Targeting CD276 (B7-H3) Positive Solid Tumors by 4SCAR-276

• ClinicalTrials.gov Identifier: NCT04432649
• Recruitment Status: Recruiting
• First Posted: June 16, 2020
• Last Update Posted: June 16, 2020
• Sponsor: Shenzhen Geno-Immune Medical Institute
• Collaborators: Sun Yat-sen University; Shenzhen Children's Hospital
• Information provided by (Responsible Party): Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute

Tracking Information

• First Submitted Date: June 8, 2020
• First Posted Date: June 16, 2020
• Last Update Posted Date: June 16, 2020
• Actual Study Start Date: June 1, 2020
• Estimated Primary Completion Date: May 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 11, 2020)

Number of patients with adverse events [ Time Frame: 3 years ]

Determine the toxicity profile the 4SCAR-276-modified T cells with Common Toxicity Criteria for Adverse Effects version 4.0

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: June 11, 2020)

• Anti-tumor effects [ Time Frame: 1 year ]
  Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) based on imaging analysis.
• Survival time of the patients [ Time Frame: 3 years ]
  Evaluate the survival time of the patients treated with the 4SCAR-276 T cells, including progression free survival (PFS) and overall survival (OS).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Targeting CD276 (B7-H3) Positive Solid Tumors by 4SCAR-276
• Official Title: Multicenter Trial of Phase I/II Studies on CD276 (B7-H3) Positive Solid Tumors Treated With 4SCAR-276
• Brief Summary: Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex multimodel therapy and therefore, novel approaches are urgently needed. This study attempts to treat these diseases using T cells genetically modified with a 4th generation lentiviral chimeric antigen receptor (4SCAR fused with an inducible apoptotic caspase 9 domain) targeting CD276 (B7-H3). The 4SCAR-CD276-modified T cells (4SCAR-276) can recognize and kill tumor cells through the recognition of CD276, a surface protein expressed at high levels on many types of tumors but at low levels on normal tissues. This study will evaluate the side effects and effective doses of 4SCAR-276 in treating refractory and/or recurrent tumors.

Detailed Description

Background: Patients with refractory and/or recurrent solid tumors have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. The investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a 4th generation CD276-specific chimeric antigen receptor (4SCAR-276). The CAR molecules enable the T cells to recognize and kill tumor cells through the recognition of the surface CD276, which is expressed at high levels on tumor cells including brain tumors, Ewing's sarcoma (PNET) and many other tumors but not at significant levels on normal tissues. This study will evaluate the side effects and the best dose of a novel 4th generation anti-CD276 CAR T cells to target refractory and/or recurrent solid tumors.

Design:

1. Participants will be screened through physical exam and medical history. Blood and tumor tissue samples will be collected. Imaging studies will be performed.
2. Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells will be activated and modified to express the 4SCAR-276 gene.
3. On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed by 4SCAR-276 lentiviral transduction. The total culture time is approximately 5-7 days.
4. Participants will receive a preparative conditioning regimen comprising cyclophosphamide/fludarabine to prepare their immune system to accept the modified CAR T cells. The preparative regimen will be based on patient immune condition and consistent with standard chemotherapy conditioning regimen.
5. The patients will receive ~10^6 CART cells/kg body weight per infusion, and may receive additional booster CART infusions if positive outcome is recorded.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumor

Intervention

Biological: 4SCAR-276

The 4SCAR-276 T cells can recognize and kill tumor cells through the recognition of CD276 .This study will evaluate the side effects and effective doses of 4SCAR-276 T cells in treating refractory and recurrent solid tumors

Other Name: CD276-specific 4th Generation CART

Study Arms

Experimental: Effectiveness of 4SCAR-276 T cells

The 4SCAR-276 T cells can recognize and kill tumor cells through the recognition of CD276 .This study will evaluate the side effects and effective doses of 4SCAR-276 T cells in treating refractory and recurrent solid tumors

Intervention: Biological: 4SCAR-276

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 11, 2020): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 31, 2024
• Estimated Primary Completion Date: May 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with tumors have received standard first-line therapy and have been judged to be non-resectable, metastatic, progressive or recurrent.
• The CD276 antigen status of the tumor is determined for eligibility. Positive expression is defined by antibody staining results based on immunohistochemistry or flow cytometry analysis.
• Body weight greater than or equal to 10 kg.
• Age: ≥1 year and ≤ 75 years of age at the time of enrollment.
• Life expectancy: at least 8 weeks.
• Prior Therapy: 1) There is no limit to the number of prior treatment regimens. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less. 2) Must not have received hematopoietic growth factors for at least 1 week prior to mononuclear cells collection. 3) At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinase inhibitor or a metronomic nonmyelosuppressive regimen. 4) At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody. 5) At least 1 week since any radiation therapy at the time of study entry.
• Karnofsky/jansky score of 60% or greater.
• Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55 percent .
• Pulse Ox greater than or equal to 90% on room air.
• Liver function: defined as alanine transaminase (ALT) <3x upper limit of normal (ULN), aspartate aminotransferase (AST) <3x ULN; serum bilirubin and alkaline phosphatase <2x ULN.
• Renal function: Patients must have serum creatinine less than 3 times upper limit of normal.
• Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul, Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by transfusion).
• Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria, and the marrow disease not evaluable to have hematologic toxicity.
• For all patients enrolled in this study, themselves or their parents or legal guardians must sign an informed consent and assent.

Exclusion Criteria:

Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or major organ dysfunction, or grade 3 hematologic toxicity.

• Untreated central nervous system (CNS) metastasis: Patients with CNS tumor involvement that has been treated and/or is stable for at least 6 weeks following completion of therapy are eligible.
• Previous treatment with other genetically engineered CD276-CAR T cells or CD276 antibody therapy.
• Active HIV, Hepatitis B virus (HBV), Hepatitis C virus (HCV) infection or uncontrolled infection.
• Patients who require systemic corticosteroid or other immunosuppressive therapy.
• Evidence of tumor potentially causing airway obstruction.
• Inability to comply with protocol requirements.
• Insufficient CAR T cells availability.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 75 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04432649
• Other Study ID Numbers: GIMI-IRB-20009
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Shenzhen Geno-Immune Medical Institute
• Original Study Sponsor: Same as current

Collaborators

• Sun Yat-sen University
• Shenzhen Children's Hospital

• Investigators: Not Provided
• PRS Account: Shenzhen Geno-Immune Medical Institute
• Verification Date: June 2020