The goal of this research study is to test if a new cell therapy (B7-H3.CD28Z.CART / B7-H3 CAR T cells) is safe and effective in treating children and young adults with solid cancers whose tumors have returned or stopped responding to standard treatments (relapsed or refractory) and have been identified with a B7-H3 marker. The names of the treatment interventions used in this study are: * B7-H3.CD28Z.CART / B7-H3 CAR T cells * Fludarabine * Cyclophosphamide
This is a Phase I, open-label, single-center, dose-escalation study testing the safety and effectiveness of a new cell therapy B7-H3.CD28Z.CART / B7-H3 CAR T cells in children and young adult subjects with relapsed and/or refractory solid tumors expressing B7-H3. The B7-H3 protein is found in high levels on many pediatric solid tumors (like neuroblastoma, osteosarcoma, and others), this cell therapy uses genetically altered blood cells as an investigational cell product designed to recognize, bind to and help kill cells that express B7-H3. This is the first time that these specific B7-H3 CAR T cells will be given to humans. There are several other studies using a similar genetically modified version of B7-H3 CAR T cells and other studies have shown that B7-H3 is a safe target. The U.S. Food and Drug Administration (FDA) has not approved B7-H3 CAR T cells as a treatment for any disease. The research study procedures include screening for eligibility, in-clinic visits, blood tests, urine tests, electrocardiograms (ECGs), echocardiograms (ECHOs), bone marrow biopsies and aspirations. It is expected up to 40 people will take part in this research study. Band of Parents a non-profit organization is supporting this research study by providing funding.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Modified autologous T cells administered via Intravenous (IV) infusion
Administered intravenously
Administered intravenously
Dana Farber Cancer Institite
Boston, Massachusetts, United States
RECRUITINGManufacturing Success Rate of Autologous B7-H3.CD28Z CART 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.
Time frame: Participants will receive the CART cell infusion on Day 0.
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 acceptable per the modified 3+3 design. The recommended phase 2 dose (RP2D) is the MTD of single-agent autologous B7-H3.CD28Z.CART cells. Additional details are provided in Protocol Section 13.1.
Time frame: 28 days
Number of Participants Experience Dose-Limiting Toxicity (DLT)
Any ≥ grade 3 adverse event per Common Terminology Criteria for Adverse Events (CTCAE v6) within 28 days of initial B7-H3.CD28Z.CART infusion that is at least possibly related to the product is a Dose-Limiting Toxicity (DLT).
Time frame: 28 days
Adverse Events of Special Interest (AESI) Rate on the First Infusion
The AESI rate is defined as the proportion of participants experiencing at least one adverse event meeting the AESI criteria during the protocol-specified adverse event reporting period. The definition of AESI are defined in protocol section 7.2.
Time frame: 15 years
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Objective Response Rate (ORR)
ORR is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) during study treatment. Disease assessed per revised International Neuroblastoma Response Criteria (INRC) in participants with relapsed or refractory high-risk neuroblastoma or per RECIST1.1 in participants with other solid tumors.
Time frame: Disease assessments will be performed at Day 28, month 3, and then every 3 months through month 24 or up to month 48, if received second infusion.
Median Progression-Free Survival (PFS)
PFS based on Kaplan-Meier method is defined as the time from start of treatment to the earlier of relapse, progression, or death due to any cause. Participants alive without disease relapse or progression are censored at date of last disease evaluation. Disease assessed per revised International Neuroblastoma Response Criteria (INRC) in participants with relapsed or refractory high-risk neuroblastoma or per RECIST1.1 in participants with other solid tumors.
Time frame: Disease assessments will be performed at Day 28, month 3, and then every 3 months through month 24 or up to month 48, if received second infusion.
Median Overall Survival (OS)
OS based on Kaplan-Meier method is defined as the time from start of lymphodepleting chemotherapy to death due to any cause, or censored at date last known alive.
Time frame: 15 years
Adverse Events of Special Interest (AESI) Rate on a Second Infusion
The AESI rate is defined as the proportion of participants experiencing at least one adverse event meeting the AESI criteria during the protocol-specified adverse event reporting period. The definition of AESI are defined in protocol section 7.2.
Time frame: 15 years
Second Intravenous B7-H3.CD28Z.CART Cell Infusion Rate
Second intravenous B7-H3.CD28Z.CART cell infusion rate is defined as the proportion of participants who undergo an optional second infusion of B7-H3.CD28Z.CART cells, administered intravenously according to protocol-specified criteria.
Time frame: up to 2 years