Status and phase
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About
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:
Full 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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
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:
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:
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
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
Adequate hepatic function
Adequate cardiac function
--Ejection fraction ≥50% or fractional shortening ≥28%, measured by echocardiography
Adequate pulmonary function
Adequate neurologic function
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:
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
Concomitant medications
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.
Primary purpose
Allocation
Interventional model
Masking
70 participants in 4 patient groups
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Central trial contact
Susan Chi, MD
Data sourced from clinicaltrials.gov
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