Autologous B7-H3 Chimeric Antigen Receptor T Cells (B7-H3CART) for the Treatment of Children and Young Adults with Relapse or Refractory Neuroblastoma, Soft Tissue Sarcoma, Osteosarcoma, Ewing Sarcoma, and Wilms Tumor
This phase I trial tests the safety, side effects, and best dose of autologous B7-H3 chimeric antigen receptor T cells (B7-H3CART) and how well it works in treating patients with neuroblastoma, soft tissue sarcoma, osteosarcoma, Ewing sarcoma or Wilms tumor that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chimeric antigen receptor (CAR) T cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein, such as B7-H3, on the patient’s tumor cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving B7-H3CART may be safe, tolerable, and/or effective in treating patients with relapsed or refractory neuroblastoma, soft tissue sarcoma, osteosarcoma, Ewing sarcoma or Wilms tumors.
Inclusion Criteria
- Histologically confirmed malignant solid tumor (including neuroblastoma, soft tissue sarcoma, osteosarcoma, Ewing Sarcoma, and Wilms tumor) with evidence of incurable disease and tumor recurrence/progression after all available curative standard therapies * Subjects with neuroblastoma must have received or be intolerant to anti-disialoganglioside (GD2) antibody therapy * Subjects with Wilm’s tumor must have received or be intolerant to ifosfamide/etoposide therapy * Subjects with embryonal rhabdomyosarcoma must have received or be intolerant to Adriamycin-based therapy * Subjects with osteosarcoma at first recurrence must have undergone surgical resection of resectable metastatic nodules
- Subjects during dose escalation must have evaluable or measurable disease. Subjects during dose expansion must have measurable disease, except neuroblastoma which may have MIBG positive disease only
- B7-H3 positive expression on malignant cells is NOT required but archival tissue must be available, or the subject must be willing to undergo tissue biopsy for expression analysis
- Must be ≥ 2 and < 26 years of age * For the first three subjects treated with B7-H3CART, must be ≥ 12 and < 26 years of age
- Patients > 16 years of age must have Karnofsky ≥ 50%. Patients ≤ 16 years of age must have Lansky scale ≥ 50%; or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Prior Therapy * No limit to the number of prior therapies * Prior therapy wash-out: At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives. Radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the subject has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression
- Absolute neutrophil count (ANC) ≥ 750/uL * If cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia ≥ grade 3 if it is due to disease, based on the results of bone marrow studies
- Platelet count ≥ 75,000/uL * If cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia ≥ grade 3 if it is due to disease, based on the results of bone marrow studies
- Absolute lymphocyte count ≥ 150/uL * If cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia ≥ grade 3 if it is due to disease, based on the results of bone marrow studies
- Creatinine within institutional norms for age (i.e. ≤ 2 mg/dL in adults or according to table below in children < 18 years) OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min * Age ≤ 5 years: Maximum serum creatinine 0.8 * Age < 5 to ≤ 10: Maximum serum creatinine 1.0 * Age > 10 to 18: Maximum serum creatinine 1.2 * Age > 18: Maximum serum creatinine 2.0
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) (unless elevated ALT/AST is associated with disease involvement of the liver, in which case this criterion will be waived and not disqualify a patient)
- Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome
- Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an ECHO
- No clinically significant electrocardiogram (ECG) findings
- No clinically significant pleural effusion
- Baseline oxygen saturation > 92% on room air
- Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
- Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen or for as long as CAR T cells are detectable in peripheral blood
- Must provide informed consent. For subjects < 18 years old, or adults with limited decision-making capacity, their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and assent will be obtained for those > 7 years of age, when appropriate. If a minor becomes of age during participation of this study, he/she will be asked to reconsent as an adult
Exclusion Criteria
- Receiving any other current investigational agents
- History of other malignancy, except non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast), unless disease free for at least 3 years
- Presence of untreated brain metastases will be excluded. Subjects with previous central nervous system (CNS) tumor involvement that has been treated and is stable for at least 3 months following completion of therapy are permitted. Patients who are clinically stable as evidenced by no requirements for corticosteroids, no evolving neurologic deficits, and no progression of residual brain abnormalities without specific therapy, are permitted
- Presence of fungal, bacterial, viral, or other infection that is uncontrolled. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
- Ongoing infection with HIV or hepatitis B (hepatitis B surface antigen [HBsAg] positive) or hepatitis C virus (anti-hepatitis C virus [HCV] positive) as the immunosuppression contained in this study will pose unacceptable risk. A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing
- History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment
- Any medical condition that in the judgement of the sponsor investigator is likely to interfere with assessment of safety or efficacy of study treatment
- History of severe immediate hypersensitivity reaction to any of the agents used in this study
- Pregnant females are excluded from this study because the effects of autologous B7-H3CART on the developing human fetus are unknown and because the chemotherapy agents used in this trial (cyclophosphamide and fludarabine) are category D agents with the potential for teratogenic or abortifacient effects. Additionally, because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with cyclophosphamide/fludarabine, breastfeeding should be discontinued if the mother is treated with cyclophosphamide/fludarabine. These potential risks may also apply to other agents used in this study
- Primary immunodeficiency or history of systemic autoimmune disease (e.g., Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
- Patients who require systemic corticosteroid or other immunosuppressive therapy. (A one-week washout from systemic corticosteroid or other immunosuppressive therapy is permitted.) Use of physiologic doses of corticosteroids (up to 3 mg/m^2/day prednisone equivalent) are permitted. Use of topical, ocular, intra-articular, intra-nasal, or inhaled corticosteroids are permitted
- In the investigator’s judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
Additional locations may be listed on ClinicalTrials.gov for NCT06500819.
Locations matching your search criteria
United States
California
Palo Alto
PRIMARY OBJECTIVES:
I. Determine the feasibility of manufacturing autologous T cells transduced with Ef1a-CAR276 lentiviral vector expressing B7-H3 chimeric antigen receptor (B7-H3-CART), using the Miltenyi CliniMACS Prodigy, registered trademark, system with dasatinib and protamine sulfate.
II. Assess the safety and identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of a single dose of intravenous B7-H3CART in children and young adults with relapsed and refractory solid tumors (i.e. soft tissue sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma) using the proposed dose escalation schedule.
SECONDARY OBJECTIVES:
I. In a preliminary manner, assess clinical response in children and young adults with relapsed and refractory solid tumors treated with intravenous (IV) B7-H3CART.
II. Assess the safety of B7-H3CART at the MTD/RP2D in children and young adults with relapsed and refractory solid tumors treated with IV B7-H3CART.
EXPLORATORY OBJECTIVES:
I. Measure expansion/persistence/phenotype of adoptively transferred B7-H3CART in the blood and correlate with antitumor effects after initial IV dose.
II. Conduct analysis of manufactured B7-H3CART product, as well as baseline and post-infusion immune cell populations to identify biomarkers of CAR T cell activity in subjects.
III. Analyze the cytokine inflammatory trajectory in patient peripheral blood at baseline and following CAR T cell administration in relation to CAR T cell expansion and activity.
IV. Assess B7-H3 antigen density and tumor microenvironment prior to and following (if available) B7-H3CART treatment and correlate with response and durability of response.
V. Evaluate clinical response to re-infusion of B7-H3CART in subjects who meet criteria for a second dose.
OUTLINE: This is a dose-escalation study of B7-H3CART followed by a dose-expansion study.
LEUKAPHERESIS: Patients undergo leukapheresis over 2-4 hours 4-5 weeks prior to planned infusion.
BRIDGING THERAPY: Patients may receive bridging therapy at the discretion of the investigator.
CONDITIONING LYMPHODEPLETION: Patients receive fludarabine IV on days -5, -4, -3, and -2 and cyclophosphamide IV on days -5, -4, -3.
B7-H3CART INFUSION: Patients receive B7-H3CART IV over 10-30 minutes on day 0. After at least 60 days, patients may receive a second infusion.
Patients undergo echocardiography (ECHO) or cardiac magnetic resonance imaging (MRI) at screening. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, computed tomography (CT), positron emission tomography (PET)/CT, or MRI, and optional Iobenguane (MIBG) scan throughout the study.
After completion of study treatment, patients are followed up at 28 days, months 2, 3, 6, 9, 12, 18 and 24, then annually for years 2-15.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationStanford Cancer Institute Palo Alto
Principal InvestigatorSneha Ramakrishna
- Primary IDCCT6010
- Secondary IDsNCI-2025-00267
- ClinicalTrials.gov IDNCT06500819