A Study of HY004 Treatment in Adult Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r B-ALL)

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, phase I/II trial to evaluate the safety and efficacy of HY004 treatment in Adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-cell ALL).

Detailed Description
-----------------
This trial is a multi-center, open label, single-arm, phase I/II trial to evaluate the safety and efficacy of HY004 treatment in Adult (aged 18 65 years old) patients with r/r B-cell ALL. The phase I part of the trial is to evaluate the safety, optimal dose of HY004, Pharmacokinetics/Pharmacodynamics(PK/PD)and preliminary efficacy in the treatment of Adult patients with r/r B-cell ALL. The phase II part of the trial is to evaluate the efficacy and safety of HY004 in in the treatment of Adult patients with r/r B-cell ALL. The study includes screening, pre-treatment (Cell Product manufacture & lymphodepletion), HY004 infusion, safety and efficacy follow-up, and survival follow-up. All subjects who have received HY004 infusion will be followed for up to 2 years.

Official Title
-----------------
A Phase I/II, Single Arm, Multi-center Study Evaluating the Safety and Efficacy of HY004 in Adult Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r B-ALL)

Conditions
-----------------
B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Biological: HY004
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed written informed consent prior to any study procedures (patient and/or parent or legal guardian); Gender is not limited, and the age at the time of screening is ≥ 18 years old and ≤ 65 years old; Relapsed or refractory acute lymphoblastic leukemia (ALL); Documentation of CD19 and/orCD22 tumor expression demonstrated in bone marrow or peripheral blood within 3 months before screening; Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening; ECOG score 0-1 points; Organ function requirements: All patients must have adequate renal and liver functions. Exclusion Criteria: Active Central Nervous System (CNS) involvement by malignancy; Isolated extra-medullary disease relapse; Patients with Burkitt's lymphoma/leukemia; History of concomitant genetic syndrome; Patients with acute graft-versus-host disease (GVHD) or moderate-tosevere chronic GVHD within 4 weeks before screening; Patients with a history of allogeneic hematopoietic stem cell transplantation within 12 weeks before single collection; 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 have used CAR-T cell therapy before screening; Patients with an expected lifespan of less than 3 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: Participant Group<br>Participants with relapsed or refractory B-precursor acute lymphoblastic leukemia (r/r B-ALL) will receive conditioning chemotherapy (fludarabine 25-30 mg/m^2 intravenously [IV] over 30 minutes on Day -5, Day -4, and Day -3 and cyclophosphamide 500 mg/m^2 IV over 60 minutes on Day -5, Day -4), following a single IV infusion of chimeric antigen receptor (CAR) transduced autologous T cells(HY004). | Biological: HY004<br>* A single infusion of Autologous 2nd generation CD19/CD22-directed CAR-T cells administered intravenously.<br>Drug: Cyclophosphamide<br>* Administered intravenously.<br>Drug: Fludarabine Phosphate<br>* Administered intravenously.<br>|

What is the study measuring?
-----------------
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). | at the end of Month 3 | 

Secondary 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. | within 3 months | 
| Best overall response (BOR) | The proportion of patients who have achieved the best response (CR or CRi) after HY004 treatment. | up to 2 years | 
| Overall Remission Rate (ORR) with minimal residual disease (MRD) negativity | 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 | 
| 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 HY004 treatment. | First infusion date of HY004 to data cutoff date(up to 2 years) | 
| Relapse Free Survival (RFS) | RFS is defined as the time from the HY004 infusion date to the date of disease relapse or death from any cause. | up to 2 years | 
| Event-Free Survival(EFS) | EFS is defined as the time from the HY004 infusion date to the date of any event, including disease progression, cessation of treatment for any reason, or death. | up to 2 years | 
| Overall survival (OS) | OS is defined as the time from the HY004 Cell Injection infusion to the date of death from any cause. | 2 years | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events（TEAE） | Evaluate the type, frequency, severity of adverse events, and abnormal laboratory test values; Evaluate the frequency and severity of adverse events related to HY004. | up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HY004, Cluster of differentiation antigen 19 and/or 22(CD19 and/or 22), CD19/22-directed CAR-T cells