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

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.

• HY004 (Biological): 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

Primary outcomes

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

Secondary outcomes

• 【Phase I】Overall Remission Rate (ORR), which includes Complete Remission (CR) and Partial Remission (PR) [3 months]: Efficacy of HY004 as measured by ORR at 3 months after HY004 Cell Injection infusion, which includes CR and PR.
• Safety of CNCT19 therapy: CTCAE v5.0 [24 months]: Safety measures include adverse events as assessed by CTCAE v5.0.
• Complete Remission Rate (CRR) [3 months]: Efficacy of HY004 as measured by CR at 3 months after HY004 Cell Injection infusion.
• ORR（CR+PR）/CRR [28 days]: Efficacy of HY004 as measured by ORR/CRR at 28 days after cell infusion.
• ORR（CR+PR）/CRR [6 months]: Efficacy of HY004 as measured by ORR/CRR at 6 months after cell infusion.
• Best Overall Response (BOR) [24 mouths]: The best overall response after HY004 infusion.
• Duration of Remission (DOR) [24 mouths]: 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.
• Progression-free survival (PFS) [24 mouths]: PFS means duration from the HY004 Cell Injection infusion to progression of lymphoma, or death for any reason.
• Event-free survival (EFS) [24 mouths]: 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.
• Overall survival (OS) [24 mouths]: 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.

Other outcomes

• In vivo cellular Pharmacokinetic (PK) profile of HY004. [24 mouths]: To characterize the in vivo cellular pharmacokinetic (PK) profile (levels, persistence, trafficking) of HY004 cells in blood by quantitative polymerase chain reaction(qPCR) and Flow Cytometry.
• In vivo cellular pharmacodynamics (PD) profile of HY004. [3 mouths]: To characterize the concentration of cytokines ,including Interleukin-6(IL-6) at least in Serum.
• Prevalence and incidence of humoral immunogenicity to HY004. [24 mouths]: To characterize the concentration of anti-drug antibodies

Sex: All, ages: 18 Years to 75 Years

Key Inclusion Criteria:

1. Patients who are willing to sign the informed consent form;
2. Aged 18-75 years, male or female;
3. 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:

   1. Diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS);
   2. Primary mediastinal large B cell lymphoma (PMBCL);
   3. Grade 3b follicular lymphoma;
   4. Transformed follicular lymphoma;
   5. High grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high grade B cell lymphoma - not otherwise specified.
4. 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 .
5. PET-positive disease BY Lugano classification
6. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function.
7. Adequate vascular access for leukapheresis procedure
8. 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:

1. Active Central Nervous System (CNS) involvement by malignancy.
2. Patients with existing central nervous system disease or with a history of central nervous system disease.
3. Patients receiving any of the following drugs or therapies within the specified period prior to apheresis:

   1. Alemtuzumab and Bendamustine within 6 months prior to apheresis;
   2. Cladribine within 3 months prior to apheresis;
   3. Lenalidomide within 1 mouth prior to apheresis;
   4. Lymphocytotoxic chemotherapy within 2 weeks prior to apheresis - use in more than 3 half-lives prior to apheresis is eligible;
   5. Anti-CD20 monoclonal antibody and therapeutic dose of hormones within 7 d prior to apheresis;
   6. Non-lymphocytotoxic chemotherapy within 7 d prior to apheresis - use in more than 3 half-lives prior to apheresis is eligible;
   7. Venetoclax (BCL-2 inhibitor) within 4 d prior to apheresis;
   8. Idelalisib (PI3Kδ kinase inhibitor) within 2 d prior to apheresis;
   9. DLI within 6 weeks prior to apheresis;
   10. Radiotherapy within 6 weeks prior to apheresis - progressive disease at radiotherapy site, or PET positive lesion at other non-radiotherapy site is eligible;
4. Patients previously received CAR-T cell therapy, the products that have same indication and have beenlisted in China are eligible;
5. Patients who have previously received allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 mouths.
6. Patients with acute graft-versus-host disease (GVHD) or moderate-tosevere chronic GVHD within 4 weeks before screening.
7. Active systemic autoimmune disease.
8. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti- HCV positive).
9. Patients with active infections at screening.
10. History of cardiovascular disease.
11. Pregnant or nursing women.