatric Neuro-Oncology Consortium
  • Bristol-Myers Squibb
Investigators  ICMJE
Study Chair: Sabine Mueller, MD, PhD, MAS University of California, San Francisco
Study Chair: Hideho Okada, MD, PhD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP