Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T) for Relapsed or Refractory B-cell Lymphoma
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CD19-targeted chimeric antigen receptor T-cell 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. |
Biological: CD19-targeted chimeric antigen receptor T-cell
Drug: Fludarabine
patients will receive a lymphodepletion chemotherapy with Fludarabine 25 mg/m2/day IV for 3 days on Day-5 to Day-3(a safe window for a small subset of patients will be D -7 to D -3).
Drug: Cyclophosphamide
patients will receive a lymphodepletion chemotherapy with cyclophosphamide 300 mg/m2/day IV for 3 dys Day-5 to Day-3(a safe window for a small subset of patients will be D -7 to D -3).
Biological: CD19 CAR-T
CD19 CAR-T cells will be administered using as a single dose at 0.1-9*10^6 cells/kg on Day 0 after completion of the lymphodepletion chemotherapy. The body weight calculated for PL001 dose is the actual body weight on the day of leukapheresis.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Phase 1: Dose-limiting toxicities [30 days]
Dose-limiting toxicities through 30 days after PL001 infusion
- Phase 2: best overall response (BOR) [12 months]
The BOR comprising of patients with partial and complete responses according to Lugano criteria assessed by the Independent Central Review.
Secondary Outcome Measures
- Phase 1 and Phase 2: Treatment-related adverse events [12 months]
Treatment-related adverse events assessed by CTCAE v 5.0. Overall grading of Cytokine Release Syndrome, immune effector cell associated neurotoxicity syndrome, based on the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.
- Phase 1 and Phase 2: Best overall response (BOR) [12 months]
The BOR of patients with partial and complete responses according to Lugano criteria assessed by the Investigator.
- Phase 1 and Phase 2: Median duration of response (mDOR) [12 months]
Median duration of response (mDOR) measured from the time of initial documented response (complete response or partial response) until documented disease progression or death.
- Phase 1 and Phase 2: Progression-free survival (PFS) [12 months]
Progression-free survival (PFS) defined as the time from the infusion of PL001 until objective disease progression or death, whichever occurs first.
- Phase 1 and Phase 2: Overall survival (OS) [12 months]
Overall survival (OS) defined as the time from the infusion of PL001 until death from any cause.
- Phase 1 and Phase 2: the health-related quality of life (HRQoL) [12 months]
Change in the health-related quality of life (HRQoL) by FACT-Lym (the Functional Assessment of Cancer Therapy-Lymphoma)® version 4
Other Outcome Measures
- Phase 1 and Phase 2: Pharmacokinetic (PK) profile of PL001-Persistence of PL001 by flow cytometry [12 months]
Persistence of PL001 in peripheral blood using flow cytometry
- Phase 1 and Phase 2: Pharmacokinetic (PK) profile of PL001-Persistence of PL001 by qPCR [12 months]
PL001 transgene levels by qPCR (quantitative polymerase chain reaction) in peripheral blood
- Phase 1 and Phase 2: Quality assurance of the product [[From start of CAR-T manufacturing to CAR-T infusion, estimated to be 45 days]]
Rates for successful production and infused patients
- Phase 1 and Phase 2: To assess the cytokine biomarkers [12 months]
Cytokine concentrations in peripheral blood
Eligibility Criteria
Criteria
Inclusion Criteria:
Screening 1:
-
Patient is 14 to 70 years of age, inclusive, at the time of signing the informed consent.
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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.
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On-site documentation of CD19 on the dominant population of cancer cells.
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Disease status should meet any one of the below:
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Patients with previous autologous-hematopoietic stem cell transplantation (auto HSCT) have relapsed or progressive disease after transplantation regardless of lines of systemic therapy.
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Patients without previous HSCT have relapsed or progressive disease after at least 2 lines of systemic therapy, including anti-CD20 (cluster of differentiation 20) antibody and anthracycline.
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Have no available effective systemic therapy as judged by the Investigator.
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At least one measurable non-CNS (central nervous system) lesion based on Lugano classification for lymphoma.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
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Life expectancy of at least 3 months.
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Patient is male or female.
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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:
- 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.
- 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:
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
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CAR-T manufacture is completed from a non-mobilized leukapheresis product and is ready for use.
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Female patients of childbearing potential must have a negative serum pregnancy test at Screening 2.
Exclusion Criteria:
Screening 1:
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Chronic lymphocytic leukemia with Richter's transformation.
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Primary CNS lymphoma.
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Primary intra-ocular lymphoma.
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Prior CD19 targeted therapy, such as CAR-T, Bi-specific T-cell engagers (BiTE), or monoclonal antibody.
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History of cancers 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.
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History of allogeneic HSCT.
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History of autologous HSCT within 3 months prior to consent.
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Received any investigational product within 4 weeks prior to consent.
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Systemic anticancer therapy within 3 weeks prior to apheresis.
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Corticosteroids, defined as >10mg/day of prednisolone or equivalent, within 2 weeks prior to leukapheresis.
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Use of long-acting and short-acting myeloid growth factor within 2 weeks, 5 days prior to leukapheresis, respectively.
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Received anti-thymocyte globulin within 4 weeks prior to consent.
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Intrathecal chemotherapy within 1 week prior to leukapheresis.
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Inadequate major organ functions at Screening, which were defined as any of below:
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absolute neutrophil count (ANC) <500/µL
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Absolute lymphocyte count (ALC) <300/µL, excluding leukemic cells.
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Hemoglobin (Hb) <8.0 g/dL
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Platelet count <75,000/µL without transfusion support within 3 days
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Baseline O2 saturation <92% by pulse oximetry on room air
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Significant CNS diseases such as dementia, major stroke, seizure while under antiepileptic drug
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Aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) and alanine aminotransferase (ALT) >5 × ULN, or total bilirubin >2 × ULN (except for constitutional jaundice)
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Estimated glomerular filtration rate (eGFR) <60 mL/min as calculated by Cockcroft-Gault formula with overweight adjustment
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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.
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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.)
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Active hepatitis C virus (HCV) infection defined as positive anti- HCV antibody plus detectable HCV RNA.
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Positive for human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV) infection.
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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).
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Patient has active clinical signs and symptoms consistent with COVID-19 (coronavirus disease 2019), e.g., fever, dry cough, dyspnea, sore throat, fatigue, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission.
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Patient who had severe course of COVID-19 (extracorporeal membrane oxygenation [ECMO, extracorporeal membrane oxygenation], mechanically ventilated).
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Any medical condition which might compromise the patient's safety because of leukapheresis, lymphodepletion chemotherapy, or CAR-T therapy and anticipated AEs(adverse events), according to the Investigator's opinion.
Screening 2:
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Inadequate major organ functions at Screening which were defined as any of below:
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ANC <500/µL
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Hb <8.0 g/dL
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Platelet count <50,000/µL, without transfusion support within 3 days
-
Baseline O2 saturation <92% by pulse oximetry on room air
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AST >5 × ULN and ALT>5 × ULN, or total bilirubin >2 × ULN (except for constitutional jaundice)
-
Significant CNS diseases such as dementia, major stroke, seizure while under antiepileptic drug
-
eGFR <60 mL/min as calculated by Cockcroft-Gault formula with overweight adjustment
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Corticosteroids, defined as >10mg/day of prednisolone or equivalent.
-
Use of long-acting and short-acting myeloid growth factor within 12 days, 2 days prior to lymphodepletion therapy, respectively.
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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).
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Kaohsiung Medical University Chung-Ho Memorial Hospital | Kaohsiung | Taiwan | 807377 | |
| 2 | National Taiwan University Hospital | Taipei | Taiwan | 100225 | |
| 3 | Taipei Veterans General Hospital | Taipei | Taiwan | 112201 |
Sponsors and Collaborators
- Pell Bio-Med Technology Co., Ltd.
Investigators
- Study Director: Chien-Ting Lin, MD, Pell Bio-Med Technology Co., Ltd.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PL001-NHL-201