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Trial record 1 of 1 for:    03500991
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HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors

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ClinicalTrials.gov Identifier: NCT03500991
Recruitment Status : Recruiting
First Posted : April 17, 2018
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
Julie Park, Seattle Children's Hospital

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.


Condition or disease Intervention/treatment Phase
Central Nervous System Tumor, Pediatric Glioma Ependymoma Medulloblastoma Germ Cell Tumor Atypical Teratoid/Rhabdoid Tumor Primitive Neuroectodermal Tumor Choroid Plexus Carcinoma Pineoblastoma Biological: HER2-specific chimeric antigen receptor (CAR) T cell Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of HER2-Specific CAR T Cell Locoregional Immunotherapy for HER2 Positive Recurrent/Refractory Pediatric Central Nervous System Tumors
Actual Study Start Date : July 26, 2018
Estimated Primary Completion Date : July 26, 2021
Estimated Study Completion Date : July 26, 2036


Arm Intervention/treatment
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

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

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

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




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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


Other Outcome Measures:
  1. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 26 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • First 3 enrolled subjects: age ≥ 15 and ≤ 26 years Subsequent subjects: age ≥ 1 and ≤ 26 years
  • Histologically diagnosed HER2-positive Central Nervous System (CNS) tumor
  • Evidence of refractory or recurrent CNS disease that has failed first-line therapy
  • Willing and able to provide tumor specimens
  • Able to tolerate apheresis
  • Functional 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 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
  • Unwilling or unable to provide consent/assent for participation in the study and 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03500991


Contacts
Contact: Nicholas Vitanza, MD 206-987-2106 immunotherapy@seattlechildrens.org

Locations
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Principal Investigator: Nicholas Vitanza, MD         
Sponsors and Collaborators
Seattle Children's Hospital
Investigators
Study Chair: Nicholas Vitanza, MD Seattle Children's Hospital

Responsible Party: Julie Park, Medical Director, ICC, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT03500991     History of Changes
Other Study ID Numbers: BrainChild-01
First Posted: April 17, 2018    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Julie Park, Seattle Children's Hospital:
CNS, CAR T cell, HER2-positive, brain tumor
pediatric, young adults

Additional relevant MeSH terms:
Neoplasms
Neoplasms, Germ Cell and Embryonal
Ependymoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Medulloblastoma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Rhabdoid Tumor
Pinealoma
Neoplasms by Histologic Type
Glioma
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Neoplasms, Complex and Mixed
Brain Neoplasms
Brain Diseases
Central Nervous System Diseases