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HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03500991
Recruitment Status : Recruiting
First Posted : April 18, 2018
Last Update Posted : April 6, 2020
Sponsor:
Information provided by (Responsible Party):
Julie Park, Seattle Children's Hospital

Tracking Information
First Submitted Date  ICMJE March 21, 2018
First Posted Date  ICMJE April 18, 2018
Last Update Posted Date April 6, 2020
Actual Study Start Date  ICMJE July 26, 2018
Estimated Primary Completion Date July 26, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • 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 [ Time Frame: up to 6 months ]
    The type, frequency, severity, and duration of adverse events as a result of HER2-specific CAR T cell infusion will be summarized
  • 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 [ Time Frame: 28 days ]
    The proportion of products successfully manufactured and infused will be measured
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Assess the distribution of CNS-delivered HER2-specific CAR T cells within the cerebrospinal fluid (CSF) and peripheral blood [ Time Frame: up to 6 months ]
    The trafficking of HER2-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 HER2-specific CAR T cells from the CSF into the peripheral blood will be evaluated
  • Assessment of whether HER2 expression changes in relapsed CNS tumors that were HER2 positive prior to treatment with CAR T cells [ Time Frame: 28 days ]
    The changes in HER2 expression at diagnosis and recurrence of central nervous system (CNS) tumors, if samples from multiple time points is available, will be investigated by evaluating pathology specimens from previous surgeries
  • 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 [ Time Frame: up to 6 months ]
    The response of recurrent or refractory central HER2-expressing CNS tumors to HER2-specific CAR T cell therapy delivered directly into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 9, 2018)
Analysis of CSF for biomarkers of anti-tumor CAR T cell functional activity [ Time Frame: up to 6 months ]
The presence of biomarkers of anti-tumor CAR T cell functional activity in the CSF will be evaluated and correlated with response by disease evaluations of the CSF and by CNS imaging with MRIs
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors
Official Title  ICMJE Phase 1 Study of HER2-Specific CAR T Cell Locoregional Immunotherapy for HER2 Positive Recurrent/Refractory Pediatric Central Nervous System Tumors
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 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 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Central Nervous System Tumor, Pediatric
  • Glioma
  • Ependymoma
  • Medulloblastoma
  • Germ Cell Tumor
  • Atypical Teratoid/Rhabdoid Tumor
  • Primitive Neuroectodermal Tumor
  • Choroid Plexus Carcinoma
  • Pineoblastoma
Intervention  ICMJE Biological: HER2-specific chimeric antigen receptor (CAR) T cell
Autologous CD4 and CD8 T cells lentivirally transduced to express a HER2 specific chimeric antigen receptor (CAR) and EGFRt given via indwelling central nervous system (CNS) catheter
Study Arms  ICMJE
  • Experimental: ARM A (Tumor Cavity Infusion)

    patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity

    Intervention: HER2-specific chimeric antigen receptor (CAR) T cell

    Intervention: Biological: HER2-specific chimeric antigen receptor (CAR) T cell
  • Experimental: ARM B (Ventricular System Infusion)

    patients with either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the fourth ventricle or lateral ventricle, respectively

    Intervention: HER2-specific chimeric antigen receptor (CAR) T cell

    Intervention: Biological: HER2-specific chimeric antigen receptor (CAR) T cell
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 2, 2020)
48
Original Estimated Enrollment  ICMJE
 (submitted: April 9, 2018)
36
Estimated Study Completion Date  ICMJE July 26, 2036
Estimated Primary Completion Date July 26, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥ 1 and ≤ 26 years
  • Histologically diagnosed HER2-positive Central Nervous System (CNS) tumor
  • Evidence of refractory or recurrent CNS disease for which there is no standard therapy
  • Willing and able to provide tumor specimens
  • Able to tolerate apheresis, or has apheresis product available for use in manufacturing
  • CNS reservoir catheter, such as an Ommaya or Rickham catheter
  • Life expectancy ≥ 8 weeks
  • Lansky or Karnofsky score ≥ 60
  • Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy
  • ≥ 7 days post last chemotherapy administration
  • 3 half-lives or 30 days, whichever is shorter post last dose of anti-tumor antibody therapy
  • No prior virotherapy. Prior genetically modified cell therapy is allowed if not detectable at enrollment.
  • Stable or decreasing dosing of steroid treatment for symptomatic relief from CNS disease, with maximum dexamethasone dose of 2.5 mg/m2/day
  • Adequate organ function
  • Adequate laboratory values
  • Patients of childbearing/fathering potential must agree to use highly effective contraception

Exclusion Criteria:

  • Diagnosis of classic diffuse intrinsic pontine glioma (DIPG)
  • 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
  • Presence of active malignancy other than the primary CNS tumor under study
  • Presence of active severe infection
  • Receiving any anti-cancer agents or chemotherapy
  • Pregnant or breastfeeding
  • Subject and/or authorized legal representative unwilling or unable to provide consent/assent for participation in the 15-year follow up period
  • Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 26 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nicholas Vitanza, MD 206-987-2106 CBDCIntake@seattlechildrens.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03500991
Other Study ID Numbers  ICMJE BrainChild-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Julie Park, Seattle Children's Hospital
Study Sponsor  ICMJE Seattle Children's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Nicholas Vitanza, MD Seattle Children's Hospital
PRS Account Seattle Children's Hospital
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP