Clinical Trial of HY004 Cell Injection in the Treatment of Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This is a multi-center, open-label, single-arm, phase I/II trial to evaluate the safety and efficacy of HY004 treatment in Adult patients with relapsed or refractory B-cell Non-Hodgkin's Lymphoma (r/r B-NHL).

Detailed Description
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This trial is a multi-center, open label, single-arm, phase I/II trial to evaluate the safety and efficacy of HY004 in Adult(aged 18 75 years old) patients with r/r B-NHL. 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-NHL. 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-NHL. 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
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A Multi-center, Open Label, Single-arm, Phase I/II Clinical Trial of HY004 Cell Injection in the Treatment of Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Conditions
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Non-hodgkin Lymphoma

Intervention / Treatment
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* Biological: HY004


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients who are willing to sign the informed consent form; Aged 18-75 years, male or female; Previously received≥2nd-line adequate therapy or hematopoietic stem cell transplantation (HSCT), and patients with CD19+/CD22+ relapsed/refractory B-NHL according to the WHO classification 2017, which are provided specifically as follows: Diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS); Primary mediastinal large B cell lymphoma (PMBCL); Grade 3b follicular lymphoma; Transformed follicular lymphoma; High grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high grade B cell lymphoma - not otherwise specified. Measurable imaging lesion at screening: Intranodal lesion must have a long diameter of more than 1.5 cm, and extranodal lesion must have a long diameter of more than 1.0 cm with PET-positive disease by Lugano classification . PET-positive disease BY Lugano classification Adequate bone marrow, renal, hepatic, pulmonary and cardiac function. Adequate vascular access for leukapheresis procedure Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy. Key Exclusion Criteria: Active Central Nervous System (CNS) involvement by malignancy. Patients with existing central nervous system disease or with a history of central nervous system disease. Patients receiving any of the following drugs or therapies within the specified period prior to apheresis: Alemtuzumab and Bendamustine within 6 months prior to apheresis; Cladribine within 3 months prior to apheresis; Lenalidomide within 1 mouth prior to apheresis; Lymphocytotoxic chemotherapy within 2 weeks prior to apheresis - use in more than 3 half-lives prior to apheresis is eligible; Anti-CD20 monoclonal antibody and therapeutic dose of hormones within 7 d prior to apheresis; Non-lymphocytotoxic chemotherapy within 7 d prior to apheresis - use in more than 3 half-lives prior to apheresis is eligible; Venetoclax (BCL-2 inhibitor) within 4 d prior to apheresis; Idelalisib (PI3Kδ kinase inhibitor) within 2 d prior to apheresis; DLI within 6 weeks prior to apheresis; Radiotherapy within 6 weeks prior to apheresis - progressive disease at radiotherapy site, or PET positive lesion at other non-radiotherapy site is eligible; Patients previously received CAR-T cell therapy, the products that have same indication and have beenlisted in China are eligible; Patients who have previously received allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 mouths. Patients with acute graft-versus-host disease (GVHD) or moderate-tosevere 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. History of cardiovascular disease. Pregnant or nursing women.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose of HY004<br>Patients received a single dose of anti-CD22/CD19 CAR T cells after receiving a conditioning regimen of cyclophosphamide and fludarabine. | Biological: HY004<br>* Autologous 2nd generation bispecific CAR-T cells targeting both CD22 and CD19, single infusion intravenously. Start Dose level: 2.00 x 10^6/kg CAR+T-cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 【Phase I】Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and Recommended Phase II Dose (RP2D) | Determine the MTD and DLT of HY004 in the Treatment and recommend the dose for Phase II study. | 28 days | 
| 【Phase II】Overall Remission Rate (ORR), which includes Complete Remission (CR) and Partial Remission (PR) | Efficacy of HY004 as measured by ORR at 3 months after HY004 Cell Injection infusion, which includes CR and PR. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 【Phase I】Overall Remission Rate (ORR), which includes Complete Remission (CR) and Partial Remission (PR) | Efficacy of HY004 as measured by ORR at 3 months after HY004 Cell Injection infusion, which includes CR and PR. | 3 months | 
| Safety of CNCT19 therapy: CTCAE v5.0 | Safety measures include adverse events as assessed by CTCAE v5.0. | 24 months | 
| Complete Remission Rate (CRR) | Efficacy of HY004 as measured by CR at 3 months after HY004 Cell Injection infusion. | 3 months | 
| ORR（CR+PR）/CRR | Efficacy of HY004 as measured by ORR/CRR at 28 days after cell infusion. | 28 days | 
| ORR（CR+PR）/CRR | Efficacy of HY004 as measured by ORR/CRR at 6 months after cell infusion. | 6 months | 
| Best Overall Response (BOR) | The best overall response after HY004 infusion. | 24 mouths | 
| Duration of Remission (DOR) | DOR means the duration from reaching the response (e.g., CR or PR) criteria of the therapy to the first, clearly defined progressive disease, or death for disease under investigation. | 24 mouths | 
| Progression-free survival (PFS) | PFS means duration from the HY004 Cell Injection infusion to progression of lymphoma, or death for any reason. | 24 mouths | 
| Event-free survival (EFS) | EFS means duration from the HY004 Cell Injection infusion to progression of lymphoma, start of new anti-cancer treatment, relapse, death of any cause or discontinued due to any adverse events. | 24 mouths | 
| Overall survival (OS) | OS is defined as the time from the signing of informed consent form to the date of the last survival follow-up or death due to any cause. | 24 mouths | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HY004, CD22/CD19 Chimeric Antigen Receptor T-cells