A Study of pCAR-19B in the Treatment of CD19-positive Relapsed/Refractory B-ALL in Children and Adolescents

Study Overview
=================
Brief Summary
-----------------
This is a phase II clinical study to evaluate the safety and efficacy of pCAR-19 B cell autologous infusion preparation in the treatment of CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia.

Detailed Description
-----------------
This is a multiple-center, single-arm, open-label study. After meeting the eligibility criteria and enrolling on the trial, patients will undergo leukapheresis for collection of autologous lymphocytes. Once cells have been manufactured, patients will then proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 for 3 consecutive days followed by the infusion of CD19 CAR T-cells at a target dose of 0.6-2 x106 cells/kg.

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

Conditions
-----------------
Acute Lymphoblastic Leukemia, Relapsed Pediatric ALL, Refractory Acute Lymphoblastic Leukemia

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient himself or his guardian agrees to participate in this clinical trial and signs the Informed Consent Form (ICF), indicating that he understands the purpose and procedures of this clinical trial and is willing to participate in the research; Diagnosed with B-ALL，and meet one of the following conditions: Refractory B-ALL: early-stage refractory patients who failed to achieve complete remission after 2 courses of standard induction chemotherapy; Relapsed B-ALL: patients with early relapse (<12 months) after complete remission;or late relapse (≥12 months) after complete remission, and relapsed patients who have not achieved complete remission after standard treatment or have poor response to early treatment; experience Patients with 2 or more bone marrow recurrences; patients with recurrence after allogeneic hematopoietic stem cell transplantation; For Ph+ALL patients, patients who have not achieved complete remission after receiving at least two Tyrosine kinase inhibitors (TKI) treatments or have relapsed after complete remission (except those who cannot tolerate TKI treatment or have contraindications to TKI treatment or have T315i mutation resistance to TKI drugs); The malignant cells in the bone marrow were confirmed to express CD19 by flow cytometry; Bone marrow morphology at the time of screening indicated that blasts≥ 5%; Eastern Cooperative Oncology Group (ECOG) 0-1 points ; Expected survival is ≥ 12 weeks; The function of important organs is basically normal: Cardiac function: echocardiography showed cardiac ejection fraction ≥50%, and no obvious abnormality was found on electrocardiogram; Renal function: serum creatinine≤2.0×ULN; Liver function: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤5.0×ULN; Total bilirubin≤2.0×ULN (for Gilbert syndrome, total bilirubin≤3.0×ULN); Blood oxygen saturation≥92% in non-oxygen state. No serious mental disorder; Have apheresis or venous blood collection standards, and have no other contraindications for cell collection; Subjects of childbearing age agree to use reliable and effective contraceptive methods for contraception (excluding rhythm contraception) from signing the informed consent to receiving pCAR-19B cell infusion within 1 year. Exclusion Criteria: Relapse of isolated extramedullary disease; Active central nervous system leukemia at screening, defined as Central Nervous System (CNS)-grade 2 and 3 according to National Comprehensive Cancer Network (NCCN) guidelines (note: those with central nervous system involvement but improved after treatment can be included); Those who have received CAR-T therapy or other gene-modified cell therapy before screening; Received anti-CD19 drug treatment before screening; Received the following anti-tumor treatments before screening: Received chemotherapy, targeted therapy and other drug treatments within 14 days or at least 5 half-lives (whichever is shorter); Received radiotherapy within 14 days; HBsAg or HBcAb positive and hepatitis B virus (HBV) DNA is greater than the normal range; hepatitis C virus (HCV) antibody is positive and HCV RNA greater than the normal range; HIV antibody positive; syphilis positive; Cytomegalovirus (CMV) DNA positive; Have any of the following heart conditions: New York Heart Association (NYHA) stage III or IV congestive heart failure; Myocardial infarction or coronary artery bypass grafting within 6 months prior to enrollment (CABG); Clinically significant ventricular arrhythmia, or history of syncope of unknown origin (by vasovagal except those caused by menstruation or dehydration); History of severe non-ischemic cardiomyopathy; Active infection or uncontrollable infection requiring systemic treatment within 1 week before screening; The presence of grade 2-4 acute graft-versus-host disease (GVHD) or moderate to severe chronic GVHD within 4 weeks before screening; Cerebrovascular accident or epileptic seizure within 6 months 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; Received live attenuated vaccine within 4 weeks before screening; Participated in other interventional clinical studies before screening, including: the last use of unmarketed new drugs is less than 3 months from the time of cell reinfusion, or the last use of marketed drugs is less than 5 half-lives from the time of cell reinfusion; 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 investigators deem it inappropriate to participate in the study.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 21 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 of 0.6-2 x106 cells/kg | 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 |
| --- | --- | --- |
| Objective response rate after pCAR-19B infusion [Effectiveness] | Objective response rate includes CR, CRi. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal residual disease（MRD） | MRD-negative ORR within 3 months by flow cytometry as assessed by Independent Review Committee (IRC) and investigator. | 3 months | 
| Best overall response after pCAR-19B infusion [Effectiveness] | Best overall response means the proportion of patients with the best efficacy (CR or CRi) after pCAR-19B cell therapy. | 2 years | 
| Overall survival after pCAR-19B infusion [Effectiveness] | Overall survival means the time from infusion of pCAR-19B cells to death of subjects from any cause | 2 years | 
| Duration of response after pCAR-19B infusion [Effectiveness] | Duration of response means the time from first assessment of CR or CRi to first assessment of disease recurrence or death from any cause, whichever occurs first | 2 years | 
| Relapse free survival after pCAR-19B infusion [Effectiveness] | Relapse free survival means time from subject infusion of pCAR-19B cells to first disease relapse or death from any cause (whichever occurs first) | 2 years | 
| Event free survival after pCAR-19B infusion [Effectiveness] | Event free survival means the time from the infusion of pCAR-19B cells to the time of the following events (whichever occurs first): Death from any cause after remission; Disease recurrence; Withdrawal from the clinical trial after treatment failure or meeting the withdrawal criteria. | 2 years | 
| The incidence of Treatment Emergent Adverse Events (TEAE) of pCAR-19B infusion | Number of participants with adverse events as assessed by CTCAE v5.0 | 2 years | 
| the incidence of adverse events related to treatment of pCAR-19B infusion | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | 2 years | 
| the incidence of adverse event of special interest (AESI) of pCAR-19B infusion | Number of participants with special interest adverse events as assessed by CTCAE v5.0,The following adverse events were defined as adverse events of special interest for this study: Cytokine release syndrome (CRS) of grade 3 and above; Immune effector cell-associated neurotoxicity syndrome (ICANS) of grade 3 and above; Grade 3 and above infection; Grade 3 and above acute tumor lysis syndrome; Unresolved cytopenias lasting 28 days. | 2 years | 
| the incidence of RCL of pCAR-19B infusion | RCL Detection: the incidence of Replication Competent Lentivirus. | 2 years | 
| Pharmacokinetic data parameters of Cmax | Analysis using CAR DNA copy number measured by qPCR: the highest concentration of pCAR-19B cells expanded in peripheral blood after administration | 3 months | 
| Pharmacokinetic data parameters of Tmax | Analysis using CAR DNA copy number measured by qPCR: the time to reach the highest concentration; | 3 months | 
| Pharmacokinetic data parameters of AUC0-90d | Analysis using CAR DNA copy number measured by qPCR: Area under the curve at 28 days and 90 days. | 3 months | 
| Pharmacodynamics data parameters of the degree of clearance | The degree of clearance of CD19-positive B cells at different blood collection time points after cell infusion | 3 months | 
| Pharmacodynamics data parameters of CAR-T-related serum cytokines | the concentration levels of IL-6 at each time point. | 3 months | 
| Immunogenicity of pCAR-19B cells | Analysis using anti-CAR antibodies measured by Meso Scale Discovery（Electrochemiluminescence） | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
B-ALL, CAR-T, CD19