JY231(JY231) Injection for the Treatment of Relapsed or Refractory B Cell Lymphoma/ Leukemia

An Early Exploratory Clinical Study of the Safety, Tolerability and Preliminary Efficacy of JY231 Injection in the Treatment of Relapsed or Refractory B-cell Lymphoma/Leukaemia

This study is an investigator-initiated single center, single arm clinical study with a target population of patients with relapsed or refractory B cell lymphoma / leukemia. It is an early exploratory clinical study of the safety, tolerability and initial efficacy of JY231 injection in the treatment of relapsed or refractory B cell lymphoma / leukemia.

This open-label, single-arm study is designed to evaluate the efficacy and safety of in vivo CAR-T cell therapy in patients with relapsed/refractory B-cell lymphoma/leukaemia. This study incorporates two pretreatment regimens: lymphodepletion and non-lymphodepletion.

In the lymphodepletion regimen:

Upon enrolment, leukapheresis will be performed. Subjects will then undergo 3-5 days of lymphodepleting therapy with fludarabine and cyclophosphamide, followed by concomitant intravenous infusion of the JY231 preparation and autologous peripheral blood mononuclear cell(PBMC) via a double-lumen catheter.

In the non-lymphodepletion regimen:

Patients will receive direct intravenous injection of the JY231 preparation.

Following infusion, subjects will undergo safety and efficacy assessments for up to 3 months. For those achieving sustained remission at 3 months post-infusion, follow-up will be conducted for at least 24 months to evaluate disease control status.

Inclusion Criteria:

1. Subject voluntarily sign informed consent and are willing and able to comply with all trial requirements;

2. Age is 18-75 years old and gender is not limited;

3. Malignancy cells in bone marrow or peripheral blood are Cluster of Differentiation 19 - positive(CD19+) detected by flow cytometric analysis;

4. Meet the clinical criteria for relapsed or refractory B-cell lymphoma, including: indolent lymphoma (iNHL), such as follicular lymphoma (FL) and marginal zone lymphoma (MZL); aggressive B-cell lymphoma, like diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed follicular lymphoma (TFL), and T-rich lymphocyte-bearing large B-cell lymphoma (TCRBCL), or have a diagnosis of acute B-lymphocytic leukemia (B-ALL) and meet one of the following conditions:

   • Refractory B-ALL: those who did not achieve complete remission after 2 courses of standard induction regimen chemotherapy, or those who did not achieve complete remission after first-line or multi-line salvage chemotherapy;
   • Relapsed B-ALL: relapse within 12 months after first remission, or relapse after first-line / multi-line salvage chemotherapy;
   • Relapse after autologous or allogeneic hematopoietic stem cell transplantation; In addition, patients with Philadelphia chromosome positive (Ph +) should be relapsed after at least two tyrosine kinase inhibitors (TKI) treatment, or they could not tolerate TKI therapy, or have a t315i mutation, resistant to TKI drugs.

5. Morphological examination of bone marrow cells showed the proportion of primitive and naive lymphocytes was> 5%;

6. No Hematopoietic Stem Cell Transplantation(HSCT) within 6 months before enrollment;

7. At least one measurable lesion was imaging for relapsed or refractory B cell lymphoma, long diameter of> 15mm, or extranodal lesion of> 10mm, along with a positive Positron Emission Tomography - Computed Tomography(PET-CT) examination.

8. More than 12 weeks of expected survival period

9. Baseline Eastern Cooperative Oncology Group(ECOG) score was 0-1;

10. Adequate organ function (criteria regarding liver and kidney function can be moderately relaxed):

    • Glutamic aminotransferase (ALT) ≤3 times upper limit of normal (ULN);
    • Grass aminotransferase (AST) ≤3 times ULN;
    • Total bilirubin ≤1.5 times ULN;
    • Serum creatinine ≤ 1.5 times ULN, or creatinine clearance ≥ 60 mL/min;
    • Indoor oxygen saturation ≥ 92%;
    • Left ventricular ejection fraction (LVEF)≥55%, echocardiography confirmed no pericardial effusion and no clinically significant ECG findings;
    • There is no clinically significant pleural effusion;

11. Adequate bone marrow reserve without transfusion, defined as:

    • Absolute neutrophil count (ANC)>1.000 / mm3;
    • Absolute lymphocyte count (ALC)≥ 300 / mm3;
    • Platelet≥50.000/mm3;
    • Hemoglobin>8.0 g/dl;

12. Subjects using the following drugs need to meet the following conditions:

    • Steroids: The therapeutic dose of steroids must be stopped 72 hours before JY231 infusion. However, physiological alternative doses of steroids are allowed;
    • Immunosuppression: Any immunosuppressive drug must be stopped at ≥4 weeks prior to enrollment;
    • Antiproliferative therapy other than lymphodepletion chemotherapy within two weeks of infusion;
    • Cluster of Differentiation 20(CD20) antibody-related therapy must be stopped within 4 weeks before infusion or 5 half-lives after the CD20 antibody;
    • CNS disease prophylaxis must be stopped 1 week before JY231 infusion (e. g. intrathecal methotrexate).

13. Reproductive men, sexual partners ensure effective contraception; fertile women, adopted effective contraception and agreed to use contraception throughout the study period.

Exclusion Criteria:

1. Subjects with active cerebrospinal fluid malignant cells or brain metastases, or subjects with active central nervous system (CNS) lymphoma, or CNS leukaemia;

2. Subjects with a history of active CNS disease, such as seizures, cerebrovascular ischemia / hemorrhage, dementia, cerebellar disease, or any autoimmune disease associated with CNS involvement;

3. Subjects who have received other study drugs within 30 days before screening, or are still in the washout period;

4. Patients who have previously received any anti-CD19 / anti-Cluster of Differentiation 3(CD3) therapy or any other anti-CD19 therapy (except for those with normal T cell numbers and function and with CD19-positive tumors);

5. Patients who have been previously treated with any gene therapy product, including Chimeric Antigen Receptor T(CAR-T) therapy (except patients who do not have CAR-T cells in vivo and have normal T cell number and function and are with CD19 positive tumors);

6. Subjects with radiation therapy within 2 weeks prior to the infusion;

7. Subjects with active hepatitis B (defined as Hepatitis B Virus(HBV) DNA test value> 500 IU / mL) or hepatitis C (HCV RNA positive); subjects with HIV positive or treponema pallidum positive;

8. Subjects with uncontrolled acute life-threatening bacterial, viral, or fungal infection (e. g. positive blood culture 72 hours before infusion);

9. Subjects with unstable angina pectoris and / or myocardial infarction within the 6 months prior to screening;

10. Subjects with concurrent or previously diagnosed with other malignancies, except for the patients under following conditions:

    • Well treated basal cells, papillary thyroid carcinoma, squamous cell carcinoma (adequate wound healing is required before enrollment into this study);
    • Carcinoma in situ of cervical cancer or breast cancer, after curative treatment, showed no signs of recurrence for at least 3 years before the study;
    • The primary malignancy has been completely removed and is in complete remission for 5 years.

11. Arrhythmic subjects without medical management control;

12. Subjects receiving oral anticoagulation within 1 week before JY231 injection infusion;

13. Having active neurological autoimmune or inflammatory conditions (such as Guillain-Barre syndrome, amyotrophic lateral sclerosis);

14. Female subjects in pregnant or lactating, or women with planned pregnancy within 2 years after JY231 infusion or male partner with planned pregnancy within 2 years after JY231 infusion;

15. Subjects with taboo study procedures or other medical conditions that may put them at unacceptable risk according to the investigator's judgment and / or clinical criteria.

16. Other conditions that the investigator believes that the subjects should not be enrolled in this clinical trial, such as poor compliance.