CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age ≥ 1 and ≤ 24 years.
2. Tissue diagnosis of RMS, ES or DSRCT
3. Expression of B7-H3 in the tumour
4. Relapsed or refractory disease after one or multiple lines of previous treatment.
5. Measurable disease by cross sectional imaging. Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study.
6. At least 3 weeks or 5 half-lives, whichever is shorter, after treatment with agents on other early phase clinical trial.
7. Performance status: Karnofsky (age ≥ 10 years) or Lansky (age \< 10) score ≥ 50%.
8. Creatinine ≤1.5 x Upper Limit of Normal (ULN) for age, if higher, an estimated (calculated) creatinine clearance must be ≥ 60 ml/min/1.73 m2.
9. Left ventricular ejection fraction (LVEF) ≥ 50%
10. Absolute lymphocyte count ≥ 0.25 x 109/L.
11. Women of childbearing potential (WOCBP) must have a negative pregnancy test and agree to comply with the pregnancy reporting requirements of the protocol (if applicable).
12. Written informed consent.

Exclusion Criteria:

1. Patients with only bone marrow detectable disease in the absence of measurable disease by cross sectional imaging.
2. Patients with active, inoperative central nervous system (CNS) disease including leptomeningeal disease.
3. Active hepatitis B, C or HIV infection.
4. Inability to tolerate leukapheresis.
5. Clinically significant systemic illness or medical condition (e.g., significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
6. Any contraindication to lymphodepletion or to the use of Cyclophosphamide or Fludarabine as per the local SmPC.
7. Any contraindication to the use of Anticoagulant Citrate Dextrose Solution.
8. Known allergy to albumin, EDTA or DMSO.
9. Primary immunodeficiency or history of autoimmune disease (e.g., Crohn's, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression /systemic disease modifying agents within the last 2 years.
10. Prior treatment with investigational or approved gene therapy or cell therapy products.
11. Life expectancy \<3 months.
12. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) at time of hBRCA84D CAR T cells infusion.
13. Women who are pregnant or breastfeeding.
14. Patients who have received any live vaccine in the six weeks prior to planned lymphodepletion

Exclusion criteria for the ATIMP infusion:

1. Uncontrolled fungal, bacterial, viral, or other infection. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted if responding to treatment and clinically stable at the time of scheduled hBRCA84D CAR T cell infusion.
2. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) at time of hBRCA84D CAR T cell infusion.

主要终点：Safety of administering the ATIMP · Incidence of grade 3-5 toxicity causally related to the ATIMP, particularly severe cytokine release syndrome and severe neurotoxicity. · 28 days；Number of therapeutic products generated and the number of ATIMPs infused after successful manufacture · Feasibility of generation of the ATIMP as evaluated by the number of therapeutic products generated and the number of ATIMPs infused after successful manufacture. · 28 days
次要终点：Objective response rate；Progression Free Survival (PFS)；Time to Progression (TTP)；Overall survival

• hBRCA84D CAR T cells · EXPERIMENTAL · Treatment with hBRCA84D CAR T cells

MIGHTY is a multicentre, open label, phase 1 clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children, teenagers and young adults aged 1-24 with relapsed or refractory (r/r) rhabdomyosarcoma (RMS), Ewing sarcoma (ES) or desmoplastic small round cell tumour (DSRCT). The study will assess the feasibility of generating the ATIMP and administering hBRCA84D CAR T cells to patients with r/r RMS, ES or DSRCT.