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

NCT03396575 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: IRB201701296OCR16024
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diffuse Intrinsic Pontine Glioma (DIPG); Brain Stem Glioma

Keywords

Tumor mRNA-pulsed autologous Dendritic Cells (TTRNA-DCs); Tumor-specific 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

Outcome Measures

Primary Outcomes (2)

• Feasibility and safety of adoptive cellular therapy in pediatric patients with DIPG with or without dose-intensified TMZ during cycles of DC vaccination

  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.

  From first DC Vaccine through 30 days after administration of the last dose of trial drug or subject death

• Determine the maximally achievable dose (MAD) or maximum tolerated dose (MTD) of xALT plus DC and HSC in Group A and Group B subjects

  The first 6 patients in Group A (receiving DI TMZ) at a dose of 3 x 107 cells /kg xALT and if dose-limiting toxicities are observed in no more than 1 of 6 patients, the study team will enroll another 6 patients at the next dose level of 3 x108 cells /kg. If no more than 1 patient suffers dose limiting toxicity (DLT) at this dose level, it will declared the MAD of T cells. Subjects enrolled in Group B will be treated at the MAD or MTD determined in the Group A Cohort.

  From first DC vaccine in Group A until 14 days after administration of the last dose of investigational product is given.

Secondary Outcomes (3)

• Post-immunotherapy functional anti-tumor immune responses

  Up to 10 months

• Analysis of progression-free survival (PFS)

  Up to 5 years

• Analysis of overall survival (OS)

  Up to 5 years

Study Arms (2)

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

Biological: TTRNA-DC vaccines with GM-CSF; Biological: TTRNA-xALT; Drug: Dose-Intensified TMZ; Drug: Td vaccine; Biological: 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

Biological: TTRNA-DC vaccines with GM-CSF; Biological: TTRNA-xALT; Drug: Cyclophosphamide + Fludarabine Lymphodepletive Conditioning; Drug: Td vaccine; Biological: Autologous Hematopoietic Stem Cells (HSC)

Interventions

TTRNA-DC vaccines with GM-CSF BIOLOGICAL

After chemoradiation subjects will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. Monthly DC vaccines will be given during TMZ Cycles 2-5 for Groups A and B and 48-96 hours after completion of TMZ Cycle 6 Day 21 for Group A and 12-36 hours after HSCs for Group B. All subjects will receive an additional two bi-weekly vaccines during Cycle 6 for a total of 10 DC vaccines. All DC vaccines will be embedded with GM-CSF (150 µg per injection) and given intradermal.

Group A; Group B

TTRNA-xALT BIOLOGICAL

During TMZ Cycle 4 and with DC vaccine #6, an infusion of T-cells will be administered to all subjects.

Group A; Group B

Cyclophosphamide + Fludarabine Lymphodepletive Conditioning DRUG

Subjects in Group B, however, will receive lymphodepletion with cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of ex vivo expanded tumor-reactive lymphocytes.

Group B

Dose-Intensified TMZ DRUG

After chemoradiation, subjects in Group A will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. All subjects will have an additional five cycles of dose-intensified TMZ (for a total of 6 Cycles) with concurrent monthly DC vaccinations.

Group A

Td vaccine DRUG

A full Td booster vaccine will be administered IM at Vaccine #1 to all subjects, and vaccine site pretreatment will be administered to all subjects prior to Vaccine#3, #6, and #8.

Group A; Group B

Autologous Hematopoietic Stem Cells (HSC) BIOLOGICAL

During Cycle 4, all patients will receive HSCs prior to xALT infusion and DC vaccine #6.

Group A; Group B

Eligibility Criteria

• Age: 3 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead
• Accelerate Brain Cancer Cure: collaborator
• Lyla Nsouli Foundation: collaborator

Study Sites (1)

UF Health Shands Children's Hospital

Gainesville, Florida, 32610, United States

Location

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma; Xanthomatosis, Cerebrotendinous; Influenza, Human; Brain Neoplasms

Interventions

Granulocyte-Macrophage Colony-Stimulating Factor; Cyclophosphamide; Diphtheria-Tetanus Vaccine

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Xanthomatosis; Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures; Diphtheria Toxoid; Toxoids; Tetanus Toxoid; Vaccines, Combined

Study Officials

• Elias Sayour, MD, PhD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients in this study will either receive concurrent TMZ during RT and dose-intensive TMZ as maintenance treatment (Group A) or radiotherapy only prior to DC vaccination and 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. Once Group A accrual is completed and evaluated for toxicity, 6 Group B patients will be enrolled and treated at the Maximally Achievable Dose (MAD) or (Maximum Tolerated Dose) MTD determined in Group A cohort.

Study Record Dates

• First Submitted: January 4, 2018
• First Posted: January 11, 2018
• Study Start: July 17, 2018
• Primary Completion: March 20, 2025
• Study Completion: March 20, 2025
• Last Updated: October 29, 2025

Record last verified: 2025-10

Locations

US (1)