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

NCT ID: NCT04432649

Last Updated: 2020-06-16

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-01
• Study Completion Date: 2024-05-31

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.

Conditions

Solid Tumor

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

4SCAR-276

Intervention Type: BIOLOGICAL

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

Interventions

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

Intervention Type: BIOLOGICAL

Other Intervention Names

CD276-specific 4th Generation CART

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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sun Yat-sen University

OTHER

Sponsor Role: collaborator

Shenzhen Children's Hospital

OTHER_GOV

Sponsor Role: collaborator

Shenzhen Geno-Immune Medical Institute

OTHER

Sponsor Role: lead

Responsible Party

Lung-Ji Chang

President

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Shenzhen Children's Hospital

Shenzhen, Guangdong, China

Site Status: RECRUITING

Shenzhen Geno-immune Medical Institute

Shenzhen, Guangdong, China

Site Status: RECRUITING

Sun Yat-Sen University

Shenzhen, Guangdong, China

Site Status: RECRUITING

Countries

China

Facility Contacts

Sixi Liu, MD

Role: primary

tiger647@126.com

86-189 3869 0206

Xiuli Yuan, MD

Role: backup

18938690212@163.com

86-18938690212

Lung-Ji Chang, PhD

Role: primary

c@szgimi.org

86-075586725195

Bo Wang, MD

Role: primary

wangb68377@sina.com

86-0755-23242570

Other Identifiers

GIMI-IRB-20009

Identifier Type: -

Identifier Source: org_study_id