Safety and Efficacy of PRG-1801 in Recurrent/Refractory Immune Thrombocytopenia (ITP)

This is a single center, open-label, 3+3 dose escalation, early phase 1 study to evaluate the safety, tolerability, and preliminary efficacy of PRG-1801 for patients with relapsed/refractory immune thrombocytopenia (ITP).

This investigator-initiated clinical study aims to evaluate PRG-1801, a BCMA-targeted CAR-T cell therapy, in patients with relapsed refractory immune thrombocytopenia (ITP). The study employs a dose-escalation design to assess safety, tolerability, and preliminary efficacy.

Approximately 1 sites are planned to be selected for the clinical trial. The subjects, who sign the informed consent forms and been screened by inclusion/exclusion criteria, will be assigned into 35×10\^6, 100×10\^6, and 300×10\^6 CAR-T cells groups in order of sequence. And the subjects will undergo leukapheresis, lymphodepletion pre-treatment, and a single infusion of PRG-1801. Dose escalation will follow 3 + 3 design and 3-6 subjects in each group will complete a single dose. Within the same dose group, the next subject will be administered after the previous subject has completed at least 14 days of safety observation. After the last subject in each dose group has completed the dose-limiting toxicity (DLT) assessment window of 28 days after single dose, the 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.

When DLT occurs in 1 of 3 subjects in a dose group, 3 additional subjects in the same dose group will be required (up to 6 subjects in the dose group have completed DLT assessment): if no DLT occurs in the additional 3 subjects, dose escalation will continue; if 1 of the 3 additional subjects experiences one DLT, dose escalation will be discontinued; if more than 1 of the 3 additional subjects experiences DLTs, dose escalation will be discontinued, and 3 additional subjects will be required to be enrolled at one lower dose level for DLT assessment. After the end of escalation for the maximum dose group, if no MTD is observed, the highest dose level is defined as the MTD

Eligibility Criteria:
Inclusion Criteria:

* 1. Age ≥18 years, regardless of gender.
* 2. Clinically diagnosed with primary immune thrombocytopenia for at least 6 months, with a platelet count \<30×10\^9/L within 48 hours before participating in the study.
* 3. Positive for anti-platelet glycoprotein autoantibodies (such as GPIIb/IIIa).
* 4. 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) and/or rituximab, etc.), but the treatment was ineffective (platelet count \<30×10\^9/L after treatment, or platelet count did not increase to twice the baseline value, or there was bleeding), or relapsed after effective treatment (platelet count dropped below 30×10\^9/L after effective treatment, or dropped to less than twice the baseline value, or bleeding symptoms occurred) or difficult to maintain after stopping TPO receptor agonists.
* 5. Bone marrow examination shows increased or normal megakaryocytes.
* 6. Basic normal function of important organs:

  * Echocardiography indicates an ejection fraction ≥50%, and the electrocardiogram shows no significant abnormalities.
  * Creatinine clearance rate (CrCl) (Cockcroft-Gault formula) ≥30 mL/min.
  * Alanine transaminase (ALT) and aspartate transaminase (AST) ≤3.0× the upper limit of normal (ULN).
  * Total bilirubin (TBIL) and alkaline phosphatase (AKP or ALP) ≤2.0×ULN (Gilbert's syndrome ≤ 3.0×ULN).
  * Absolute lymphocyte count (ALC) ≥0.5×10\^9/L; absolute neutrophil count (ANC) ≥1×10\^9/L; hemoglobin (Hb) ≥60 g/L; platelet count ≥10×10\^9/L.
  * Blood oxygen saturation \>92%.
* 7. Meet the standards for apheresis or venous blood collection, and have no contraindications to cell collection.
* 8. Men of reproductive potential and women of childbearing age must agree to use effective contraception from the signing of the informed consent form until 1 year after the use of the study drug. Blood pregnancy tests for women of childbearing age must be negative at screening and before cell infusion, and they must not be breastfeeding.
* 9. The participant or their guardian agrees to participate in this clinical trial and signs the informed consent form (ICF), indicating their understanding of the purpose and procedures of this clinical trial and their willingness to participate in the study.

Exclusion Criteria:

* 1. Thrombocytopenia caused by myelodysplastic syndromes, early aplastic anemia, atypical aplastic anemia, thrombotic thrombocytopenic purpura, etc.
* 2. Bone marrow examination during the screening period suggests myelofibrosis MF≥2 (European consensus scoring standard Thieleja2005) or bone marrow examination indicates the presence of primary diseases other than ITP that can cause thrombocytopenia.
* 3. Allergic history to any component in the cell product.
* 4. Suffering from any of the following heart diseases:

  * Congestive heart failure of NYHA class III or IV.
  * Myocardial infarction or coronary artery bypass grafting (CABG) or coronary stent implantation within ≤6 months before signing the ICF.
  * Clinically significant ventricular arrhythmias, or history of unexplained syncope (excluding vasovagal syncope or dehydration).
  * Severe non-ischemic cardiomyopathy history.
* 5. Malignant tumors within the past 3 years before screening, except for the following: malignant tumors that have been treated radically and have no known active disease for ≥3 years before enrollment; or well-treated non-melanoma skin cancer with no evidence of disease.
* 6. Symptomatic deep vein thrombosis or pulmonary embolism within the past 6 months or currently requiring anticoagulant therapy.
* 7. Participation in other interventional clinical studies within 1 month before screening.
* 8. Vaccination with attenuated live vaccines within 4 weeks before screening.
* 9. Stroke or epileptic seizure within 6 months before signing the ICF (excluding old lacunar cerebral infarction).
* 10. The following treatments before CAR-T reinfusion: immunosuppressive treatment within 3 days; use of prednisone (or equivalent drugs) at a dose \>10mg/day within 3 days.
* 11. The following treatments before CAR-T reinfusion: treatment with B-cell depleting agents such as rituximab within 24 weeks (unless B cells have recovered); immunoglobulin reinfusion treatment within 4 weeks.
* 12. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and peripheral blood hepatitis B virus (HBV) DNA titer detection exceeds the normal range; positive for hepatitis C virus (HCV) antibody and peripheral blood hepatitis C virus (HCV) RNA titer detection exceeds the normal range; positive for human immunodeficiency virus (HIV) antibody; positive syphilis test.
* 13. Other conditions deemed unsuitable for participation in the study by the researcher.