B7-H3.CD28Z.CART in CNS Neoplasms

A Phase 1/1b Study of Autologous b7-h3 Chimeric Antigen Receptor t Cells (b7-h3.cd28z.Cart) in Children and Young Adults With Recurrent or Progressive Cns Neoplasms Expressing b7-h3 Target

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)

Study Overview

• Status: Not yet recruiting
• Conditions: Central Nervous System Neoplasms; Brain Tumor; Ependymoma; Medulloblastoma; Medulloblastoma, Childhood; Embryonal Tumor With Multilayered Rosettes; Pineoblastoma; Brain Tumor, Recurrent; Medulloblastoma Recurrent; Leptomeningeal Disease; Atypical Teratoid/Rhabdoid Tumor; Brain Tumor Adult; Brain Tumor, Pediatric; Medulloblastoma, Adult
• Intervention / Treatment: Biological: B7-H3.CD28Z.CART; Drug: Fludarabine; Drug: Cyclophosphamide

Detailed Description

This is a single-institution, Phase 1/1b, open-label study 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 U.S. Food and Drug Administration (FDA) has not approved B7-H3 CAR T cells as a treatment for any disease.

Fludarabine and cyclophosphamide are standard lymphodepleting chemotherapy medications that are being used in this study to prepare the body for cell therapy. They are approved by the U.S. Food & Drug Administration (FDA) for this purpose and are not intended to be treatment for recurrent or progressive brain tumors.

The structure of the study will be by dose-escalation using a modified 3+3 design in two risk strata (standard risk, high risk), followed by a two-stage Phase 1b expansion at the recommended Phase 2 dose.

Participation in this study is expected to last up to 15 years.

It is expected that about 70 people will participate in this study.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Susan Chi, MD; Phone Number: 617-632-3270; Email: Susan_Chi@dfci.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Pre-screening Inclusion Criteria:

• 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.

  --Eligible CNS embryonal tumor types include:

  • Medulloblastoma
  • Atypical Teratoid Rhabdoid Tumor (ATRT)
  • Embryonal Tumor with Multilayered Rosettes (ETMR) Pineoblastoma
  • Other CNS embryonal tumor types, at the discretion of the study chair (or designee)
• Participants must have adequate pre-trial tumor material available to determine B7- H3 expression status. Tumor tissue from the most recent resection or biopsy of recurrent disease is preferred. If unavailable, tumor tissue from prior recurrences or from time of initial diagnosis is acceptable. Biopsies will not be performed for participation in this research trial or for research purposes.
• Pre-screening IHC Consent: All participants ≥ 18 years of age must be able to give informed consent. For participants <18 years of age, their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric participants will be included in age-appropriate discussion and written assent will be obtained for those ≥10 years of age, where appropriate. If a minor becomes of age during participation of this study, they will be asked to reconsent as an adult.

Inclusion Criteria:

• 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.

  --Eligible CNS embryonal tumor types include:

  • Medulloblastoma
  • Atypical Teratoid Rhabdoid Tumor (ATRT)
  • Embryonal Tumor with Multilayered Rosettes (ETMR)
  • Pineoblastoma
  • Other CNS embryonal tumor types, at the discretion of the study chair (or designee)
• B7-H3 expression: Demonstration of B7-H3 expression with H score greater than 100 by immunohistochemistry (IHC) is required.
• Age: greater than or equal to two (2) years of age and less than or equal to 21 years of age. The first participant treated at each dose level within each stratum (Standard Risk and High Risk) will be ≥ 6 years of age when feasible.

• Disease status: Participants must have evaluable disease in the central nervous system to be eligible. Evaluable disease includes either measurable OR non-measurable disease, defined as follows:

  --Measurable disease (contrast-enhancing or non-enhancing tumor)

  • Clearly defined lesional margins with two perpendicular diameters of at least 10mm, OR

  • At least two times (in both perpendicular diameters) the MRI slice thickness, plus the interslice gap

    --Non-measurable disease (tumor that is too small to be accurately measured)

  • Lesion that is measurable in only one perpendicular dimension, OR
  • Lesion that is less than 10mm in at least one perpendicular dimension, OR
  • Lesion that is less than two times the MRI slice thickness, plus the interslice gap
  • Note: Leptomeningeal (LM) disease is considered non-measurable but evaluable.
• Performance status: Karnofsky performance status ≥60% for participants ≥16 years of age and Lansky performance status ≥60% for participants <16 years of age (see APPENDIX A PERFORMANCE STATUS CRITERIA). NOTE: Participants with neurologic deficits must have a stable neurologic exam for seven (7) days prior to enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Life expectancy of greater than 12 weeks
• Prior therapy: Participants must have received prior standard of care therapy, including maximal safe surgical resection, radiation therapy and/or standard chemotherapy, and is recovered from all acute treatment-related toxicities (defined as ≤ Grade 1 or stable) from all prior therapy before entering this study There is no upper limit to the number of prior therapies allowed, but must have received all standard curative options for their tumor type.

• Participants must meet the following washouts prior to enrollment:

  • Radiation therapy - Participants must have had their last fraction of:

    ---Craniospinal irradiation, whole brain radiation therapy, or radiation therapy to >50% of the pelvis or spine >28 days prior to enrollment

    ---Focal irradiation (small port) >14 days prior to enrollment

  • At least 14 days since any prior cytotoxic chemotherapy
  • At least 7 days since any biologic antineoplastics, tyrosine kinase inhibitor, targeted agent
  • At least 21 days or 5 half-lives (whichever is shorter) since any investigational antineoplastic or disease-directed agent (but at least 28 days from prior investigational antineoplastic vaccine therapy)
  • At least 21 days since any monoclonal antibody therapy
  • At least 90 days since any systemic inhibitor/stimulatory immune checkpoint therapy
  • At least 28 days from prior autologous stem cell transplantation, with no ongoing toxicities
  • At least 14 days after peg-filgrastim and 7 days for hematopoietic growth factor support
• Steroid use: Must not require concurrent systemic steroid therapy, although physiologic corticosteroid replacement therapy for management of pituitary/adrenal insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed. Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted per PI

discretion.

• Participants must have adequate organ function, as defined below

  --Adequate bone marrow function

  • Hemoglobin ≥ 8 g/dL
  • Absolute neutrophil count (ANC) ≥ 1000 cells/uL
  • Absolute lymphocyte count (ALC) ≥ 150 cells/uL
  • Platelets ≥100,000/uL (unsupported, defined as no platelet transfusion within 4 days)

• Adequate renal function defined as creatinine within normal limits for age OR creatinine clearance (as estimated by Cockcroft Gault Equation for participants ≥ 18yo and Bedside Schwartz for participants <18yo) ≥70mL/min

  • Maximum Serum Creatinine mg/DL ---6 months to 1 year Male 0.5 Female 0.5 ---1 to < 2 years Male 0.6 Female 0.6 ---2 to < 6 years Male 0.8 Female 0.8

    • 6 to < 10 years Male 1 Female 1
    • 10 to < 13 years Male 1.2 Female 1.2

    • 13 years to < 16 years Male 1.5 Female 1.4

      • 16 years Male 1.7 Female 1.4

• Adequate hepatic function

  • Serum ALT/AST ≤3.0 upper limit of normal (ULN)
  • Total bilirubin ≤1.5mg/dL, except in subjects with confirmed Gilbert's syndrome

• Adequate cardiac function

  --Ejection fraction ≥50% or fractional shortening ≥28%, measured by echocardiography

• Adequate pulmonary function

  • No evidence of dyspnea at rest
  • Pulse oximetry >92% whilst breathing room air

• Adequate neurologic function

  • Participants with seizure disorders on anticonvulsants may be enrolled if seizures are well controlled (no seizure activity within 7 days prior to enrollment)
  • Nervous system disorders (CTCAE v6.0) resulting from prior therapy must be ≤ Grade 2, with the exception of decreased tendon reflex (DTR; any Grade eligible). Participants with neurological deficits should be stable for a minimum of 7 days prior to enrollment. (A baseline detailed neurological exam should clearly document the neurological status of the participant prior at enrollment).
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization are not considered to be of childbearing potential)
• Participants of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for one year after receiving the preparative lymphodepletion regimen, or for as long as B7- H3.CD28Z.CART cells are detectable in peripheral blood or CSF, whichever is later.
• Participant or parent of participant or legally recognized representative must be able to sign a written informed consent document. Pediatric participants will be included in age-appropriate discussion and written assent will be obtained for those ≥10 years of age, where appropriate.

Exclusion Criteria:

• Participants with bulky tumor are ineligible. Bulky tumor is defined as:

  • 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.
• Participants who have received other B7-H3 targeted cellular therapies. Other prior cellular therapies are eligible, including immune checkpoint inhibition and vaccine therapy. These prior therapies should be discussed with the study chair (or designee) prior to participant enrollment.

• Concurrent illness

  • Participants with any prior immunodeficiency or history of autoimmune disease requiring systemic steroids/ immunosuppressive medication/ disease-modifying agents within the last two (2) years.
  • Uncontrolled (Grade 3) bacterial, viral, fungal, or other infection.
  • Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
  • Evidence of severe or uncontrolled systemic disease (e.g. Grade 3 significant cardiac, pulmonary, hepatic, renal or other organ dysfunction) that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
  • Known sensitivity or allergy to any of the agents/reagents used in this study (i.e. DSMO, cyclophosphamide, fludarabine)
  • History of severe hypersensitivity reaction to compounds of similar chemical or biologic compositions to any agent used in the study or in the manufacturing of cells.

• Concomitant medications

  • Current systemic corticosteroid therapy
  • Note, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency will be allowed.
  • Participants who are receiving any other anti-cancer or investigational drug therapy are ineligible.
  • Participants who have received the last vaccination of a live vaccine ≤ 30 days prior to the start of treatment are ineligible.
  • Ongoing use of dietary supplements, alternative therapies or extreme diets, or any medication not approved by the study chair (or designee).
• Any other condition which in the principal investigator's opinion makes the individual clinically unsuitable to participate in this trial, or which would jeopardize compliance with the protocol, or would make it difficult to interpret adverse events or study data.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation for B7-H3.CD28Z.CART in Standard Risk Stratum; Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.; Baseline visit; Apheresis to obtain T cells; Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily; Day 0: B7-H3 CAR T cell infusion 1x daily; 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response; Follow up every 3 months after last infusion up until 2 years; Long term follow annually for an additional 13 years	Biological: B7-H3.CD28Z.CART; Autologous CAR T cells targeting B7-H3 (CD276), administered intravenously (into the vein) per protocol.; Drug: Fludarabine; Lymphodepleting chemotherapy administered intravenously per institutional standards.; Drug: Cyclophosphamide; Lymphodepleting chemotherapy administered intravenously per institutional standards.
Experimental: Dose Escalation for B7-H3.CD28Z.CART in High Risk Stratum; Participants will be enrolled in a staggered, sequential fashion using a modified 3 + 3 dose escalation design, assigning participants to one of three intravenous dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IV B7-H3.CD28Z.CART. Dose escalation will occur per dose-limiting toxicity rules.; Baseline visit; Apheresis to obtain T cells; Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily; Day 0: B7-H3 CAR T cell infusion 1x daily; 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response; Follow up every 3 months after last infusion up until 2 years; Long term follow annually for an additional 13 years	Biological: B7-H3.CD28Z.CART; Autologous CAR T cells targeting B7-H3 (CD276), administered intravenously (into the vein) per protocol.; Drug: Fludarabine; Lymphodepleting chemotherapy administered intravenously per institutional standards.; Drug: Cyclophosphamide; Lymphodepleting chemotherapy administered intravenously per institutional standards.
Experimental: Dose Expansion for B7-H3.CD28Z.CART in Standard Risk Stratum; Dose expansion will occur per dose-limiting toxicity rules.; Baseline visit; Apheresis to obtain T cells; Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily; Day 0: B7-H3 CAR T cell infusion 1x daily; 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response; Follow up every 3 months after last infusion up until 2 years; Long term follow annually for an additional 13 years	Biological: B7-H3.CD28Z.CART; Autologous CAR T cells targeting B7-H3 (CD276), administered intravenously (into the vein) per protocol.; Drug: Fludarabine; Lymphodepleting chemotherapy administered intravenously per institutional standards.; Drug: Cyclophosphamide; Lymphodepleting chemotherapy administered intravenously per institutional standards.
Experimental: Dose Expansion for B7-H3.CD28Z.CART in High Risk Stratum; Dose expansion will occur per dose-limiting toxicity rules.; Baseline visit; Apheresis to obtain T cells; Days -4, -3, -2: predetermined doses of Fludarabine and Cyclophosphamide 1x daily; Day 0: B7-H3 CAR T cell infusion 1x daily; 2 doses of B7-H3 CAR T cell infusion Intracerebroventricular (ICV) Infusion every 28 days until 8 doses total according to clinical response; Follow up every 3 months after last infusion up until 2 years; Long term follow annually for an additional 13 years	Biological: B7-H3.CD28Z.CART; Autologous CAR T cells targeting B7-H3 (CD276), administered intravenously (into the vein) per protocol.; Drug: Fludarabine; Lymphodepleting chemotherapy administered intravenously per institutional standards.; Drug: Cyclophosphamide; Lymphodepleting chemotherapy administered intravenously per institutional standards.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 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).	28 days
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).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	28 years
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).	28 days
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.	From Day 0 (initial IV infusion) through Day 56 (third ICV 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.	From Day 0 (initial IV infusion) through Day 56 (third ICV infusion) plus a 28-day follow-up period, for a total of 74 days.
Complete Response Rate (CRR) at Day 28	CRR is defined as the proportion of participants who achieve complete response (CR) assessed by Response Assessment in Pediatric Neuro-Oncology (RAPNO) response guidelines for medulloblastoma and ependymoma. Immune-related response criteria (irRC) as defined in RANO 2.0 may be used to interpret responses potentially influenced by immune effects.	Day 28
Partial Response Rate (PRR) at Day 28	PRR is defined as the proportion of participants who achieve partial response (PR) assessed by Response Assessment in Pediatric Neuro-Oncology (RAPNO) response guidelines for medulloblastoma and ependymoma. Immune-related response criteria (irRC) as defined in RANO 2.0 may be used to interpret responses potentially influenced by immune effects.	Day 28
Stable Disease Rate (SDR) at Day 28	SDR is defined as the proportion of participants who achieve stable disease (SD) assessed by Response Assessment in Pediatric Neuro-Oncology (RAPNO) response guidelines for medulloblastoma and ependymoma. Immune-related response criteria (irRC) as defined in RANO 2.0 may be used to interpret responses potentially influenced by immune effects.	Day 28
3 Month Complete Response Rate (CRR3)	CRR3 is defined as the proportion of participants who achieve complete response (CR) at 3 months, which assessed by Response Assessment in Pediatric Neuro-Oncology (RAPNO) response guidelines for medulloblastoma and ependymoma. Immune-related response criteria (irRC) as defined in RANO 2.0 may be used to interpret responses potentially influenced by immune effects.	3 months
3 Month Partial Response Rate (PRR3)	PRR3 is defined as the proportion of participants who achieve partial response (PR) at 3 months, which assessed by Response Assessment in Pediatric Neuro-Oncology (RAPNO) response guidelines for medulloblastoma and ependymoma. Immune-related response criteria (irRC) as defined in RANO 2.0 may be used to interpret responses potentially influenced by immune effects.	3 months
3 Month Stable Disease Rate (SDR3)	SDR3 is defined as the proportion of participants who achieve stable disease (SD) at 3 months, which assessed by Response Assessment in Pediatric Neuro-Oncology (RAPNO) response guidelines for medulloblastoma and ependymoma. Immune-related response criteria (irRC) as defined in RANO 2.0 may be used to interpret responses potentially influenced by immune effects.	3 months
Best Overall Response Rate (BORR)	BORR is defined as the proportion of participants who achieve a best overall response of complete response (CR), partial response (PR), or stable disease (SD) from the start of treatment until progressive disease (PD) or recurrence, taking as reference for progression the smallest measurements recorded since treatment initiation. Per Pediatric Neuro-Oncology (RAPNO) response guidelines, PD is defined as meeting any of the following criteria: a ≥25% increase in the sum of perpendicular diameters of measurable lesions or clear progression of non-measurable disease on MRI (brain/spine), appearance of any new lesion (biopsy confirmation if feasible), conversion of CSF cytology from negative to positive, clinical deterioration not attributable to other causes, or new extra-CNS disease.	Treatment duration may be up to 224 days, and disease evaluations will be performed at Day 28 (±4 days), at Months 2 and 3 (±1 week), and every 3 months thereafter through Month 24 (±4 weeks) after the end of treatment.
Median Duration of Response (DOR)	DOR, estimated using the Kaplan-Meier method, is measured from the time when the criteria for complete response (CR) or partial response (PR) are first met until the first documented date of recurrent or progressive disease (PD) or death from any cause, using as reference for progression the smallest measurements recorded since treatment initiation. Participants without events are censored at the date of their last disease evaluation. Per Pediatric Neuro-Oncology (RAPNO) response guidelines, PD is defined as meeting any of the following criteria: a ≥25% increase in the sum of perpendicular diameters of measurable lesions or clear progression of non-measurable disease on MRI (brain/spine), appearance of any new lesion (biopsy confirmation if feasible), conversion of CSF cytology from negative to positive, clinical deterioration not attributable to other causes, or new extra-CNS disease.	Treatment duration may be up to 224 days, and disease evaluations will be performed at Day 28 (±4 days), at Months 2 and 3 (±1 week), and every 3 months thereafter through Month 24 (±4 weeks) after the end of treatment.
2 Year Progression-Free Survival (PFS2)	PFS2 is the percent probability estimate at 2 years based on the Kaplan-Meier method. PFS is defined as the time from infusion of B7-H3.CD28Z.CART to the first occurrence of an event (progression, relapse, or death due to any cause). Participants alive without an event are censored at date of last disease evaluation. Per Pediatric Neuro-Oncology (RAPNO) response guidelines, PD is defined as meeting any of the following criteria: a ≥25% increase in the sum of perpendicular diameters of measurable lesions or clear progression of non-measurable disease on MRI (brain/spine), appearance of any new lesion (biopsy confirmation if feasible), conversion of CSF cytology from negative to positive, clinical deterioration not attributable to other causes, or new extra-CNS disease.	2 years
Median Overall Survival (OS)	OS based on Kaplan-Meier method is defined as the time from infusion of B7-H3.CD28Z.CART to death due to any cause, or censored at date last known alive.	15 years

Collaborators and Investigators

• Sponsor: Robbie Majzner
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Susan Chi, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): August 31, 2030
• Study Completion (Estimated): August 31, 2032

Study Registration Dates

• First Submitted: January 28, 2026
• First Submitted That Met QC Criteria: January 28, 2026
• First Posted (Actual): February 5, 2026

Study Record Updates

• Last Update Posted (Actual): February 5, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Brain Tumor; Medulloblastoma; Ependymoma; Central Nervous System Neoplasms; Atypical Teratoid/Rhabdoid Tumor; Pineoblastoma; Leptomeningeal Disease; Brain Tumor, Pediatric; Brain Tumor, Adult; Brain Tumor Recurrent; Medulloblastoma, Childhood; Medulloblastoma, Adult; Medulloblastoma Recurrent; Embryonal Tumor with Multilayered Rosettes
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neoplasms, Complex and Mixed; Brain Neoplasms; Central Nervous System Neoplasms; Ependymoma; Medulloblastoma; Neuroectodermal Tumors, Primitive; Rhabdoid Tumor; Meningeal Neoplasms; Pinealoma; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; fludarabine
• Other Study ID Numbers: 25-642

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No