Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade in Patients With Medulloblastoma

NCT06514898 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: IRB202400861-AOCR45772
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This is a pilot study in a small number of children and young adults with relapsed/progressive medulloblastoma (MB) looking at the feasibility and safety of adoptive cell therapy plus PD-1 blockade.

Conditions

Recurrent Group 3 Medulloblastoma; Recurrent Group 4 (Non-SHH/Non-WNT) Medulloblastoma

Outcome Measures

Primary Outcomes (2)

• Number of participants with immunotherapy-related dose-limiting toxicities after treatment with TTRNA-DCs, TTRNA-xALT and HSCs plus PD1 blockade

  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. For the purposes of evaluating the safety of ACT combined with PD-1 blockade, dose limiting toxicities will be assessed during the period beginning with administration of ex vivo expanded tumor-reactive (TTRNA- xALT) through 2 weeks post TTRNA -DC vaccine #9. Safety will be defined as \< 1 DLT out of six enrolled and treated subjects.

  enrollment to completion of DLT window; up to 12 months

• Number of enrolled participants who receive qualified immunotherapy products out of the total number of participants enrolled.

  Feasibility will be defined as capacity to enroll, manufacture, and administer qualified immunotherapy products (TTRNA-DCs, TTRNA-xALT and HSCs) to at least 66.7% of enrolled subjects.

  enrollment up to 12 months

Study Arms (1)

Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

EXPERIMENTAL

ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.

Biological: TTRNA-DC vaccines with GM-CSF; Biological: TTRNA-xALT; Drug: Td vaccine; Biological: autologous HSCs; Drug: Pembrolizumab

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. up to 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment)

Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

TTRNA-xALT BIOLOGICAL

All participants will receive a single infusion of T-cells.

Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

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, #5, #7 and #9.

Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

autologous HSCs BIOLOGICAL

All participants will receive a single intravenous infusion of autologous HSCs.

Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

Pembrolizumab DRUG

Participants will receive PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.

Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

Eligibility Criteria

• Age: 4 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children and young adults age 4-30 years with suspected recurrence/progression of Group 3 or 4 (non-SHH/non-WNT) MB since completion of definitive focal +/- craniospinal irradiation who are a candidate for surgical resection or biopsy. Of the 6 evaluable subjects, a minimum of 3 slots must be reserved for patients with confirmed Group 4 MB. Patients who are unable to receive radiation therapy due to genetic disorders that put them at significant risk for radiation-induced secondary malignancies (i.e. Gorlin's syndrome or NF1 mutation) are eligible for enrollment at first disease recurrence/progression.
• Must be a candidate for surgery/biopsy Or tumor tissue obtained clinically, has been previously stored in a biorepository suitable for tumor RNA extraction and amplification and sample is made available to the PI.
• Karnofsky or Lansky Performance Status (KPS) ≥ 60% (KPS for \> 16 years of age) or Lansky performance Score (LPS) of ≥ 60 (LPS for \< 16 years of age)
• Adequate bone marrow and organ function as defined below:
• ANC ≥ 1,000/mcL (unsupported)
• Platelets ≥ 100,000/mcL (unsupported for at least 3 days)
• Hemoglobin ≥ 9 g/dL (may be supported)
• Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine \> 1.5 x IULN
• Serum total bilirubin ≤ 1.5 x IULN for age OR Direct bilirubin ≤ IULN for patients with total bilirubin \> 1.5 x IULN for age
• AST (SGOT) and ALT (SGPT) ≤ 3 x IULN for age
• Cardiac shortening fraction ≥27% or LVEF ≥50% by echocardiogram
• Adequate pulmonary function defined as baseline pulse oximetry of ≥92% on room air
• For females of childbearing potential, negative serum pregnancy test at enrollment
• For women of childbearing potential (WOCBP) must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.
• or For males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.

You may not qualify if:

• this study:
• Prior discontinuation of PD-1 inhibitor treatment due to toxicity or disease progression.
• Corticosteroids equivalent to ≥ 4mg dexamethasone daily.
• HIV, Hepatitis B, or Hepatitis C seropositive.
• Known active infection or immunosuppressive disease.
• Autoimmune disease requiring medical management with immunosuppressant.
• Pregnancy or lactation, due to possible adverse effects on the developing fetus or infant.
• Treatment with another investigational drug or other intervention within 30 days prior to projected first dose of study treatment (Priming phase with TTRNA-DC).
• Severe, active co-morbidity, defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization.
• Transmural myocardial infarction within the last 6 months.
• Acute bacterial or fungal infection requiring intravenous antibiotics at time of enrollment.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy.
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

Sponsors & Collaborators

• University of Florida: lead
• Children's National Research Institute: collaborator

Study Sites (1)

University of Florida Health

Gainesville, Florida, 32608, United States

Location

MeSH Terms

Conditions

Medulloblastoma

Interventions

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

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

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; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures; Diphtheria Toxoid; Toxoids; Tetanus Toxoid; Vaccines, Combined

Study Officials

• Duane Mitchell, MD, PhD

  University of Florida

  STUDY CHAIR

• John Ligon, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2024
• First Posted: July 23, 2024
• Study Start: May 5, 2025
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: December 18, 2025

Record last verified: 2025-12

Locations

US (1)