Evaluate the Safety, Efficacy and Pharmacokinetics of ThisCART19A in Patients With R/R B-ALL

Study Overview
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Brief Summary
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This is an open label, phase I study to assess the safety, efficacy and pharmacokinetics of ThisCART19A in patients with relapsed and refractory acute B-cell leukemia

Official Title
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To Evaluate the Safety, Efficacy and Pharmacokinetics of ThisCART19A in Patients With Relapsed and Refractory Acute B-cell Leukemia

Conditions
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B-ALL

Intervention / Treatment
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* Biological: ThisCART19A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects or legal representatives must sign a voluntary letter of consent approved by the IRB in person prior to the commencement of any screening procedure; Patients diagnosed with B-ALL according to the Chinese Guidelines for the Diagnosis and Treatment of Adult Acute Lymphoblastic Leukemia (2021 edition); There is no gender limitation, age 18-65 (upper limit not included); Consistent with the diagnosis of recurrent refractory B-ALL. Recurrence： was defined as the recurrence of lymphoblasts（≥5%） in peripheral blood or bone marrow or extramedullary diseasefor patients who had acquired CR ; Refractory ：was defined as failure to CR or CRi at the end of induction therapy (generally referred to 4-week regimen or Hyper-CVAD regimen);Patients with Ph+ R/R ALL who failed after 2-line TKI treatment, were intolerant to TKI treatment or were not suitable for TKI treatment; The following factors can coexist: A) Failure to prepare autologous CAR-T (definition: too few autologous lymphocytes [200/ML] or cannot meet the release standard); B) Experienced treatment with auto car-T/berintoomumab/ CD22 antibody conjugation drugs; C) ≥100 days after hematopoietic stem cell transplantation; D) high-risk patients (High risk was defined as a high white blood cell count ≥30×109/L at diagnosis or with poor cytogenetic prognosis); Hypodiploid (<44 chromosomes); KMT2A rearrangement: t (4;11) or otherwise; t (v;q32)/IgH; t (9;22) (q34;q11.2) or BCR-ABL1; Complex karyotype (≥5 chromosomal abnormalities); BCR-ABL1-like (Ph-like) ALL; JAK-STAT (CRLF2r, EPORr, JAK1/2/3r, TYK2r, mutations of SH2B3, IL7r, Jak1/2/3 ); ABL class( rearrangement of ABL1, ABL2, PDGFRA, PDGFRB, FGFR); Other (NTRKr, FLT3r, LYNr, PTK2Br); Intrachromosomal amplification of chromosome 21 (IAMP21-ALL); t (17;19) : TCF3-HLF fusion ; Alterations of IKZF1; E) Extramedullary lesions. The expected survival time is ≥12 weeks; ECOG score 0-1; Had good organic function during screening CD19 was still expressed in leukemia cells in bone marrow, peripheral blood or biopsy tissue by flow cytometry within one month prior to informed consent (after the last treatment). Exclusion Criteria: Allergic to preconditioning measures. Patients with other malignancies other than B-cell malignancies within 5 years prior to screening. Patients with cured skin squamous carcinoma,basal carcinoma, non-primary invasive bladder cancer, localized low-risk prostate cancer, in situ cervical/breast cancer can be recruited. Uncontrollable bacterial, fungal and viral infection during screening. Patients had pulmonary embolism within 3 months prior to enrollment. Had intolerant severe cardiovascular and cerebrovascular diseases and hereditary diseases prior to enrollment. Imaging confirmed the presence of central nervous system involvement (both primary and secondary) and obvious symptoms at the time of screening. Active HBV or HCV or HIV or Syphilis infection. HBV-DNA < 2000 IU/mL can be enrolled, but should admitted to use anti-virus drugs such as entecavir, tenufovir, etc, and supervisory the relative indication during the treatment. Combined systemic steroid use (e.g., prednisone ≥20mg) within 3 days prior to screening. Or systemic diseases that require long-term use of immunization Inhibitor. Vaccinated with influenza vaccine within 2 weeks prior to cleansing (SARS-COV19 can be included, inactivated, live/non-live adjuvant vaccinations allowed to be included) . Patients who are receiving GvHD treatment; Patients without GvHD and who had stopped immunosuppressive drugs for at least 1 month were eligible for inclusion. Women who are in pregnant or lactating, and female subjects or partners who plan to be pregnant within 1 year after cell infusion. Male subjects who plan pregnancy within 1 year after infusion. Any ineligibility conditions considered by the investigator that may increase the risk of the subject or interfere with the results of the study;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ThisCART19A 5×10^6 cells/kg for dose level 1<br>Patients will receive 5×10^6 cells/kg of ThisCART19A | Biological: ThisCART19A<br>* ThisCART19A is a new type CAR-T cells therapy for patients with acute B-cell leukemia<br>|
| Experimental: ThisCART19A 8×10^6 cells/kg as dose level 2<br>Patients will receive 8×10^6 cells/kg of ThisCART19A | Biological: ThisCART19A<br>* ThisCART19A is a new type CAR-T cells therapy for patients with acute B-cell leukemia<br>|
| Experimental: ThisCART19A 12×10^6 cells/kg as dose level 3<br>Patients will receive 12×10^6 cells/kg of ThisCART19A | Biological: ThisCART19A<br>* ThisCART19A is a new type CAR-T cells therapy for patients with acute B-cell leukemia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limited toxicity(DLT) observation and the incidence of treatment-emergent adverse events(TEAE) which more than or equal to grade 3 in each dose level | DLT is defined as the incidence of severe adverse events related to ThisCART19A more than 33% in each dose level. | 28 days | 
| The incidence of all grade TEAEs and ≥3 grade TEAEs | Incidence of treatment-emergent adverse events (TEAEs) and ≥3 grade TEAEs | Up to 2 years after ThisCART19A infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Objective response rate (ORR = CR + CRi) of ThisCART19A within 3 months after administration | At Month 1, 2, 3 | 
| The change characteristics of chimeric antigen receptor(CAR)-T cell number and copy number in patients after infusion | Track CAR-T cells expansion in patients after infusion by flow cytometry and qPCR | 3 months | 
| Changes in cytokine level after ThisCART19A infusion. | Calculate the change of cytokine level in peripheral blood by flow cytometry after ThisCART19A infusion. Cytokines include IL-1β、IL-2、IL-4、IL-6、IL-8、IL-10、IL-12、IL-17、TNF-α、IFN-γ、TGF-β. | 3 months | 
| Changes in immune effect cells count after ThisCART19A infusion. | Calculate the change of immune effect cells count in peripheral blood by flow cytometry after ThisCART19A infusion. Immune effect cells include T cell, B cell, NK cell. | 3 months | 
| MRD response rate | Percentage of participants with minimal residual disease (MRD) response in patients with CR (complete response) and CRi (CR with incomplete blood count recovery) ; MRD Response is defined as leukemic cells in bone marrow <0.01% by flow cytometry (sensitivity at least 0.001%) | 24 months |