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.
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)
- Brain Stem Glioma
Interventions
Drug | Synonyms | Arms |
---|
TTRNA-DC vaccines with GM-CSF | | Group A |
TTRNA-xALT | | Group A |
Cyclophosphamide + Fludarabine Lymphodepletive Conditioning | | Group B |
Dose-Intensified TMZ | | Group A |
Td vaccine | | Group 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
Name | Type | Description | Interventions |
---|
Group A | Experimental | TTRNA-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 B | Experimental | TTRNA-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 or other diffuse intrinsic brain stem glioma (Grade III
or IV).
- Patient and/or parents/guardian willing to consent to biopsy for obtaining tumor
material for confirmatory diagnosis and/or tumor RNA extraction and amplification.
- Biopsy confirmation of any grade of glioma (for patients with classic DIPG on
neuroimaging or at least grade III glioma in case of other diffuse intrinsic brain
stem gliomas)
- 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.
- Signed informed consent according to institutional guidelines.
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)
- Immunotherapy
- Pediatric
- Young Adult
- Brain Tumor
- CNS
- Vaccine Therapy
Last Updated
July 13, 2021