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B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults

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: NCT04483778
Recruitment Status : Recruiting
First Posted : July 23, 2020
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Julie Park, Seattle Children's Hospital

Brief Summary:
This is a phase I, open-label, non-randomized study that will enroll pediatric and young adult research participants with relapsed or refractory non-CNS solid tumors to evaluate the safety, feasibility, and efficacy of administering T cell products derived from the research participant's blood that have been genetically modified to express a B7H3-specific receptor (chimeric antigen receptor, or CAR) that will target and kill solid tumors that express B7H3. On Arm A of the study, research participants will receive B7H3-specific CAR T cells only. On Arm B of the study, research participants will receive CAR T cells directed at B7H3 and CD19, a marker on the surface of B lymphocytes, following the hypothesis that CD19+ B cells serving in their normal role as antigen presenting cells to T cells will promote the expansion and persistence of the CAR T cells. Arm A CAR T cells include the protein EGFRt and Arm B CAR T cells include the protein HER2tG. These proteins can be used to both track and destroy the CAR T cells in case of undue toxicity. The primary objectives of the study will be to determine the feasibility of manufacturing the cell products, the safety of the T cell product infusion, to determine the maximum tolerated dose of the CAR T cells products, to describe the full toxicity profile of each product, and determine the persistence of the modified cell in the participant's body on each arm. Participants will receive a single dose of T cells comprised of two different subtypes of T cells (CD4 and CD8 T cells) felt to benefit one another once administered to the research participants for improved potential therapeutic effect. The secondary objectives of this protocol are to study the number of modified cells in the patients and the duration they continue to be at detectable levels. The investigators will also quantitate anti-tumor efficacy on each arm. Participants who experience significant and potentially life-threatening toxicities (other than clinically manageable toxicities related to T cells working, called cytokine release syndrome) will receive infusions of cetuximab (an antibody commercially available that targets EGFRt) or trastuzumab (an antibody commercially available that targets HER2tG) to assess the ability of the EGFRt on the T cells to be an effective suicide mechanism for the elimination of the transferred T cell products.

Condition or disease Intervention/treatment Phase
Pediatric Solid Tumor Germ Cell Tumor Retinoblastoma Hepatoblastoma Wilms Tumor Rhabdoid Tumor Carcinoma Osteosarcoma Ewing Sarcoma Rhabdomyosarcoma Synovial Sarcoma Clear Cell Sarcoma Malignant Peripheral Nerve Sheath Tumors Desmoplastic Small Round Cell Tumor Soft Tissue Sarcoma Neuroblastoma Melanoma Biological: second generation 4-1BBζ B7H3-EGFRt-DHFR Biological: second generation 4-1BBζ B7H3-EGFRt-DHFR(selected) and a second generation 4-1BBζ CD19-Her2tG Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
Actual Study Start Date : July 13, 2020
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2040


Arm Intervention/treatment
Experimental: SCRI-CARB7H3(s)
Autologous CD4+ and CD8+ T-cells genetically modified to express an B7H3-specific CAR
Biological: second generation 4-1BBζ B7H3-EGFRt-DHFR
Autologous CD4+ and CD8+ T-cells lentivirally transduced to express a second generation 4-1BBζ B7H3-EGFRt-DHFR

Experimental: SCRI-CARB7H3(s)x19
Autologous CD4+ and CD8+ T-cells genetically modified to a bispecific B7H3xCD19 CAR
Biological: second generation 4-1BBζ B7H3-EGFRt-DHFR(selected) and a second generation 4-1BBζ CD19-Her2tG
Autologous CD4+ and CD8+ T-cells lentivirally transduced to express a second generation 4-1BBζ B7H3-EGFRt-DHFR(selected) and a second generation 4-1BBζ CD19-Her2tG




Primary Outcome Measures :
  1. Assess the safety and tolerability of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express B7H3-specific CAR (Arm A) [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized

  2. Assess the safety and tolerability of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express a bispecific B7H3xCD19 CAR (Arm B) [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized

  3. Determine the maximum tolerated dose (MTD) of B7H3-specific CAR (Arm A) [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized to determine maximal tolerated dose

  4. Determine the maximum tolerated dose (MTD) of bispecific B7H3xCD19 CAR (Arm B) [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized to determine maximal tolerated dose

  5. Assess the dose limiting toxicities (DLTs) and describe the full toxicity profile for each study arm [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized

  6. Assess the feasibility of manufacturing B7H3 specific CARs from patient-derived lymphocytes [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized

  7. Assess the feasibility of manufacturing B7H3xCD19 bispecific CARs from patient-derived lymphocytes [ Time Frame: 28 days ]
    Type, frequency, severity, and duration of adverse events will be tabulated and summarized


Secondary Outcome Measures :
  1. Determine the duration of in vivo persistence of adoptively transferred T cells in the peripheral blood and compare engraftment between T cell products [ Time Frame: 84 days ]
    Presence of CAR T cells in the peripheral blood will be assessed

  2. Determine the magnitude of in vivo persistence of adoptively transferred T cells in the peripheral blood and compare engraftment between T cell products [ Time Frame: 84 days ]
    Number of CAR T cells in the peripheral blood will be assessed

  3. Quantitate anti-tumor responses by measuring changes in tumor burden using disease-specific evaluations [ Time Frame: 84 days ]
    Presence of CAR T cells in the peripheral blood will be assessed

  4. Describe the relative expansion and persistence of the CAR T cell product and retention of function for B7H3xCD19 bispecific CARs determined by maintenance of B cell aplasia (BCA) [ Time Frame: 84 days ]
    Presence of CAR T cells in the peripheral blood will be assessed


Other Outcome Measures:
  1. Evaluate for the presence of B7H3 CAR T cells in tumor tissue and/or normal tissue if a tissue biopsy, tumor biopsy, or resection is clinically indicated post-treatment [ Time Frame: 84 days ]
    Tumor tissue, when obtained, will be assessed for the presence of adoptively transferred CAR T cells

  2. Evaluate B7H3 antigen expression in tumor tissue and/or normal tissue if a tissue biopsy, tumor biopsy, or resection is available [ Time Frame: 84 days ]
    Tumor tissue, when obtained, will be assessed for the presence of B7H3 antigen

  3. Analyze blood, bone marrow, CSF, normal tissue, and/or tumor tissue for biomarkers of safety and/or anti-tumor activity [ Time Frame: 84 days ]
    If a tissue biopsy, tumor biopsy, or resection is clinically indicated post-treatment, pathology will be assessed for the presence of B7H3 CAR T cells

  4. Assess the efficacy of infusional cetuximab and/or trastuzumab in ablating transferred T cells and ameliorating acute toxicities in treated participants [ Time Frame: 84 days ]
    Biologic specimens, when obtained, will be assessed for biomarkers of safety and/or anti-tumor efficacy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Participants age ≤ 26 years at the time of consent for study participation; the first 2 participants enrolled and treated with CAR T cells in both Arms A and B will be ≥ 15 years. and ≤ 26 years at time of consent for study participation
  • Histologically diagnosed malignant, non-primary CNS solid tumor
  • Evidence of refractory or recurrent disease
  • Lansky or Karnofsky score ≥ 50
  • Life expectancy ≥ 8 weeks
  • Recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy and radiotherapy
  • If no apheresis product or usable T cell product is available, all chemotherapy has been discontinued ≥ 7 days prior to enrollment
  • If no apheresis or usable T cell product is available, all biologic therapy has been discontinued ≥ 7 days prior to enrollment
  • If no apheresis product or T cell product is available, all systemic corticosteroid therapy has been discontinued ≥ 7 days prior to enrollment
  • If no apheresis product or usable T cell product is available, at least 3 half-lives or 30 days (whichever is shorter) from time of last dose of anti-tumor directed antibody therapy at time of enrollment
  • If no apheresis product or usable T cell product is available, at least 6 weeks post last dose of myeloablative therapy and autologous and/or allogeneic stem cell transplant, or non-myeloablative therapy and allogeneic stem cell transplant (all timed from stem cell infusion). Participants who receive autologous stem cell infusion following non-myeloablative therapy are eligible once all other eligibility requirements are met.
  • Participants with neuroblastoma must be at least 12 weeks from I131 MIBG therapy.
  • Adequate organ function
  • Adequate laboratory values
  • Participant is able to tolerate apheresis, including placement of temporary apheresis catheter, if necessary
  • Participants of childbearing potential must agree to use highly effective contraception

Exclusion Criteria:

  • Presence of active malignancy other than primary malignant solid tumor diagnosis
  • Current relevant CNS pathology
  • Receiving external beam radiation therapy
  • Presence of active GVHD, or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment
  • Participant is pregnant or breastfeeding
  • Participant has presence of active severe infection
  • Participant has presence of any condition that, in the option of an investigator, would prohibit the participant from undergoing treatment under this protocol
  • Participant has primary immunodeficiency syndrome
  • Unwilling or unable to provide consent/assent for participation in the study and 15 year follow up period

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): NCT04483778


Contacts
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Contact: Navin Pinto, MD 206-987-2106 immunotherapy@seattlechildrens.org

Locations
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United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Navin Pinto, MD    206-987-2106    immunotherapy@seattlechildrens.org   
Principal Investigator: Navin Pinto, MD         
Sponsors and Collaborators
Seattle Children's Hospital
Investigators
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Principal Investigator: Navin Pinto, MD Seattle Children's Hospital
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Responsible Party: Julie Park, Medical Director, Immunotherapy Coordinating Center, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT04483778    
Other Study ID Numbers: STRIvE-02
First Posted: July 23, 2020    Key Record Dates
Last Update Posted: July 23, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
CAR T cell
Pediatric
Young adults
Non-CNS solid tumor
Additional relevant MeSH terms:
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Neoplasms
Sarcoma
Neuroblastoma
Osteosarcoma
Rhabdomyosarcoma
Sarcoma, Ewing
Wilms Tumor
Retinoblastoma
Sarcoma, Synovial
Rhabdoid Tumor
Hepatoblastoma
Nerve Sheath Neoplasms
Desmoplastic Small Round Cell Tumor
Neurofibrosarcoma
Sarcoma, Clear Cell
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Neoplasms, Connective and Soft Tissue
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Myosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Complex and Mixed
Kidney Neoplasms