A Clinical Study Evaluating the Safety and Preliminary Efficacy of Universal Allogeneic CAR T-cell Therapy Targeting CD19 and BCMA(QT-019C)in Patients With Refractory Primary Immune Thrombocytopenia

This study is a single-arm, open-label clinical trial aimed at evaluating the safety, tolerability, and efficacy of QT-019C in patients with refractory primary ITP, and obtaining pharmacokinetic(PK) and pharmacodynamic(PD) data. The study comprises two phases: dose escalation and dose expansion， and plans to recruit 10 to 27 participants. Dose escalation will follow a 3 + 3 design, and 10 to 21 participants will be included in this phase. Four dose groups (Group A, Group B, Group C, and Group D) will be set up. Participants who sign the informed consent forms and have been screened by inclusion/exclusion criteria will undergo leukapheresis, lymphodepletion pre-treatment, and a single infusion of QT-019C. Participants will undergo regular checks to evaluate the safety and tolerability of the treatment, along with data on PK, PD, and preliminary efficacy. After the last subject in each dose group has completed the dose-limiting toxicity (DLT) assessment window of 28 days after a single dose, enrollment and treatment for the next dose group may be initiated after the Safety Review Committee (SRC) agrees to enter the next dose group based on clinical safety data assessment. After the dose escalation is completed, the SRC will determine whether to conclude the study or select a dose level or dose range as the recommended dose (RD) for a dose expansion study based on the conditions of the dose escalation phase. 6 participants will be included in this phase for further assessment of QT-019C's safety and early efficacy. All participants will complete a follow-up up to 24 months.

Inclusion criteria

• 1. Participants aged ≥18 years and ≤75 years, regardless of gender.
• 2. Clinically diagnosed with primary immune thrombocytopenia for no less than 6 months, with platelet counts < 30×10^9/L in two separate tests conducted within 15 days before the initiation of study treatment, with at least 7 days between the tests.
• 3. Presence of any anti-platelet glycoprotein autoantibody (GPIb/GPIX/GPIIb/GPIIIa/GMP140) positive.
• 4. Meet the criteria for refractory ITP: previously received first-line and/or second-line ITP treatment (first-line treatment includes corticosteroids or immunoglobulins; second-line treatment includes thrombopoietin receptor agonists (such as eltrombopag, romiplostim), rituximab, splenectomy, etc.), but ineffective (post-treatment platelet count <30×10^9/L, or platelet count increase less than twice the baseline value, or presence of bleeding), or relapse after initial response or difficult to maintain after discontinuation.
• 5. Important organ functions are basically normal during the selection period:

• Echocardiogram indicates ejection fraction >50%, ECG shows no significant abnormalities;
• Creatinine clearance (CrCl) (Cockcroft-Gault formula) >30 mL/min;
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3.0x the upper limit of normal (ULN);
• Total bilirubin (TBIL) and alkaline phosphatase (AKP or ALP) <2.0x ULN (Gilbert's syndrome <3.0x UN);
• Absolute lymphocyte count (ALC) >0.5x10^9; absolute neutrophil count (ANC) >1x10^9; hemoglobin (Hb) >60g;
• Oxygen saturation >92%.
• 6. Female participants of childbearing potential and male participants who are partners of women of childbearing age must use medically accepted contraceptive measures or abstain for at least 12 months during and after the study treatment; female participants of childbearing age must have a negative serum HCG test within 7 days before study enrollment and must not be breastfeeding.
• 7. Volunteer to participate in this clinical study, sign informed consent, demonstrate good compliance, and cooperate with follow-up.

Exclusion criteria

• 1. Secondary thrombocytopenia caused by myelodysplastic syndromes, splenic hyperfunction, autoimmune diseases, early aplastic anemia, atypical aplastic anemia, and thrombotic thrombocytopenic purpura, among other causes.
• 2. Bone marrow examination results during the screening phase indicate bone marrow fibrosis MF>2 (European expert consensus scoring criteria for bone marrow fibrosis, Thiele et al., 2005) or the bone marrow examination suggests the presence of other primary conditions causing thrombocytopenia aside from ITP.
• 3. History of any of the following heart diseases:

• NYHA class II or IV congestive heart failure;
• Myocardial infarction within 6 months before signing the ICF, or having undergone coronary artery bypass grafting (CABG) or coronary artery stent implantation;
• Clinically significant ventricular arrhythmias or a history of unexplained syncope (excluding cases caused by vasovagal or dehydration);
• History of severe non-ischemic cardiomyopathy.
• 4. Patients who have previously received gene-modified cell therapies such as TCR-T, CAR-T, CAR-NK, etc.
• 5. Patients who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA levels exceeding the upper limit of detection; those who are positive for hepatitis C virus (HCV) antibodies and have positive peripheral blood HCV RNA; those who are positive for human immunodeficiency virus (HIV) antibodies; and those who test positive for syphilis.
• 6. Subjects who have received the following drug treatments before the start of the study will be excluded:

• B-cell and antibody-secreting cell (ASC) depletion therapy:

i. Subjects who have received anti-CD20 monoclonal antibody treatment (such as rituximab) within 3 months before screening will be excluded. If such treatment occurred more than 3 months but not more than 6 months before screening, and if the absolute count of peripheral blood CD19⁺ B cells is above the lower limit of normal (as determined by local or central laboratory), then enrollment may be allowed after confirmation by the investigator and the medical director of the sponsor (or designated representative).

ii. Subjects who have previously received simultaneous CD19-targeting and BCMA-targeting treatments will be excluded. Subjects who have received CD19-targeting or BCMA-targeting treatment (either one) within 6 months before screening will also be excluded. If such treatment occurred more than 6 months before screening, and if the absolute count of peripheral blood CD19⁺ B cells is above the lower limit of normal (as determined by local or central laboratory), then enrollment may be allowed after confirmation by the investigator and the medical director of the sponsor (or designated representative).

iii. Subjects who have used or adjusted the dosage of BTK and SyK inhibitors within 2 weeks before screening should be excluded. If the dosage has been stable for ≥ 2 weeks before screening, then they may be included.

• Subjects who have used or adjusted TPO-RA treatment within 2 weeks before screening should be excluded. However, those who have been on a stable dose for more than 2 weeks before screening may continue treatment.
• Subjects who have used IVIG or undergone plasma exchange within 4 weeks before screening should be excluded.
• Subjects who have used immunosuppressants (such as cyclophosphamide, mycophenolate mofetil (MMF), azathioprine, and methotrexate) within 2 weeks before lymphocyte depletion will be excluded.
• 7. Subjects who have used prednisone > 10 mg/day or have had dosage adjustments within 2 weeks before screening. Oral glucocorticoid treatment equivalent to ≤ 10 mg/day of prednisone is acceptable at enrollment, provided the dosage has been stable for at least 2 weeks before enrollment.
• 8. Subjects with a history of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before screening, or who currently require anticoagulation therapy.
• 9. Subjects with a history of any organ system malignancy (except well-prognosed tumors such as localized basal cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of the breast, follicular or papillary thyroid carcinoma, etc.) within the past 5 years, regardless of whether there is evidence of local recurrence or metastasis; or known concomitant life-threatening diseases.
• 10. Subjects with any active infection or any infection requiring systemic anti-infective treatment within 30 days before screening.
• 11. Any known factors, diseases, or clinically relevant medical conditions or surgical situations that the investigator believes may place the subjects at risk, interfere with treatment compliance, study implementation, or outcomes.