The purpose of this research study is to test the safety and effectiveness of a cell therapy at different doses for children and young adults with recurrent or progressive brain tumors. Recurrent/recurred means a tumor that has gone away and then came back. This cell therapy is called B7- H3.CD28Z.CART, referred to as B7-H3 CAR T cells. B7-H3 is a protein that is over-expressed on many tumor cells, making it a good target for cancer cell therapy.
The names of the study investigational therapies involved in this study are:
* Fludarabine (a type of chemotherapy) * Cyclophosphamide (a type of chemotherapy) * B7-H3 CAR T cells (a type of cellular therapy)
Participants must have histologically and/or molecularly confirmed CNS embryonal tumor (see eligible tumor types below), OR ependymoma that is recurrent/progressive following standard of care treatment.
Medulloblastoma
Atypical Teratoid Rhabdoid Tumor (ATRT)
Embryonal Tumor with Multilayered Rosettes (ETMR) Pineoblastoma
Tumor with diameter of >5cm in one dimension on T2/FLAIR sequence
Tumor with evidence of clinically significant midline shift or uncal herniation
Tumor that, in opinion of the site investigator, shows significant mass effect in either the brain or spine
Participants with clinical or radiological evidence of brain herniation.
Sequential
B7-H3.CD28Z.CART
Biological/VaccineAutologous CAR T cells targeting B7-H3 (CD276), administered intravenously (into the vein) per protocol.
Fludarabine
DrugLymphodepleting chemotherapy administered intravenously per institutional standards.
Cyclophosphamide
DrugLymphodepleting chemotherapy administered intravenously per institutional standards.
Manufacturing Success Rate of Autologous B7-H3.CD28Z CAR T Cells
Each participant's product will be tested for the following criteria: cell viability ≥ 70%; cell number within ± 20% of the planned dose; CD3+ T cells ≥ 80% of leukocytes; CAR-positive cells ≥ 10% of CD3+ T cells; endotoxin ≤ 5 EU/kg; mycoplasma not detected; vector copy number (VCN) per transduced cell ≤ 10; replication-competent retrovirus (RCR) not detected; and sterility confirmed as "No Growth to Date" (NGTD) after a minimum of 5 days in culture. A participant will be classified as a manufacturing success if the final product satisfies all release criteria. If any criterion is not met, the participant will be classified as a manufacturing failure. The manufacturing success rate is defined as the proportion of participants classified as a success.
Maximum Tolerated Dose (MTD) of B7-H3.CD28Z.CART Cells
The MTD is defined as the highest dose level of B7-H3.CD28Z.CART cells at which the rate of dose-limiting toxicity (DLT) is considered acceptable according to the modified 3+3 rules. Additional details are provided in Protocol Section 13.1. Definition of DLT is outlined in protocol. The definition of DLT uses NCI's Common Terminology Criteria for Adverse Events (CTCAEv6.0).
Recommended Phase 2 Dose (RP2D) of B7-H3.CD28Z.CART Cells
The recommended phase 2 dose (RP2D) is the dose of B7-H3.CD28Z.CAR T cells selected for Phase 2 based on Phase 1 results, considering safety, tolerability, manufacturing feasibility, and observed clinical activity, and may be at or below the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD).
Number of Participants Experience Dose-Limiting Toxicity (DLT) during Dose Escalation
Definition of DLT is outlined in protocol. The definition of DLT uses NCI's Common Terminology Criteria for Adverse Events (CTCAEv6.0).
Number of Participants Experience Dose-Limiting Toxicity (DLT) at Maximum Tolerated Dose (MTD) / Recommend Phase 2 Dose (RP2D)
Definition of DLT is outlined in protocol. The definition of DLT uses NCI's Common Terminology Criteria for Adverse Events (CTCAEv6.0).
Number of Participants with Two Additional ICV B7-H3.CD28Z.CAR T Infusions
The number of participants in the High-Risk Stratum who receive two additional intracerebroventricular (ICV) infusions of B7-H3.CD28Z.CAR T cells following the initial intravenous(IV) infusion.
Adverse Events of Special Interest (AESIs) Rate
AESIs rate is defined as the proportion of participants who experience AESIs during treatment period. AESIs is defined in protocol section 7.3. Adverse events will be summarized and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
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Robbie Majzner
Lead sponsor
Dana-Farber Cancer Institute
Sponsor institution
National Institutes of Health (NIH)
Collaborator
