CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

Screening 1:

1. Patient is ≥14 years of age, inclusive, at the time of signing the informed consent.
2. Histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBCL), large B-cell lymphoma transformed from follicular lymphoma (FL), or grade 3a or 3b FL.
3. On-site documentation of CD19 on the dominant population of cancer cells.
4. Disease status should meet any one of the below:

   1. Patients with previous autologous-hematopoietic stem cell transplantation (auto HSCT) have relapsed, progressive, or refractory disease (defined as having not achieved a CR) after transplantation regardless of lines of systemic therapy.
   2. Patients without previous HSCT have relapsed, progressive, or refractory disease (defined as having not achieved a CR) after at least 2 lines of systemic therapy, including anti-CD20 antibody and anthracycline.
5. Have no available effective systemic therapy as judged by the Investigator.
6. At least one measurable non-CNS (central nervous system) lesion based on Lugano classification for lymphoma.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
8. Life expectancy of at least 3 months.
9. Patient is male or female.
10. A male patient must agree to use a highly effective contraception as detailed in Section 10.4 (Appendix 4) during the treatment period and for at least 2 years after the dose of PL001 and refrain from donating sperm during this period.

    Female Patients:
11. A female patient is eligible to participate if she is not pregnant (Section 10.4; Appendix 4), not breastfeeding, and at least one of the following conditions applies:

    • Not a woman of childbearing potential (WOCBP) as defined in Section 10.4 (Appendix 4).

    OR

    • A WOCBP who agrees to follow the contraceptive guidance in Section 10.4 (Appendix 4) during the treatment period and for at least 2 years after the dose of PL001 and refrain from donating ova during this period.
12. Patient/patient's parent/legal guardian is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Screening 2:

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
2. CAR-T is successfully manufactured and ready for use, from cells harvested by non mobilized leukapheresis.
3. WOCBP who have a negative serum pregnancy test at Screening 2.

Exclusion Criteria:

Screening 1:

1. Chronic lymphocytic leukemia with Richter's transformation.
2. Primary CNS lymphoma. (Non-primary CNS lymphoma with CNS involvement is eligible).
3. Primary intra-ocular lymphoma.
4. Prior CD19 targeted therapy, such as CAR-T, Bi-specific T-cell engagers (BiTE), or monoclonal antibody.
5. History of cancers (includes myelodysplastic syndrome) other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless disease-free without active treatment for at least 3 years.
6. History of allogeneic HSCT.
7. History of autologous HSCT within 3 months prior to consent.
8. Received any investigational product within 4 weeks prior to consent.
9. Systemic anticancer therapy within 3 weeks prior to apheresis.
10. Long-term use of systemic corticosteroids, defined as daily use \>10 mg of prednisolone or equivalent, within 2 weeks prior to leukapheresis.

    Exception examples:
    * Nasal, ophthalmic, inhaled, intra-articular, and topical steroid preparation.
    * Short term systemic steroid for drug, contrast, or blood transfusion allergic reaction management.
    * Low dose maintenance steroid therapy for other conditions (e.g., asthma).
11. Use of long-acting and short-acting myeloid growth factor within 2 weeks, 5 days prior to leukapheresis, respectively.
12. Received anti-thymocyte globulin within 4 weeks prior to consent.
13. Intrathecal chemotherapy within 1 week prior to leukapheresis.
14. Inadequate major organ functions at Screening, which were defined as any of below:

    1. absolute neutrophil count (ANC) \<500/µL
    2. Absolute lymphocyte count (ALC) \<300/µL, excluding leukemic cells.
    3. Hemoglobin (Hb) \<8.0 g/dL
    4. Platelet count \<75,000/µL without transfusion support within 3 days
    5. e. Baseline O2 saturation \<92% by pulse oximetry at room air
    6. Significant CNS diseases such as dementia, major stroke, seizure while under antiepileptic drug
    7. Aspartate aminotransferase (AST) \>5 × upper limit of normal (ULN) and alanine aminotransferase (ALT) \>5 × ULN, or total bilirubin \>2 × ULN (except for constitutional jaundice)
    8. Serum creatinine \> 1.5 × ULN and estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m², as calculated by the Cockcroft-Gault formula.
    9. Significant cardiac disease including but not limited to: left ventricular ejection fraction (LVEF) \<50%, QTc(the corrected QT interval) \> 480 msec based on Fredericia's formula, clinically significant arrhythmias, history of myocardial infarction or unstable angina within 3 months prior to consent.
15. Active hepatitis B virus (HBV) infection defined as detectable HBV DNA (Patients with positive anti-hepatitis B core antibody \[HBcAb\] must consent to regular monitoring of HBV DNA, and anti-HBV prophylaxis with oral anti-viral agent (such as entecavir) is mandatory until End-of-Study visit \[Visit 15\].)
16. Active hepatitis C virus (HCV) infection defined as positive anti- HCV antibody plus detectable HCV RNA.
17. Positive for human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV) infection.
18. Uncontrolled acute life-threatening bacterial, viral, or fungal infection (e.g., the need for intravenous therapeutic antibiotics, blood culture positive ≤72 hours prior to apheresis).

21\. Any medical conditions which might compromise the patient's safety from leukapheresis, lymphodepletion chemotherapy, or CAR-T therapy and anticipated AEs, according to the Investigator's evaluation.

22.Patients with insufficient leukapheresis cells.

Screening 2:

1. Inadequate major organ functions at Screening which were defined as any of below:

   1. ANC \<500/µL
   2. Hb \<8.0 g/dL
   3. Platelet count \<50,000/µL, without transfusion support within 3 days
   4. Baseline O2 saturation \<92% by pulse oximetry on room air
   5. AST \>5 × ULN and ALT\>5 × ULN, or total bilirubin \>2 × ULN (except for constitutional jaundice)
   6. Significant CNS diseases such as dementia, major stroke, seizure while under antiepileptic drug
   7. Serum creatinine \> 1.5 × ULN and estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m², as calculated by the Cockcroft-Gault formula.
2. Long-term use of systemic corticosteroids, defined as daily use \>10 mg of prednisolone or equivalent.

   Exception examples:
   * Nasal, ophthalmic, inhaled, intra-articular, and topical steroid preparation.
   * Short term systemic steroid for drug, contrast, or blood transfusion allergic reaction management.
   * Low dose maintenance steroid therapy for other conditions (e.g., asthma).
3. Use of long-acting and short-acting myeloid growth factor within 12 days, 2 days prior to lymphodepletion therapy, respectively.
4. Uncontrolled acute life-threatening bacterial, viral, or fungal infection (e.g. the need for intravenous therapeutic antibiotics, blood culture positive ≤72 hours prior to lymphodepletion).
5. Any medical condition which might compromise the patient's safety because of lymphodepletion chemotherapy or CAR-T therapy and anticipated AEs, according to the Investigator's opinion.

主要终点：Phase 1: Dose-limiting toxicities · Dose-limiting toxicities through 30 days after PL001 infusion · 30 days；Phase 2: best overall response (BOR) · The best overall response (BOR) comprising patients with partial and complete responses according to Lugano criteria assessed based on the image review result provided by the Independent Central Review from the start of infusion of PL001 until next subsequent cancer-specific therapy, disease progression, death, or end of study, whichever comes first · 12 months
次要终点：Phase 1 and Phase 2: Treatment-related adverse events；Phase 1 and Phase 2: Best overall response (BOR)；Phase 1 and Phase 2: Median duration of response (mDOR)；Phase 1 and Phase 2: Progression-free survival (PFS)；Phase 1 and Phase 2: Overall survival (OS)；Phase 1 and Phase 2: the health-related quality of life (HRQoL)

• CD19-targeted chimeric antigen receptor T-cell · EXPERIMENTAL · Patients will receive a lymphodepletion chemotherapy with fludarabine plus cyclophosphamide for three consecutive days(Day -5 to Day -3) before infusion of CD19-targeted chimeric antigen receptor T-cell (CD19 CAR-T). Patients will receive the CD19 CAR-T(also known as PL001) infusion on Day 0.

This is a multiple center, non-randomized, open-label, phase 1/2 study. The primary objective of Phase 1 is to evaluate the safety of PL001 and find the recommended Phase 2 dose (RP2D). The objective of Phase 2 is to evaluate the safety and efficacy of CD19 CAR-T(known as PL001).