Genetically Engineered Cells (B7-H3-Specific CAR T Cells) in Treating Pediatric Patients with Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, or Recurrent or Refractory Central Nervous System Tumors
This phase I trial studies the side effects and best dose of genetically engineered cells (B7-H3-specific CAR T cells) and how well it works in treating patients with diffuse intrinsic pontine glioma, diffuse midline glioma, or central nervous system tumors that have come back (recurrent) or do not respond to treatment (refractory). Immunotherapy with B7-H3-specific CAR T cells may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread.
Inclusion Criteria
- Subjects must be age >= 1 and =< 26 years (except for the first 3 subjects, who will be enrolled in Arm A or Arm B and must be age >= 15 and =< 26 years) (this requirement has been met as of 8/27/2020).
- Subject disease classified as one of the following: * DIPG at any timepoint following completion of standard radiotherapy * DMG at any timepoint following completion of standard radiotherapy * Evidence of refractory or recurrent CNS disease for which there is no standard therapy, defined by either of the following: ** Recurrent disease (e.g., new site[s] of measurable or evaluable disease by radiographic imaging or histologic confirmation following completion of standard of care first-line therapy for which curative salvage therapy is not available or amenable, OR ** Refractory disease (e.g., measurable or evaluable disease that persists following completion of standard of care first-line therapy for which curative salvage therapy is not available or amendable)
- Able to tolerate apheresis or already has an apheresis product available for use in manufacturing.
- CNS reservoir catheter, such as an Ommaya or Rickham catheter, present in the proper location for CNS-directed therapy delivered as specified for BrainChild-03.
- Life expectancy >= 8 weeks.
- Lansky or Karnofsky score >= 60. Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for purposes of assessing performance status.
- If subject does not have a previously obtained apheresis product that is acceptable and available for manufacturing of CAR T cells, subject must discontinue all anti-cancer agents and radiotherapy and, in the opinion of the investigator, have fully recovered from significant acute toxic effects of the following: * Cytotoxic chemotherapy/biologic therapy: All cytotoxic chemotherapy/biologic therapy must be discontinued >= 7 days prior to enrollment. * Antibody therapy: The last dose of anti-tumor antibody therapy (including check point inhibitor) must be at least 3 half-lives or 30 days, whichever is shorter, from the time of enrollment. Bevacizumab will be considered biologic therapy. * Cellular therapy: must be at least 30 days from most recent cell infusion prior to enrollment * Steroid use: All systemically administered (i.e. subcutaneous, intramuscular, orally [PO] or intravenously [IV]) corticosteroid therapy (unless physiologic replacement dosing) must be stable or decreasing for >= 1 week prior to enrollment, with a maximum dexamethasone dose of 2.5 mg/m^2/day ongoing at enrollment. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed.
- Absolute lymphocyte count (ALC) >= 100 cells/uL. * Value not required to be met if subject has previously obtained apheresis product acceptable and available for manufacturing of CAR T cells
- Absolute neutrophil count (ANC) >= 500 cells/uL.
- Hemoglobin >= 9 g/dL. * Subjects receiving blood product transfusion(s) are acceptable as long as they are not determined to be transfusion refractory.
- Platelets >= 100,000/uL. * Subjects receiving blood product transfusion(s) are acceptable as long as they are not determined to be transfusion refractory.
- Serum creatinine =< the upper limit of normal (ULN) based on age and sex. * Maximum serum creatinine (mg/dL): ** Age 1 to < 2 years (yrs): 0.6 mg/dL (male); 0.6 mg/dL (female) ** Age 2 to < 6 yrs: 0.8 mg/dL (male); 0.8 mg/dL (female) ** Age 6 to < 10 yrs: 1 mg/dL (male); 1 mg/dL (female) ** Age 10 to < 13 yrs: 1.2 mg/dL (male); 1.2 mg/dL (female) ** Age 13 to < 16 yrs: 1.5 mg/dL (male); 1.4 mg/dL (female) ** Age >= 16 yrs: 1.7 mg/dL (male); 1.4 mg/dL (female)
- Total bilirubin < 3 times ULN for age OR conjugated bilirubin < 2 mg/dL.
- Oxygen saturation >= 90% on room air without supplemental oxygen or mechanical ventilation, AND no dyspnea at rest.
- Signs and symptoms of neurologic deficit must be stable for >= 1 week prior to enrollment, AND =< two anti-epileptic agents are required to control seizure activity, AND no clinically evident encephalopathy present.
- Virology negative within 3 months prior to enrollment, to include all of the following: * Human immunodeficiency virus (HIV) antigen & antibody, AND * Hepatitis B surface antigen, AND * Hepatitis C antibody OR if antibody positive, hepatitis C polymerase chain reaction (PCR) is negative.
- Subjects of childbearing/fathering potential must agree to use highly effective contraception from the time of enrollment through 12 months following the last T cell infusion.
Exclusion Criteria
- Presence of >= grade 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention.
- Presence of primary immunodeficiency/bone marrow failure syndrome.
- Presence of clinical and/or radiographic evidence of impending herniation.
- For Arm C subjects only: Presence of > grade 3 dysphagia.
- Presence of active malignancy other than the CNS tumor under study.
- Presence of active severe infection, defined as either of the following * Positive blood culture within 48 hours of enrollment, OR * Fever >= 38.2 degrees Celsius AND clinical signs of infection within 48 hours of enrollment.
- Pregnant or breastfeeding.
- Subject and/or authorized legal representative unwilling to provide consent/assent for study participation, including participation in the 15-year follow-up period, which is required if CAR T cell therapy is administered.
- Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol.
Additional locations may be listed on ClinicalTrials.gov for NCT04185038.
Locations matching your search criteria
United States
Washington
Seattle
PRIMARY OBJECTIVES:
I. To assess the feasibility of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7-H3-specific chimeric antigen receptor (CAR) EGFRt and a methotrexate resistant human dihydrofolate reductase mutein, delivered by an indwelling catheter into the tumor cavity or ventricular system in children and young adults with diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma H3 K27M-mutant (DMG), or recurrent/refractory CNS tumors.
II. To assess the safety of CNS locoregional adoptive therapy with autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7-H3-specific CAR, EGFRt and a methotrexate resistant human dihydrofolate reductase mutein, delivered by an indwelling catheter into the tumor cavity or ventricular system in children and young adults with DIPG, DMG, or recurrent/refractory CNS tumors.
III. To establish the tolerability of a fractionated CNS-delivered anti-B7-H3 CAR T-cells (B7-H3 CAR T cell) infusion schedule employing intra-subject dose escalation in children and young adults with DIPG, DMG, or recurrent/refractory CNS tumors.
IV. To define the maximally tolerated dose (MTD) and recommended phase 2 dose regimen (RP2DR) of CNS-delivered fractionated B7-H3 CAR T cell infusions.
SECONDARY OBJECTIVES:
I. To assess B7-H3 CAR T cell distribution within the cerebrospinal fluid (CSF) and the extent to which B7-H3 CAR T cells egress into the peripheral circulation.
II. To assess disease response to B7-H3 CAR T cell locoregional therapy in children and young adults with DIPG, DMG, or recurrent/refractory CNS tumors.
EXPLORATORY OBJECTIVES:
I. To evaluate for presence of B7-H3 CAR T cells in tumor tissue and/or normal tissue if a tissue biopsy, tumor biopsy, or resection is clinically indicated post-treatment.
II. To evaluate B7-H3 expression in tumor tissue and/or normal tissue if a tissue biopsy, tumor biopsy, or resection is available.
III. To analyze blood, CSF, and tumor tissue for biomarkers of anti-tumor B7-H3 CAR T cell expression, safety, and activity.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 arms.
ARM A: Patients with supratentorial tumors receive anti-B7-H3 CAR T-cells infusion via indwelling catheter into the tumor cavity. Treatment occurs once weekly for 3 weeks followed by a week without treatment. This 4 week course may be repeated continuously in the absence of unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) and cerebrospinal (CSF) fluid and blood sample collection.
ARM B: Patients with either infratentorial tumors or metastatic/leptomeningeal tumors receive anti-B7-H3 CAR T-cells infusion via indwelling catheter into the ventricular system. Treatment occurs weekly for 3 weeks followed by a week without treatment. This 4 week course may be repeated continuously in the absence of unacceptable toxicity. Patients undergo MRI and CSF fluid and blood sample collection.
ARM C: Patients with DIPG receive anti-B7-H3 CAR T-cells infusion via indwelling catheter into the ventricular system. Treatment occurs once during week 1 and 3 of each 4 week cycle. This 4 week course may be repeated continuously in the absence of unacceptable toxicity. Patients undergo MRI and CSF fluid and blood sample collection.
After completion of study treatment, patients are followed up at 30 days, then approximately monthly during months 3-12, then approximately every 3 months during months 12-18, every 6 months during months 18-60, then yearly until 15 years. Follow-up may occur less frequently in subjects who lose persistence of their CAR T cells.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationFred Hutch/University of Washington/Seattle Children's Cancer Consortium
Principal InvestigatorRebecca Jane Ronsley
- Primary IDRG1005749
- Secondary IDsNCI-2019-05185, BrainChild-03
- ClinicalTrials.gov IDNCT04185038