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).

Cluster of differentiation (CD) 19 chimeric antigen receptor T-cell (CAR-T) has been a very promising treatment option for multiple types of B-cell lymphoma. Kymriah® (tisagenlecleucel, Novartis) and Yescarta® (axicabtagene ciloleucel, Gilead) were licensed by the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) in 2017 to treat relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and High-grade B-cell lymphoma (HGBCL). A third anti-CD19 CAR-T product, Tecartus (brexucabtagene autoleucel, Gilead) was approved by the US FDA for relapsed and refractory mantle cell lymphoma (MCL) in July 2020. In February 2021, another product, Breyanzi® (lisocabtagene maraleucel, Juno Therapeutics, Inc.), was approved by the US FDA for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, Primary mediastinal large B cell lymphoma (PMLBCL), and Gr. 3b FL.

Currently, in Taiwan, no CD19 CAR-T therapies are available commercially.This Phase 1/Phase 2 study will test PL001, a CD19 CAR-T therapy manufactured by Pell Bio-Med Technology Co., Ltd., as a monotherapy for relapsed or refractory B-cell lymphoma. The Phase 1 of the study will be conducted to establish a dose range that is well tolerated by the majority of patients and to provide a safety profile of PL001 in the target patient population. The results of the Phase 1 of the study will recommend the dose selection for the Phase 2 of the study. Phase 2 of the study will assess the efficacy and safety of PL001 in patients with relapsed or refractory B cell lymphoma.

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.