Clinical Trials /

Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Focal Radiotherapy Recovery Alone or With Dose-intensified Temozolomide (Phase I)

NCT03396575

Description:

The standard of care for children with DIPG includes focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with RT followed by monthly TMZ was also found to be safe but ineffective. Recent studies in adults have shown that certain types of chemotherapy induce a profound but transient lymphopenia (low blood lymphocytes) and vaccinating and/or the adoptive transfer of tumor-specific lymphocytes into the cancer patient during this lymphopenic state leads to dramatic T cell expansion and potent immunologic and clinical responses. Therefore, patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Focal Radiotherapy Recovery Alone or With Dose-intensified Temozolomide (Phase I)
  • Official Title: BRAVO: Newly-Diagnosed Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Recovery From Focal Radiotherapy Alone or Focal Radiotherapy and Dose-intensified Temozolomide (Phase I)

Clinical Trial IDs

  • ORG STUDY ID: IRB201701296
  • SECONDARY ID: OCR16024
  • NCT ID: NCT03396575

Conditions

  • Diffuse Intrinsic Pontine Glioma (DIPG)

Interventions

DrugSynonymsArms
TTRNA-DC vaccines with GM-CSFGroup A
TTRNA-xALTGroup A
Cyclophosphamide + Fludarabine Lymphodepletive ConditioningGroup B
Dose-Intensified TMZGroup A
Td vaccineGroup A
Autologous Hematopoietic Stem Cells (HSC)Group A

Purpose

The standard of care for children with DIPG includes focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with RT followed by monthly TMZ was also found to be safe but ineffective. Recent studies in adults have shown that certain types of chemotherapy induce a profound but transient lymphopenia (low blood lymphocytes) and vaccinating and/or the adoptive transfer of tumor-specific lymphocytes into the cancer patient during this lymphopenic state leads to dramatic T cell expansion and potent immunologic and clinical responses. Therefore, patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups.

Detailed Description

      The standard of care for children with DIPG includes external beam focal radiotherapy (RT)
      but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide
      (TMZ) concurrently with focal irradiation followed by maintenance monthly TMZ was also found
      to be safe but ineffective. However, in the context of an immunotherapy strategy, it might be
      beneficial to use TMZ as an adjuvant therapy during and following radiotherapy. Recent
      pre-clinical and clinical studies in adults with have shown that both myeloablative (MA) and
      non-myeloablative (NMA) chemotherapy induce a profound but transient lymphopenia and,
      somewhat counterintuitively, vaccination during recovery from this lymphopenic state and/or
      the adoptive transfer of tumor-specific lymphocytes into lymphodepleted hosts leads to
      dramatic in vivo T cell expansion and potent immunologic and clinical responses. Therefore,
      the study team expects that tumor-specific lymphocytes, expanded ex vivo with the use of
      TTRNA-pulsed DCs may provide a source of lymphocytes that preferentially expand in this
      lymphopenic environment following TMZ, and serve as a source of responder cells to subsequent
      DC vaccination.

      Although TMZ does induce profound lymphopenia in children with central nervous system (CNS)
      tumors, it has not been conclusively shown to help in augmenting vaccine-induced immune
      responses in this population. Therefore, patients in this study would either receive
      concurrent TMZ during RT and immunotherapy during and after maintenance cycles of
      dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without
      maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or
      without DI TMZ will be evaluated in both treatment groups. The immunotherapy regimen will
      consist of TTRNA-DC vaccines alone followed by adoptive cellular therapy consisting of ex
      vivo expanded tumor-reactive lymphocytes coupled with TTRNA-DC vaccines and autologous HSCs.

      Patients in Group B will not receive DI TMZ, however, they will receive lymphodepletion with
      cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of
      ex vivo expanded tumor-reactive lymphocytes, as T cell engraftment and persistence has been
      shown to be augmented by lymphodepletion in numerous studies. TTRNA-pulsed DCs will be given
      in conjunction with the adjuvants GM-CSF and tetanus-diphtheria toxoid (Td) vaccine which the
      study team have shown can significantly enhance clinical responses to DC vaccination.
    

Trial Arms

NameTypeDescriptionInterventions
Group AExperimentalTTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) during cycles of Dose-intensified TMZ
  • TTRNA-DC vaccines with GM-CSF
  • TTRNA-xALT
  • Dose-Intensified TMZ
  • Td vaccine
  • Autologous Hematopoietic Stem Cells (HSC)
Group BExperimentalTTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) with Cyclophosphamide + Fludarabine Lymphodepletive Conditioning
  • TTRNA-DC vaccines with GM-CSF
  • TTRNA-xALT
  • Cyclophosphamide + Fludarabine Lymphodepletive Conditioning
  • Td vaccine
  • Autologous Hematopoietic Stem Cells (HSC)

Eligibility Criteria

        Inclusion Criteria:

        Initial Screening

          -  Radiologically confirmed DIPG and patient and/or parents/guardian willing to consent
             to biopsy;

          -  Karnofsky Performance Status (KPS) of > 50% (KPS for > 16 years of age) or Lansky
             performance Score (LPS) of ≥ 50 (LPS for ≤ 16 years of age) assessed within 2 weeks
             prior to registration;

          -  Bone Marrow;

          -  ANC (absolute neutrophil count) ≥ 1000/µl (unsupported)

          -  Platelets ≥ 100,000/µl (unsupported)

          -  Hemoglobin > 8 g/dL (can be transfused)

          -  Renal;

          -  Serum creatinine ≤ upper limit of institutional normal

          -  Hepatic;

          -  Bilirubin ≤ 1.5 times upper limit of institutional normal for age

          -  SGPT (ALT) ≤ 3 times upper limit of institutional normal for age

          -  SGOT (AST) ≤ 3 times upper limit of institutional normal for age

          -  Patients of childbearing or child-fathering potential must be willing to use medically
             acceptable forms of birth control while being treated on this study.

        Post Biopsy

          -  Patients with post-surgical neurological deficits should have deficits that are stable
             for a minimum of 1 week prior to registration;

          -  Pathologic diagnosis of glioma on tumor biopsy.

        Exclusion Criteria:

          -  Patients with severe dysphagia, obtundation, or tetraplegia (poor risks for anesthesia
             and biopsy procedure);

          -  Absence of tumor on biopsy specimen;

          -  Pregnant or need to breast feed during the study period (Negative serum pregnancy test
             required)

          -  Known autoimmune or immunosuppressive disease or human immunodeficiency virus
             infection;

          -  Patients with significant renal, cardiac, pulmonary, hepatic or other organ
             dysfunction;

          -  Severe or unstable concurrent medical conditions;

          -  Patients who require corticosteroids above physiologic doses (>4 mg/day dexamethasone)
             after chemoradiotherapy;

          -  Patients scheduled to receive any other concurrent anticancer or investigational drug
             therapy;

          -  Prior allergic reaction to TMZ, GM-CSF, or Td;

          -  Patients who are unwilling or unable to receive treatment and undergo follow-up
             evaluations at University of Florida;

          -  Patient and/or parent/guardian demonstrating an inability to comply with the study
             and/or follow-up procedures.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Feasibility and safety of adoptive cellular therapy in pediatric patients with DIPG with or without dose-intensified TMZ during cycles of DC vaccination
Time Frame:From first DC Vaccine through 30 days after administration of the last dose of trial drug or subject death
Safety Issue:
Description:Number of subjects with immunotherapy-related dose-limiting toxicities including 1) Grade III or greater non-neurologic toxicity; 2) Grade III neurologic toxicity that does not improve to Grade II or better within 5 days; or 3) Grade IV neurologic toxicity.

Secondary Outcome Measures

Measure:Post-immunotherapy functional anti-tumor immune responses
Time Frame:Up to 10 months
Safety Issue:
Description:The in vivo expansion, persistence, and function of tumor-specific lymphocytes will be followed serially in these patients using T-cell receptor (TCR) sequencing and functional immunologic analysis.
Measure:Analysis of progression-free survival (PFS)
Time Frame:Up to 5 years
Safety Issue:
Description:Days of PFS
Measure:Analysis of overall survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description:Days of OS

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Florida

Trial Keywords

  • Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs)
  • Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT)
  • Autologous G-CSF mobilized HSCs
  • Temozolomide (TMZ)
  • Cyclophosphamide (CTX)
  • Fludarabine (Flu)
  • Granulocyte Colony Stimulating Factor (G-CSF)
  • Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)
  • Tetanus Toxoid
  • Mesna

Last Updated

December 17, 2019