Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Neoplasms, Diffuse Midline Glioma, H3 K27M-Mutant, Ependymoma, Glioblastoma, High Grade Glioma, Medulloblastoma
Conditions
Brief summary
Loc3CAR is a Phase I clinical trial evaluating the use of autologous B7-H3-CAR T cells for participants ≤ 21 years old with primary CNS neoplasms. B7-H3-CAR T cells will be locoregionally administered via a CNS reservoir catheter. Study participants will be divided into two cohorts: cohort A with B7-H3-positive relapsed/refractory non-brainstem primary CNS tumors, and cohort B with diffuse midline gliomas (DMG). Participants will receive four (4) B7-H3-CAR T cell infusions over a 4 week period. The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give patients with primary brain tumors. Primary objectives * To determine the safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the locoregional delivery of autologous B7-H3-CAR T cells in patients ≤ 21 years of age with recurrent/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B). Secondary objectives * To assess the efficacy, defined as sustained objective response, a partial response (PR) or complete response (CR) observed anytime on active treatment with B7-H3-CAR T cells in patients with relapsed/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B). * To characterize and monitor neurologic toxicities in patients while on study (Cohort A and B).
Detailed description
Treatment on this study includes four (4) B7-H3-CAR T cell infusions over a 4 week period. B7-H3-CAR T cells will be locoregionally administered via a CNS reservoir catheter without lymphodepleting chemotherapy. The study will evaluate the safety and maximum tolerated dose (MTD) of B7-H3-CAR T cells using a 3+3 study design and a 4 week evaluation period. Follow up will occur on this protocol for 1 year after the final B7-H3-CAR T cell infusion and then continue on an institutional long-term follow up protocol to complete 15 years post-infusion.
Interventions
Autologous T cells transduced with a lentiviral vector expressing a B7-H3-CAR with a CD28z signaling domain and 41BB ligand (B7-H3-CAR T cells). Four (4) infusions of B7-H3-CAR T cells will be locoregionally administered via CNS reservoir catheter.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
Screening Eligibility 1. Age ≤ 21 years of age 2. Primary CNS tumor 3. For Cohort A, must have evidence of relapsed or refractory non-brainstem CNS tumor 4. For Cohort B, must meet one of the following criteria: * Adequate tumor tissue from primary tumor resection or biopsy for central pathology review (i.e., B7-H3 expression evaluation by immunohistochemistry \[IHC\] or H3K27M mutation if pontine lesion) * Has a diagnosis of diffuse midline glioma that harbors a mutation associated with this entity (e.g. H3K27M) * Has presumptive/suspected brainstem high-grade neoplasm with available imaging for central imaging review 5. Life expectancy of \> 12 weeks 6. Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
Exclusion criteria
Screening Eligibility All Participants 1\. Participant has other clinically significant medical disorders (e.g. serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with study procedure. Inclusion Criteria: Procurement and T-cell Production Eligibility 1. Age ≤ 21 years of age 2. Primary CNS tumor with measurable or evaluable disease and meets criteria for either Cohort A or B: * Cohort A: relapsed/refractory non-brainstem CNS primary tumor AND tumor is B7-H3 positive * Cohort B: Diffuse midline glioma AND tumor is: * B7-H3 positive if non-pontine * OR H3K27-altered diffuse midline pontine glioma * OR radiographically-confirmed classic/typical DIPG 3. Estimated life expectancy of \>12 weeks 4. Karnofsky or Lansky performance score ≥50 5. Participant of childbearing/child-fathering potential agrees to use contraception 6. For females of childbearing age: * Not pregnant with negative serum pregnancy test * Not lactating with intent to breastfeed 7. Chemotherapy/biologic therapy must be discontinued ≥ 7 days prior to enrollment 8. The last dose of antibody therapy (including check point inhibitor) must be at least 3 half-lives or 30 days, whichever is shorter, from the time of enrollment 9. At least 30 days from most recent cell infusion prior to enrollment. 10. All systemically administered corticosteroid therapy must be stable or decreasing for ≥1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m\^2/day 11. Meets eligibility for apheresis, or has an apheresis product previously collected at a FACT-accredited program 12. Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) | Four (4) weeks after the first B7-H3-CAR T-cell infusion or 7 days after the fourth B7-H3-CAR T cell infusion, whichever is longer | To determine the maximum tolerated dose for the locoregional delivery of autologous B7-H3-CAR T cells in patients with recurrent/refractory B7-H3- positive primary CNS tumors (Cohort A) or diffuse midline glioma (DMG) (Cohort B). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic response | Four (4) weeks post B7-H3-CAR T-cell infusion | To assess the efficacy, defined as sustained objective response, partial response (PR) or complete response (CR), observed anytime on active treatment with B7-H3-CAR T cells in patients with relapsed/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORChristopher DeRenzo, MD
St. Jude Children's Research Hospital
PRINCIPAL_INVESTIGATORKelsey Bertrand, MD, MSc
St. Jude Children's Research Hospital
PRINCIPAL_INVESTIGATORGiedre Krenciute, PhD
St. Jude Children's Research Hospital
Outcome results
None listed