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

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

NCT ID: NCT06514898

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

Conditions: Official terms:
Medulloblastoma
Recurrence
Pembrolizumab
Vaccines

Study type: Interventional

Study phase: Phase 1

Overall status: Not yet recruiting

Study design:

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Biological
Intervention name: TTRNA-DC vaccines with GM-CSF
Description: 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)
Arm group label: Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

Intervention type: Biological
Intervention name: TTRNA-xALT
Description: All participants will receive a single infusion of T-cells.
Arm group label: Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

Intervention type: Drug
Intervention name: Td vaccine
Description: 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.
Arm group label: Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

Intervention type: Biological
Intervention name: autologous HSCs
Description: All participants will receive a single intravenous infusion of autologous HSCs.
Arm group label: Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

Intervention type: Drug
Intervention name: Pembrolizumab
Description: Participants will receive PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.
Arm group label: Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab

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.

Detailed description: This is a single-site, single arm, unblinded, uncontrolled pilot study to evaluate the feasibility and safety of ACT + PD-1 blockade in children and young adults with suspected recurrence/progression of Group 3 or 4 (non-SHH/non-WNT) medulloblastoma since completion of definitive focal +/- craniospinal irradiation who are a candidate for surgical resection or biopsy. After a screening consent is obtained for the collection of tumor sample, subjects will undergo standard of care resection for tumor debulking or biopsy for confirmatory diagnosis of disease progression. Tumor tissue will be collected during surgery for tumor debulking or biopsy for total tumor RNA and generation of investigational DC vaccine in parallel. Following biopsy and confirmatory pathologic diagnosis of recurrent MB, patients will be enrolled in the treatment phase of the trial after obtaining informed consent. After surgery, patients will undergo a mobilized pheresis to collect PBMCs for DC generation and CD34+ HSCs. Amplified tumor RNA obtained from surgically resected or biopsied specimens will be used to generate total tumor RNA-pulsed DCs (TTRNA-DCs) manufactured while patients initiate post-surgical salvage chemotherapy regimen. Salvage chemotherapy prescribed by treating neuro-oncologist will initiate 1-2 weeks after G-CSF mobilized leukapheresis for 1-3 cycles after which, treatment cycles will be paused, and the patients will receive 3 priming TTRNA-DCs vaccines every 2 weeks and undergo a non-mobilized leukapheresis to collect vaccine-boosted lymphocytes for ex vivo T cell expansion and generation of additional TTRNA-DC vaccines. Treatment with salvage chemotherapy will resume with monthly TTRNA-DC vaccines for an additional 1-3 cycles until ex vivo expanded T cells are manufactured and released from the UF cGMP facility. For ACT, patients will undergo non-myeloablative conditioning with cyclophosphamide/fludarabine followed by infusion of ex vivo expanded tumor-reactive lymphocytes at 3 x 108 cells/Kg, infusion of autologous CD34+ HSCs (targeted dose of 2 x 106 CD34+ HSCs/Kg), PD-1 blockade and three biweekly intradermal TTRNA-DC vaccines to boost T cell engraftment and expansion. The total immunotherapy regimen will consist of 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), a single intravenous infusion of ex vivo expanded tumor-reactive T cells, and a. single intravenous infusion of autologous HSCs; and PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression. All patients will receive a full Td booster (5 Lf) IM vaccine 4-24 hours prior to Vaccine #1, regardless of booster history. All patients will undergo vaccine site pretreatment with a one-fifth dose of Td (1 Lf) intradermally, at the site of planned DC vaccine, 4-24 hours prior to vaccines #3, #5, #7 and #9.

Criteria for eligibility:
Criteria:
Inclusion Criteria: 1. 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. 2. 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. 3. 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) 4. 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 5. For females of childbearing potential, negative serum pregnancy test at enrollment 6. 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. 7. Signed informed consent by patient and/or legally authorized representative Exclusion Criteria: this study: 1. Prior discontinuation of PD-1 inhibitor treatment due to toxicity or disease progression. 2. Corticosteroids equivalent to ≥ 4mg dexamethasone daily. 3. HIV, Hepatitis B, or Hepatitis C seropositive. 4. Known active infection or immunosuppressive disease. 5. Autoimmune disease requiring medical management with immunosuppressant. 6. Pregnancy or lactation, due to possible adverse effects on the developing fetus or infant. 7. Treatment with another investigational drug or other intervention within 30 days prior to projected first dose of study treatment (Priming phase with TTRNA-DC). 8. 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. - Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.

Gender: All

Minimum age: 4 Years

Maximum age: 30 Years

Healthy volunteers: No

Start date: December 2024

Completion date: December 2028

Lead sponsor:
Agency: University of Florida
Agency class: Other

Collaborator:
Agency: Children's National Research Institute
Agency class: Other

Source: University of Florida

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06514898