Description:
This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with
autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3-specific chimeric
antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into
the tumor resection cavity or ventricular system in children and young adults with diffuse
intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory
CNS tumors.
A child or young adult meeting all eligibility criteria, including having a CNS catheter
placed into the tumor resection cavity or into their ventricular system, and meeting none of
the exclusion criteria, will have their T cells collected. The T cells will then be
bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells.
Patients will be assigned to one of 3 treatment arms based on location or type of their
tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their
treatment into the tumor cavity. Patients with either infratentorial or
metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment
delivered into the ventricular system. The first 3 patients enrolled onto the study must be
at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned
to Arm C and have their treatment delivered into the ventricular system. The patient's newly
engineered T cells will be administered via the indwelling catheter for two courses. In the
first course patients in Arms A and B will receive a weekly dose of CAR T cells for three
weeks, followed by a week off, an examination period, and then another course of weekly doses
for three weeks. Patients in Arm C will receive a dose of CAR T cells every other week for 3
weeks, followed by a week off, an examination period, and then dosing every other week for 3
weeks. Following the two courses, patients in all Arms will undergo a series of studies
including MRI to evaluate the effect of the CAR T cells and may have the opportunity to
continue receiving up to a total of six courses of CAR T cells if the patient has not had
adverse effects and if more of their T cells are available.
The hypothesis is that an adequate amount of B7H3-specific CAR T cells can be manufactured to
complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by
one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can
safely be administered through an indwelling CNS catheter or delivered directly into the
brain via indwelling catheter to allow the T cells to directly interact with the tumor cells
for each patient enrolled on the study. Secondary aims of the study will include evaluating
CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells
egress or traffic into the peripheral circulation or blood stream, and, if tissues samples
from multiple timepoints are available, also evaluate disease response to B7-H3 CAR T cell
locoregional therapy.
Title
- Brief Title: Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors
- Official Title: Phase 1 Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors
Clinical Trial IDs
- ORG STUDY ID:
BrainChild-03
- NCT ID:
NCT04185038
Conditions
- Central Nervous System Tumor
- Diffuse Intrinsic Pontine Glioma
- Diffuse Midline Glioma
- Ependymoma
- Medulloblastoma, Childhood
- Germ Cell Tumor
- Atypical Teratoid/Rhabdoid Tumor
- Primitive Neuroectodermal Tumor
- Choroid Plexus Carcinoma
- Pineoblastoma, Childhood
- Glioma
Interventions
| Drug | Synonyms | Arms |
|---|
| SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel | | ARM A (Tumor Cavity Infusion) |
Purpose
This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with
autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3-specific chimeric
antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into
the tumor resection cavity or ventricular system in children and young adults with diffuse
intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory
CNS tumors.
A child or young adult meeting all eligibility criteria, including having a CNS catheter
placed into the tumor resection cavity or into their ventricular system, and meeting none of
the exclusion criteria, will have their T cells collected. The T cells will then be
bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells.
Patients will be assigned to one of 3 treatment arms based on location or type of their
tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their
treatment into the tumor cavity. Patients with either infratentorial or
metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment
delivered into the ventricular system. The first 3 patients enrolled onto the study must be
at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned
to Arm C and have their treatment delivered into the ventricular system. The patient's newly
engineered T cells will be administered via the indwelling catheter for two courses. In the
first course patients in Arms A and B will receive a weekly dose of CAR T cells for three
weeks, followed by a week off, an examination period, and then another course of weekly doses
for three weeks. Patients in Arm C will receive a dose of CAR T cells every other week for 3
weeks, followed by a week off, an examination period, and then dosing every other week for 3
weeks. Following the two courses, patients in all Arms will undergo a series of studies
including MRI to evaluate the effect of the CAR T cells and may have the opportunity to
continue receiving up to a total of six courses of CAR T cells if the patient has not had
adverse effects and if more of their T cells are available.
The hypothesis is that an adequate amount of B7H3-specific CAR T cells can be manufactured to
complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by
one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can
safely be administered through an indwelling CNS catheter or delivered directly into the
brain via indwelling catheter to allow the T cells to directly interact with the tumor cells
for each patient enrolled on the study. Secondary aims of the study will include evaluating
CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells
egress or traffic into the peripheral circulation or blood stream, and, if tissues samples
from multiple timepoints are available, also evaluate disease response to B7-H3 CAR T cell
locoregional therapy.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| ARM A (Tumor Cavity Infusion) | Experimental | Patients with non-DIPG supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity | - SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
|
| ARM B (Ventricular System Infusion) | Experimental | Patients with non-DIPG either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the ventricular system | - SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
|
| ARM C (DIPG) | Experimental | Patients with DIPG for whom CAR T cells will be delivered into the ventricular system | - SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
|
Eligibility Criteria
Inclusion Criteria:
1. Age ≥ 1 and ≤ 26 years
2. Diagnosis of refractory or recurrent CNS disease for which there is no standard
therapy, or diagnosis of DIPG or DMG at any time point following completion of
standard therapy
3. Able to tolerate apheresis, or has apheresis product available for use in
manufacturing
4. CNS reservoir catheter, such as an Ommaya or Rickham catheter
5. Life expectancy ≥ 8 weeks
6. Lansky or Karnofsky score ≥ 60
7. If patient does not have previously obtained apheresis product, patient must have
discontinued, and recovered from acute toxic effects of, all prior chemotherapy,
immunotherapy, and radiotherapy and discontinue the following prior to enrollment:
1. ≥ 7 days post last chemotherapy/biologic therapy administration
2. 3 half lives or 30 days, whichever is shorter post last dose of anti-tumor
antibody therapy
3. Must be at least 30 days from most recent cellular infusion
4. All systemically administered corticosteroid treatment therapy must be stable or
decreasing within 1 week prior to enrollment with maximum dexamethasone dose of
2.5 mg/m2/day. Corticosteroid physiologic replacement therapy is allowed.
8. Adequate organ function
9. Adequate laboratory values
10. Patients of childbearing/fathering potential must agree to use highly effective
contraception
Exclusion Criteria:
1. Presence of Grade ≥ 3 cardiac dysfunction or symptomatic arrhythmia requiring
intervention
2. Presence of primary immunodeficiency/bone marrow failure syndrome
3. Presence of clinical and/or radiographic evidence of impending herniation
4. Presence of >Grade 3 dysphagia
5. Presence of active malignancy other than the primary CNS tumor under study
6. Presence of active severe infection
7. Receiving any anti-cancer agents or chemotherapy
8. Pregnant or breastfeeding
9. Subject and/or authorized legal representative unwilling or unable to provide
consent/assent for participation in the 15 year follow up period
10. Presence of any condition that, in the opinion of the investigator, would prohibit the
patient from undergoing treatment under this protocol
| Maximum Eligible Age: | 26 Years |
| Minimum Eligible Age: | 1 Year |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Establish the safety, defined by the adverse events, of B7H3-specific CAR T cell infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system |
| Time Frame: | up to 7 months |
| Safety Issue: | |
| Description: | The type, frequency, severity, and duration of adverse events as a result of B7H3-specific CAR T cell infusion will be summarized |
Secondary Outcome Measures
| Measure: | Assess the distribution of CNS-delivered B7H3-specific CAR T cells distribution within the cerebrospinal fluid (CSF) and peripheral blood |
| Time Frame: | up to 6 months |
| Safety Issue: | |
| Description: | The trafficking of B7H3-specific CAR T cell product through the CSF by measuring remaining CAR T cells from a prior infusion at the time of each infusion and the trafficking of B7H3-specific CAR T cells from the CSF into the peripheral blood will be evaluated. |
| Measure: | Assessment of disease response of B7H3-expressing DIPG and DMG tumors to B7H3 specific CAR T cell therapy delivered into the CNS |
| Time Frame: | up to 6 months |
| Safety Issue: | |
| Description: | The response of DIPG and DMG tumors to B7H3-specific CAR T cell therapy delivered into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs |
| Measure: | Assessment of disease response of B7H3-expressing refractory or recurrent central nervous system (CNS) tumors to B7H3 specific CAR T cell therapy delivered into the tumor cavity or into the CNS |
| Time Frame: | up to 6 months |
| Safety Issue: | |
| Description: | The response of refractory or recurrent CNS tumors to B7H3-specific CAR T cell therapy delivered into the tumor cavity or into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Seattle Children's Hospital |
Trial Keywords
- CNS, CAR T cell, B7-H3, pediatric, young adult, brain tumor, DIPG, DMG
Last Updated
March 15, 2021
