A Study of CNCT19 Treatment in Children and Adolescent r/r ALL Patients(Pediatric)

Study Overview
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Brief Summary
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This is a multi-center, phase Ib/II trial to evaluate the safety and efficacy of CNCT19 treatment in Children and Adolescent (pediatric) patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-cell ALL).

Detailed Description
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This trial is a multi-center, open label, single-arm, phase Ib/II trial to evaluate the safety and efficacy of CNCT19 in Children and Adolescent(aged 3 18 years old) patients (pediatric) with r/r B-cell ALL. The phase Ib part of the trial is to evaluate the safety, optimal dose of CNCT19, Pharmacokinetics/Pharmacodynamics(PK/PD)and preliminary efficacy in the treatment of Children and Adolescent patients with r/r B-cell ALL. The phase II part of the trial is to evaluate the efficacy and safety of CNCT19 in in the treatment of Children and Adolescent patients with r/r B-cell ALL. The study includes screening, pre-treatment (Cell Product manufacture & lymphodepletion), CNCT19 infusion , safety and efficacy follow-up, and survival follow-up. All subjects who have received CNCT19 infusion will be followed for up to 2 years.

Official Title
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A Phase Ib/II, Single Arm, Multi-center Study Evaluating the Safety and Efficacy of CNCT19 in Children and Adolescent(Pediatric) Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r B-ALL)

Conditions
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B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: single dose of CNCT19


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed written informed consent prior to any study procedures (patient and/or parent or legal guardian) Age 3 to 18. Weight ≥10kg Relapsed or refractory acute lymphoblastic leukemia (ALL). Documentation of CD19 tumor expression demonstrated in bone marrow or peripheral blood within 3 months before screening. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening. Karnofsky (age ≥ 16 years) performance status ≥ 70 or Lansky (age < 16 years) performance status ≥ 50 at screening Organ function requirements: All patients must have adequate renal and liver functions Key Exclusion Criteria: Active Central Nervous System (CNS) involvement by malignancy. Isolated extra-medullary disease relapse. Patients with Burkitt's lymphoma/leukemia, mixed phenotypic acute leukemia and Chronic Myelogenous Leukemia in Blast Crisis History of concomitant genetic syndrome Patients with acute graft-versus-host disease (GVHD) or moderate-to-severe chronic GVHD within 4 weeks before screening. Active systemic autoimmune disease Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive). Patients with active infections at screening. Patients who received specified chemotherapy before CNCT19 infusion Radiotherapy before CNCT19 infusion: Non-CNS site of radiation completed < 4 weeks prior to CNCT19 Infusion; CNS directed radiation completed < 8 weeks prior to CNCT19 infusion. Donor lymphocyte infusion (DLI) must be stopped > 6 week prior to CNCT19 infusion. Has had treatment with any prior CAR-T therapy. Life expectancy < 3 months.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose of CNCT19<br>A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, CNCT19. | Biological: single dose of CNCT19<br>* Autologous 2nd generation CD19-directed CAR-T cells, single infusion intravenously. Lymphodepletion treatment: Drugs:Fludarabine Drugs: Cyclophosphamide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Remission Rate (ORR) | ORR is defined as Complete Remission (CR) and Complete Remission with Incomplete Blood Count Recovery (CRi) per NCCN classification, as determined by Independent Review Committee (IRC) | within 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall complete Remission Rate (ORR) with minimal residual disease (MRD) negativity as determined by IRC and Investigators | MRD negativity status as determined using flow cytometry | within 3 months | 
| Overall Remission Rate (ORR) as determined by IRC and Investigators | The Investigators' evaluation results of ORR will be utilized in the sensitivity analysis | at the end of month 3 | 
| Overall Remission Rate (ORR) with minimal residual disease (MRD) negativity as determined by IRC and Investigators | MRD negativity as determined using flow cytometry | at the end of Month 3 | 
| Best overall response (BOR) | The proportion of patients who have achieved the best response (CR or CRi) after CNCT19 treatment | up to 2 years | 
| Duration of remission (DOR) | DOR is defined as the time between their first complete response per independent review to relapse or any death in the absence of documented relapse | to data cutoff date | 
| Allogeneic Stem Cell Transplant (Allo-SCT) rate | The proportion of patients who have received Allo-SCT after CNCT19 treatment | First infusion date of CNCT19 to data cutoff date(up to 2 years) | 
| Relapse Free Survival (RFS) | RFS is defined as the time from the CNCT19 infusion date to the date of disease relapse or death from any cause. | 2 years | 
| Overall survival (OS) | OS is defined as the time from the CNCT19 Cell Injection infusion to the date of death from any cause | 2 years | 
| Treatment-Emergent Adverse Events | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAE) and Severity of TEAE | up to 2 years | 
| Percentage of Participants Experiencing Clinically Significant Laboratory Abnormalities | Clinically significant laboratory abnormalities were defined as per investigator's discretion | From CNCT19 infusion to date of data cutoff (maximum: 2 years) | 
| In vivo cellular Pharmacokinetic (PK) profile of CNCT19 | To characterize the concentration of CAR-T cell in peripheral blood, bone marrow and cerebral spinal fluid (CSF, if available)by Flow Cytometry and quantitative polymerase chain reaction(qPCR). | Up to 3 months(BM sample); Up to 2 years(Blood sample) | 
| Pharmacokinetic (PK)- Cmax of CNCT19 | Maximum detected concentration of CNCT19 in peripheral blood | Up to 2 years | 
| Pharmacokinetic (PK)- Tmax of CNCT19. | Time to maximum concentration of CNCT19 in peripheral blood | Up to 2 years | 
| Pharmacokinetic (PK)- AUC of CNCT19. | Area under the concentration (AUC) vs time curve of CNCT19 in peripheral blood | Up to 2 years | 
| Concentration of Cytokines in Serum | Collected as pharmacodynamic data, including IL-6 at least | 28 days | 
| Percentage of participants with anti-CNCT19 antibodies in serum | To characterize prevalence and incidence of humoral immunogenicity to CNCT19 | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNCT19, Cluster of differentiation antigen 19(CD19), CD19-directed CAR-T cells