Safety and Efficacy of ThisCART19A Bridging Hematopoietic Stem Cell Transplantation in Patients With Refractory or Relapsed B-cell Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This is a a phase 1, open label study to assess the safety and efficacy of ThisCART19 (Allogeneic CAR-T targeting CD19) Bridging Hematopoietic Stem Cell Transplantation in patients with refractory or relapsed B cell acute lymphoblastic leukemia (r/r B-ALL).

Detailed Description
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This is a phase 1, single-center, nonrandomized, open-label, dose-escalation study to evaluate the safety and efficacy of ThisCART19A Bridging Hematopoietic Stem Cell Transplantation in patients with CD19 positive r/r B-ALL and identify a treatment regimen most likely to result in clinical efficacy while maintaining a favorable safety profile.

Official Title
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A Single Dose-escalation Study to Evaluate the Safety and Efficacy of Allogeneic CAR-T Targeting CD19 Bridging Hematopoietic Stem Cell Transplantation in Patients With Refractory or Relapsed B Cell Acute Lymphoblastic Leukemia

Conditions
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Allogeneic, CAR-T, Protein Sequestration, Non-gene Edited

Intervention / Treatment
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* Drug: ThisCART19A
* Drug: Fludarabine Oral Tablet
* Drug: Cyclophosphamide
* Drug: VP-16
* Procedure: HSCT


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; No gender limitation, Age 14 years to 75 years (both upper and lower limits 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: Failure to prepare autologous CAR-T (definition: too few autologous lymphocytes [200/ML] or cannot meet the release standard); Experienced treatment with auto car-T/berintoomumab/ CD22 antibody conjugation drugs; ≥100 days after hematopoietic stem cell transplantation; 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; 14q32) /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 rearrangements (such as ABL1, ABL2, PDGFRA, PDGFRB, FGFR, etc.) Others (NTRKr, FLT3r, LYNr, PTK2Br); Intrachromosomal amplification of chromosome 21 (iAMP21); t (17; 19): TCF3-HLF fusion; Alterations of IKZF1; Extramedullary lesions. The expected survival time is ≥12 weeks; ECOG score 0-2; Adequate bone marrow, renal, hepatic, pulmonary and cardiac function; 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; Diagnosis of chronic myelogenous leukemia lymphoid blast crisis; Isolated extramedullary relapse; Presence of CNS-3 disease or CNS-2 disease with neurological changes; Imaging confirmed the presence of central nervous system involvement; Severe CNS disorders such as a history of frequent epileptic seizures; 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 (PE) and/or deep vein thrombosis (DVT) within 3 months prior to enrollment; Had intolerant severe cardiovascular and cerebrovascular diseases and hereditary diseases prior to enrollment; Radiation therapy within 2 weeks prior to lymphodepletion chemotherapy (>30% bone marrow exposure); Active hepatitis B virus (HBV) or hepatitis C virus (HCV) or Human immunodeficiency virus (HIV) or Syphilis infection. HBV-DNA < 2000 IU/mL can be enrolled, but should admitted to use anti-virus drugs such as entecavir, tenofovir, etc, and supervisory the relative indication during the treatment; Vaccinated with influenza vaccine within 2 weeks prior to lymphodepleting chemotherapy (Severe Acute Respiratory Syndrome-Corona virus disease 19 can be included, inactivated, live/non-live adjuvant vaccinations allowed to be included) ; Patients who are receiving Graft versus host disease Hepatitis(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: 14 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ThisCART19A cells infusion and HSCT<br>In this study, allogeneic anti-CD19 CAR T cell (ThisCART19A) infusion is used to treat patients with refractory or relapsed CD19 positive B cell acute lymphoblastic leukemia. After patients achieve MRD- remissions through ThisCART19A, they will subsequently receive hematological stem cell transplantations. | Drug: ThisCART19A<br>* ThisCART19A is a new type CAR-T therapy for patients with r/r B-ALL.<br>Drug: Fludarabine Oral Tablet<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>Drug: VP-16<br>* VP-16 is used for lymphodepletion.<br>* Other names: etoposide;Procedure: HSCT<br>* Hematological stem cell transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limited toxicity(DLT) observation in patient with B-ALL in each dose level during dose escalation and dose expansion stage | DLT is defined as the incidence of severe adverse events related to ThisCART19A more than 33% in each dose level. | 28 days | 
| Overall Complete Response (OCR) Rate (Complete Remission [CR]+ Complete Remission With Incomplete Hematologic Recovery [CRi]) within 3 months | OCR rate within 3 months: percentage of participants achieving CR+CRi within 3 months after CAR-T cell infusion. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Residual Disease (MRD) Negative Remission Rate | MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10^-4. MRD negative remission was defined as MRD < 10^-4 threshold. Percentage of participants with MRD negative remission was reported. | 3 months | 
| Duration of response(DOR) during dose escalation stage and expansion stage | DOR was defined as the time from first CR or CRi to relapse or any death in the absence of documented relapse. | 24 months | 
| RFS (Relapse-free Survival) | RFS is defined as the time from the date of ThisCART19A infusion to the date of disease relapse or death from any cause. | 24 months | 
| EFS (Event-free Survival) | EFS is defined as the time from the date of ThisCART19A infusion to the date of disease relapse, progression, genetic relapse or death from any cause. | 24 months | 
| OS (Overall Survival) | OS is defined as the time from the date of ThisCART19A infusion to the date of death from any cause. | 24 months |