Clinical trial NCT05326243: Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) for Relapsed or Refractory B-cell Lymphoma
Official title: A Phase 1/2 Multicenter, Open-label, Single-arm Study to Evaluate the Safety and Efficacy of CD19-targeted Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) Therapy in Patients With Relapsed or Refractory B-cell Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Diffuse Large B Cell Lymphoma
Primary Mediastinal Large B Cell Lymphoma
Large B-cell Lymphoma
Follicular Lymphoma Grade 3A
Follicular Lymphoma Grade 3B
Keywords: DLBCL
PMLBCL
FL
Lead sponsor: Pell Bio-Med Technology Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2022-04-13
Enrollment: 49
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This study is a multiple-center, non-randomized, open-label, phase 1/2 study. Lymphodepletion chemotherapy (intravenous infusion of fludarabine plus cyclophosphamide will be administered for 3 consecutive days before the day of PL001 dosing (Day 0) and should take place within Day -5 to Day -3 (a safe window for a small subset of patients will be D -7 to D -3). This study will test two dose levels of PL001, dose level 1 and dose level 2. In Phase 1, doses will be tested in the modified "3 + 3" design initiating with dose level 1. The primary objective of Phase 1 is to assess the safety of PL001 and find the recommended phase 2 dose. Phase 2 expansion cohort will receive PL001 at the recommended dose determined in Phase 1. Efficacy evaluations using computed tomography (CT) and positron emission tomography (PET) will be performed at 1, 3, 6, 9, and 12 months.
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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 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.

Primary outcomes:
measure: Phase 1: Dose-limiting toxicities
timeFrame: 30 days
measure: Phase 2: best overall response (BOR)
timeFrame: 12 months
Secondary outcomes:
measure: Phase 1 and Phase 2: Treatment-related adverse events
timeFrame: 12 months
measure: Phase 1 and Phase 2: Best overall response (BOR)
timeFrame: 12 months
measure: Phase 1 and Phase 2: Median duration of response (mDOR)
timeFrame: 12 months
measure: Phase 1 and Phase 2: Progression-free survival (PFS)
timeFrame: 12 months
measure: Phase 1 and Phase 2: Overall survival (OS)
timeFrame: 12 months
measure: Phase 1 and Phase 2: the health-related quality of life (HRQoL)
timeFrame: 12 months
Other outcomes:
measure: Phase 1 and Phase 2: Pharmacokinetic (PK) profile of PL001-Persistence of PL001 by flow cytometry
timeFrame: 12 months
measure: Phase 1 and Phase 2: Pharmacokinetic (PK) profile of PL001-Persistence of PL001 by qPCR
timeFrame: 12 months
measure: Phase 1 and Phase 2: Quality assurance of the product
timeFrame: [From start of CAR-T manufacturing to CAR-T infusion, estimated to be 45 days]
measure: Phase 1 and Phase 2: To assess the cytokine biomarkers
timeFrame: 12 months
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Tainan City
country: Taiwan
facility: Chi Mei Medical Center
city: Taipei city
country: Taiwan
facility: Taipei Medical University - Taipei Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: Pell Bio-Med Technology Co., Ltd.
name: Chen-Lung Lin, MD
role: STUDY_CHAIR
References: