Clinical trial NCT03500991: HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors
Official title: Phase 1 Study of HER2-Specific CAR T Cell Locoregional Immunotherapy for HER2 Positive Recurrent/Refractory Pediatric Central Nervous System Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Central Nervous System Tumor, Pediatric
Glioma
Ependymoma
Medulloblastoma
Germ Cell Tumor
Atypical Teratoid/Rhabdoid Tumor
Primitive Neuroectodermal Tumor
Choroid Plexus Carcinoma
Pineoblastoma
Keywords: CNS, CAR T cell, HER2-positive, brain tumor
pediatric, young adults
Lead sponsor: Seattle Children's Hospital
Sponsor class: OTHER
First posted: 2018-04-18
Enrollment: 10
Sex: ALL
Minimum age (years): 1
Maximum age (years): 26
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 HER2-specific chimeric antigen receptor (CAR) and EGFRt, delivered by an indwelling catheter in the tumor resection cavity or ventricular system in children and young adults with recurrent or refractory HER2-positive CNS tumors. A child or young adult with a refractory or recurrent CNS tumor will have their tumor tested for HER2 expression by immunohistochemistry (IHC) at their home institution or at Seattle Children's Hospital. If the tumor is HER2 positive and the patient meets all other eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meets none of the exclusion criteria, then they can be apheresed, meaning T cells will be collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets HER2-expressing tumor cells. The patient's newly engineered T cells will then be administered via the indwelling CNS catheter for two courses. In the first course they 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. Following the two courses, patient's 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 additional 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 HER2-specific CAR T cells can be manufactured to complete two courses of treatment with three doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that HER-specific CAR T cells safely can be administered through an indwelling CNS catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study safely can be delivered directly into the brain via indwelling catheter. Secondary aims of the study will include to evaluate 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 time points are available, also evaluate the degree of HER2 expression at diagnosis versus at recurrence.


Eligibility criteria: Inclusion Criteria:

1. Age ≥ 1 and ≤ 26 years
2. Histologically diagnosed HER2-positive Central Nervous System (CNS) tumor
3. Evidence of refractory or recurrent CNS disease for which there is no standard therapy
4. Able to tolerate apheresis, or has apheresis product available for use in manufacturing
5. CNS reservoir catheter, such as an Ommaya or Rickham catheter
6. Life expectancy ≥ 8 weeks
7. Lansky or Karnofsky score ≥ 60
8. If patient does not have previously obtained apheresis product, patient must have 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 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 cell 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.
9. Adequate organ function
10. Adequate laboratory values
11. Patients of childbearing/fathering potential must agree to use highly effective contraception

Exclusion Criteria:

1. Diagnosis of classic diffuse intrinsic pontine glioma (DIPG)
2. Presence of Grade ≥ 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention
3. Presence of primary immunodeficiency/bone marrow failure syndrome
4. Presence of clinical and/or radiographic evidence of impending herniation
5. Presence of active malignancy other than the primary CNS tumor under study
6. Presence of active severe infection
7. Pregnant or breastfeeding
8. Subject and/or authorized legal representative unwilling or unable to provide consent/assent for participation in the 15-year follow up period
9. Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol

Primary outcomes:
measure: Establish the safety, defined by the adverse events, of HER2-specific CAR T cell infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system
timeFrame: up to 6 months
measure: Establish the feasibility, defined by the ability to produce and administer CAR T cell product, of HER2-specific CAR T cell product infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system
timeFrame: 28 days
Secondary outcomes:
measure: Assess the distribution of CNS-delivered HER2-specific CAR T cells within the cerebrospinal fluid (CSF) and peripheral blood
timeFrame: up to 6 months
measure: Assessment of whether HER2 expression changes in relapsed CNS tumors that were HER2 positive prior to treatment with CAR T cells
timeFrame: 28 days
measure: Assessment of disease response of HER2-expressing refractory or recurrent central nervous system (CNS) tumors to HER2 specific CAR T cell therapy delivered directly into the CNS
timeFrame: up to 6 months
Other outcomes:
measure: Analysis of CSF for biomarkers of anti-tumor CAR T cell functional activity
timeFrame: up to 6 months
Locations:
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Seattle Children's Hospital
name: Rebecca Ronsley, MD
role: STUDY_CHAIR
References:
citation: Vitanza NA, Johnson AJ, Wilson AL, Brown C, Yokoyama JK, Kunkele A, Chang CA, Rawlings-Rhea S, Huang W, Seidel K, Albert CM, Pinto N, Gust J, Finn LS, Ojemann JG, Wright J, Orentas RJ, Baldwin M, Gardner RA, Jensen MC, Park JR. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat Med. 2021 Sep;27(9):1544-1552. doi: 10.1038/s41591-021-01404-8. Epub 2021 Jul 12.