Trials / Recruiting

RecruitingNCT06193759

Immunotherapy for Malignant Pediatric Brain Tumors Employing Adoptive Cellular Therapy (IMPACT)

Status: Recruiting
Phase: Phase 1
Study type: Interventional
Enrollment: 12 (estimated)

Sponsor: Children's National Research Institute · Academic / Other
Sex: All
Age: 1 Year – 30 Years
Healthy volunteers: Not accepted

Summary

This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA) derived from a patient's primary brain tumor tissues. Young patients with embryonal central nervous system (CNS) malignancies typically are unable to receive irradiation due to significant adverse effects and are treated with intensive chemotherapy followed by autologous stem cell rescue; however, despite intensive therapy, many of these patients relapse. In this study, individualized TSA-T cells will be generated against proteogenomically determined tumor-specific antigens after standard of care treatment in children less than 5 years of age with embryonal brain tumors. Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.

Detailed description

This study will be conducted at Children's National Hospital (CNH) in Washington, DC. TSA-T products will be manufactured at the cell therapy Good Manufacturing Practice (GMP) facility at CNH. Patients enrolled in the study will receive their infusions at CNH. This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA), derived from a patient's primary brain tumor tissues. Participants in this study will receive TSA-T after completion of standard-of-care/salvage therapy for either their newly diagnosed embryonal brain tumor or their recurrent ependymoma. Participants will be enrolled into one of two Groups: 1. Group A: Children younger than 5 years of age with newly diagnosed embryonal brain tumors - including medulloblastoma (MB), atypical teratoid/rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and embryonal brain tumor not otherwise specified (NOS). 2. Group B: Children, adolescents and young adults greater than 1 year and less than 30 years of age with recurrent ependymoma (EPN). Group A Standard-of-Care Backbone Therapy: Patients will undergo surgical resection, then be treated with standard-of-care therapy as required, which may include up to 3 induction chemotherapy cycles (vincristine, cyclophosphamide, cisplatin, etoposide with or without methotrexate) and up to 3 consolidation cycles (carboplatin and thiotepa, each followed by an infusion of autologous peripheral blood stem cells (PBSCs)). Please note: Methotrexate may be part of the induction chemotherapy, and radiation may be added during backbone therapy, as per treating physician's discretion. Group B Salvage Backbone Therapy: Patients will undergo surgical re-resection - aiming for gross total resection when feasible - followed by re-irradiation. Re-irradiation may be delivered as a conventional fractionated course, hypofractionated stereotactic radiotherapy, or proton therapy, depending on prior treatments, institutional guidelines and treating physician's discretion. Bridging chemotherapy may be administered between re-irradiation and TSA-T cell infusion, at the treating physician's discretion. Patients will receive the TSA-T product at assigned dose levels as per the table and details below until the highest planned dose level or the MTD is reached. The MTD will be declared when prespecified stopping/escalation rules and DLT data allow a determination, and the recommended phase 2 dose (RP2D) will be established using the MTD together with additional safety, tolerability and pharmacodynamic data. Dose Levels TSA-T cell dose -1 1x107 cells 1\* 2.5x107 cells 2 5x107 cells \*Starting dose The MTD and RP2D determinations, as well as all dose escalation and de-escalation decisions, will be based on pooled safety data from Groups A and B combined. However, the secondary objectives pertaining to objective tumor response and clinical survival, will be analyzed separately for Group A and Group B. Safety will be assessed at two planned TSA-T dose levels, 2.5×10⁷ and 5×10⁷ cells, with the option to de-escalate to 1×10⁷ cells if warranted. Dose escalation will follow a Bayesian optimal interval (BOIN) design with a 42-day DLT monitoring period. An interim safety analysis will be conducted after the first six patients. Each patient will receive at least one TSA-T infusion and may receive a maximum of 8 total infusions if they remain eligible and sufficient TSA-T cells are available. All infusions will be intracerebroventricularly (ICV) administered through the protocol-required Rickham reservoir. For any infusion following the first infusion, if a patient's remaining cryopreserved TSA-T product is insufficient to meet the dose at the enrollment dose level, the final infusion may be administered at a lower available dose at the discretion of study PI. If patients have a response of stable disease or better by RAPNO criteria at the evaluation after the second infusion OR if they have clinical stability and a clinical assessment of possible pseudoprogression (per iRANO) on MRI despite the appearance of radiographic progression (with subsequent serial MRI findings most consistent with pseudoprogression), they may be eligible to receive additional infusions of TSA-T. The first and second infusions will be administered at least 42 days apart and additional infusions will be spaced at least 28 days apart. Once a patient begins TSA-T treatment, and until they are taken off treatment, they are expected to adhere to the protocol-defined treatment schedule as closely as possible, with approximately two weeks of flexibility beyond the minimum required infusion interval. The exception is in cases of suspected pseudoprogression (PsP), where an extended interval of up to eight weeks beyond the minimum interval may be permitted to allow for repeat imaging prior to additional TSA-T infusion(s). Prior to the first infusion, if a patient's cryopreserved TSA-T product is insufficient for the dose level that the patient is assigned to, the patient may receive TSA-Ts at a lower dose level with a minimum of 1x107 cells. These patients will not count towards the overall safety objective, although they will count towards the feasibility objective of identifying TSAs and producing adequate TSA-T products.

Conditions

Interventions

Type	Name	Description
BIOLOGICAL	Multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA)	Participants in this study will receive TSA-T after completion of standard-of-care treatment.
DRUG	Group A Standard-of-Care Backbone Therapy	Patients will undergo surgical resection, then be treated with standard-of-care therapy as required, which may include up to 3 induction chemotherapy cycles (vincristine, cyclophosphamide, cisplatin, etoposide with or without methotrexate) and up to 3 consolidation cycles (carboplatin and thiotepa, each followed by an infusion of autologous peripheral blood stem cells).
RADIATION	Group B Salvage Backbone Therapy	Patients will undergo surgical re-resection - aiming for gross total resection when feasible - followed by re-irradiation. Re-irradiation may be delivered as a conventional fractionated course, hypofractionated stereotactic radiotherapy, or proton therapy.

Timeline

Start date: 2024-09-20
Primary completion: 2030-12-29
Completion: 2032-12-29
First posted: 2024-01-05
Last updated: 2026-03-10

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT06193759. Inclusion in this directory is not an endorsement.