Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) for Relapsed or Refractory B-cell Lymphoma

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.

Eligibility Criteria:
Inclusion Criteria:

Screening 1:

1. Patient is 14 to 70 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. Estimated glomerular filtration rate (eGFR) \<60 mL/min as calculated by Cockcroft-Gault formula with overweight adjustment
    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. eGFR \<60 mL/min as calculated by Cockcroft-Gault formula with overweight adjustment
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.