Description:
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.
Title
- Brief Title: B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
- Official Title: Phase I Study of B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
Clinical Trial IDs
- ORG STUDY ID:
STRIvE-02
- NCT ID:
NCT04483778
Conditions
- 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
Interventions
| Drug | Synonyms | Arms |
|---|
| second generation 4-1BBζ B7H3-EGFRt-DHFR | | SCRI-CARB7H3(s) |
| second generation 4-1BBζ B7H3-EGFRt-DHFR(selected) and a second generation 4-1BBζ CD19-Her2tG | | SCRI-CARB7H3(s)x19 |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| SCRI-CARB7H3(s) | Experimental | Autologous CD4+ and CD8+ T-cells genetically modified to express an B7H3-specific CAR | - second generation 4-1BBζ B7H3-EGFRt-DHFR
|
| SCRI-CARB7H3(s)x19 | Experimental | Autologous CD4+ and CD8+ T-cells genetically modified to a bispecific B7H3xCD19 CAR | - second generation 4-1BBζ B7H3-EGFRt-DHFR(selected) and a second generation 4-1BBζ CD19-Her2tG
|
Eligibility 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 (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
| Maximum Eligible Age: | 26 Years |
| Minimum Eligible Age: | N/A |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | 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 |
| Safety Issue: | |
| Description: | Type, frequency, severity, and duration of adverse events will be tabulated and summarized |
Secondary Outcome Measures
| Measure: | 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 |
| Safety Issue: | |
| Description: | Presence of CAR T cells in the peripheral blood will be assessed |
| Measure: | 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 |
| Safety Issue: | |
| Description: | Number of CAR T cells in the peripheral blood will be assessed |
| Measure: | Quantitate anti-tumor responses by measuring changes in tumor burden using disease-specific evaluations |
| Time Frame: | 84 days |
| Safety Issue: | |
| Description: | Presence of CAR T cells in the peripheral blood will be assessed |
| Measure: | 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 |
| Safety Issue: | |
| Description: | Presence of CAR T cells in the peripheral blood will be assessed |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Seattle Children's Hospital |
Trial Keywords
- CAR T cell
- Pediatric
- Young adults
- Non-CNS solid tumor
Last Updated
April 19, 2021
