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

Study Overview
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Brief Summary
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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.

Official Title
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Phase I Study of B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults

Conditions
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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

Intervention / Treatment
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* 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
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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 (physiologic replacement dosing is allowed) 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 (including checkpoint inhibitor) 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. If no apheresis product or usable T cell product is available, participants who have received genetically modified cell therapy must be at least 30 days from most recent cell infusion prior to enrollment If no apheresis product or usable T cell product is available, 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), or already has an apheresis product available for use in manufacturing. 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 at time of enrollment 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

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 26 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCRI-CARB7H3(s)<br>Autologous CD4+ and CD8+ T-cells genetically modified to express an B7H3-specific CAR | Biological: second generation 4-1BBζ B7H3-EGFRt-DHFR<br>* Autologous CD4+ and CD8+ T-cells lentivirally transduced to express a second generation 4-1BBζ B7H3-EGFRt-DHFR<br>|
| Experimental: SCRI-CARB7H3(s)x19<br>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<br>* 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<br>|
| Experimental: SCRI-CARB7H3(s)x19 plus pembrolizumab<br>Autologous CD4+ and CD8+ T-cells genetically modified to express a bispecific B7H3xCD19 CAR given in combination with pembrolizumab | Biological: second generation 4-1BBζ B7H3-EGFRt-DHFR(selected) and a second generation 4-1BBζ CD19-Her2tG<br>* 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<br>Drug: Pembrolizumab<br>* SCRI-CARB7H3(s)x19 plus pembrolizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety and tolerability of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express B7H3-specific CAR (Arm A) | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 
| 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) | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 
| To assess the safety and tolerability of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express a bispecific B7H3xCD19 CAR given in combination with pembrolizumab (Arm C) | Type, frequency, severity, and duration of adverse events will be tabulated and summarized to determine maximal tolerated dose | 28 days | 
| To determine the maximum tolerated dose (MTD) of B7H3-specific CAR (Arm A) | Type, frequency, severity, and duration of adverse events will be tabulated and summarized to determine maximal tolerated dose | 28 days | 
| To determine the maximum tolerated dose of bispecific B7H3xCD19 CAR (Arm B) | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 
| To determine the feasibility of administration of pembrolizumab in combination with bispecific B7H3xCD19 CAR (Arm C) | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 
| To assess the dose limiting toxicities (DLTs) and describe the full toxicity profile for each study arm | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 
| To assess the feasibility of manufacturing B7H3 specific CARs from patient-derived lymphocytes | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 
| To assess the feasibility of manufacturing B7H3xCD19 bispecific CARs from patient-derived lymphocytes | Type, frequency, severity, and duration of adverse events will be tabulated and summarized | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the duration of in vivo persistence of adoptively transferred T cells in the peripheral blood and compare engraftment between T cell products and treatment arms | Presence of CAR T cells in the peripheral blood will be assessed | 84 days | 
| Determine the magnitude of in vivo persistence of adoptively transferred T cells in the peripheral blood and compare engraftment between T cell products | Number of CAR T cells in the peripheral blood will be assessed | 84 days | 
| Quantitate anti-tumor responses by measuring changes in tumor burden using disease-specific evaluations | Presence of CAR T cells in the peripheral blood will be assessed | 84 days | 
| 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) with and without pembrolizumab | Presence of CAR T cells in the peripheral blood will be assessed | 84 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR T cell, Pediatric, Young adults, Non-CNS solid tumor