Phase I Study of pCAR-19B in the Treatment of Adult CD19-positive Relapsed/Refractory B-ALL

Study Overview
=================
Brief Summary
-----------------
This is a phase I clinical study to evaluate the safety and tolerability of pCAR-19B in adults with relapsed or refractory B-ALL, and to obtain the maximum tolerated dose of pCAR-19B and phase II Recommended dose.

Detailed Description
-----------------
This is a single-center, single-arm, open-label study. The study plans to set up 3 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 9-18 adults with relapsed or refractory B-ALL.pCAR-19B will be infused to the subject by intravenous infusion.

Official Title
-----------------
A Phase I Clinical Study of Anti-CD19 CAR-T Therapy (pCAR-19B) in the Treatment of Adult CD19-positive Relapsed/Refractory B-ALL

Conditions
-----------------
Acute Lymphoblastic Leukemia, in Relapse, Refractory Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Biological: pCAR-19B cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with B-ALL，and meet one of the following conditions: First-line or multiple-line salvage chemotherapy did not achieve complete remission； Early relapse after complete remission (<12 months), or late relapse after complete remission (≥12 months) and complete remission has not been achieved after 1 course of treatment； Relapse after autologous or allogeneic hematopoietic stem cell transplantation; Ph+ALL patients should also receive at least two TKI treatments； For allogeneic hematopoietic stem cell transplant subjects, the following conditions must be met： Allo-HSCT takes ≥6 months before pCAR-19B infusion； No GVHD of grade 2 or above occurred within 2 weeks before PBMC collection; Express CD19; 22 70 years old, no gender limit; The expected survival time is more than 12 weeks; KPS>60; No serious mental disorders; The function of important organs is basically normal: Heart function: echocardiography indicates that the cardiac ejection fraction is ≥50%, and the electrocardiogram has no obvious abnormalities; Renal function: serum creatinine≤2.0×ULN; Liver function: ALT and AST ≤3.0×ULN; Total bilirubin and alkaline phosphatase≤2.0×ULN (Gilbert syndrome ≤ 3.0×ULN); Blood oxygen saturation>92%. Have standards for apheresis or venous blood collection, and no other cell collection contraindications; The patient himself or his guardian agrees to participate in the clinical trial and signs the ICF, indicating that he understands the purpose and procedures of the clinical trial and is willing to participate in the research. Exclusion Criteria: With central nervous system disease at the time of screening; Have received CAR-T therapy or other genetically modified cell therapy; Participated in other clinical studies within 1 month before screening; Have received the following anti-tumor treatments before screening: received chemotherapy, targeted therapy or other experimental drug treatments within 14 days or at least 5 half-lives (whichever is shorter); Have received a live attenuated vaccine within 4 weeks before screening; Cerebrovascular accident or seizure occurred within 6 months before signing the ICF; Suffered from any of the following heart diseases: NYHA stage III or IV congestive heart failure; Myocardial infarction or CABG occurred ≤6 months before enrollment; Clinically significant ventricular arrhythmia, or history of unexplained syncope (except for cases caused by vasovagal or dehydration); History of severe non-ischemic cardiomyopathy. Uncontrollable infection in the 2 weeks before screening； Active autoimmune diseases； Patients with malignant tumors other than acute lymphoblastic leukemia within 5 years before screening, except for fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical resection, and duct in situ after radical resection cancer； HBsAg or HBcAb positive and HBV DNA is greater than the normal range; HCV antibody is positive and HCV RNA greater than the normal range; HIV antibody positive; syphilis positive; CMV DNA positive; Women who are pregnant or breastfeeding, and male or female subjects who plan to have children within 1 year after receiving pCAR-19B cell reinfusion; Other situations considered by the researcher to be unsuitable to participate in the study.

Ages Eligible for Study
-----------------
Minimum Age: 22 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pCAR-19B cells<br>Infusion of pCAR-19B cells by dose-escalating | Biological: pCAR-19B cells<br>* Drug: pCAR-19B cells； Administration method: intravenous infusion； Subjects will be treated with Fludarabine and Cyclophosphamide before cell infusion.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse events after pCAR-19B infusion [Safety and Tolerability] | Therapy-related adverse events were recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0) | 28 days | 
| Obtain the maximum tolerated dose of pCAR-19B cells[Safety and Tolerability] | Dose-limiting toxicity after cell infusion | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate after pCAR-19B infusion [Effectiveness] | Objective response rate includes CR, CRi | 3 months | 
| AUCS of pCAR-19B cells [Cell dynamics] | AUCS is defined as the area under the curve in 28 days and 90 days | 3 months | 
| CMAX of pCAR-19B cells [Cell dynamics] | CMAX is defined as the highest concentration of pCAR-19B cells expanded in peripheral blood | 3 months | 
| TMAX of pCAR-19B cells [Cell dynamics] | TMAX is defined as the time to reach the highest concentration | 3 months | 
| Pharmacodynamics of pCAR-19B cells[Cell dynamics] | Cytokines such as hs-CRP, IL-6 levels | 3 months | 
| Immunogenicity of pCAR-19B cells | Anti-CAR antibody | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adoptive T Cell Therapy, Chimeric antigen receptor, CD19