Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T) for Relapsed or Refractory B-cell Lymphoma
Diffuse Large B Cell Lymphoma, Primary Mediastinal Large B Cell Lymphoma, Large B-cell Lymphoma
About this trial
This is an interventional treatment trial for Diffuse Large B Cell Lymphoma focused on measuring DLBCL, PMLBCL, FL
Eligibility Criteria
Inclusion Criteria:
Screening 1:
- Patient is 14 to 70 years of age, inclusive, at the time of signing the informed consent.
- 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.
- On-site documentation of CD19 on the dominant population of cancer cells.
Disease status should meet any one of the below:
- Patients with previous autologous-hematopoietic stem cell transplantation (auto HSCT) have relapsed or progressive disease after transplantation regardless of lines of systemic therapy.
- 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.
- Have no available effective systemic therapy as judged by the Investigator.
- At least one measurable non-CNS (central nervous system) lesion based on Lugano classification for lymphoma.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Life expectancy of at least 3 months.
- Patient is male or female.
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:
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- CAR-T manufacture is completed from a non-mobilized leukapheresis product and is ready for use.
- Female patients of childbearing potential must have a negative serum pregnancy test at Screening 2.
Exclusion Criteria:
Screening 1:
- Chronic lymphocytic leukemia with Richter's transformation.
- Primary CNS lymphoma.
- Primary intra-ocular lymphoma.
- Prior CD19 targeted therapy, such as CAR-T, Bi-specific T-cell engagers (BiTE), or monoclonal antibody.
- 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.
- History of allogeneic HSCT.
- History of autologous HSCT within 3 months prior to consent.
- Received any investigational product within 4 weeks prior to consent.
- Systemic anticancer therapy within 3 weeks prior to apheresis.
- Corticosteroids, defined as >10mg/day of prednisolone or equivalent, within 2 weeks prior to leukapheresis.
- Use of long-acting and short-acting myeloid growth factor within 2 weeks, 5 days prior to leukapheresis, respectively.
- Received anti-thymocyte globulin within 4 weeks prior to consent.
- Intrathecal chemotherapy within 1 week prior to leukapheresis.
Inadequate major organ functions at Screening, which were defined as any of below:
- absolute neutrophil count (ANC) <500/µL
- Absolute lymphocyte count (ALC) <300/µL, excluding leukemic cells.
- Hemoglobin (Hb) <8.0 g/dL
- Platelet count <75,000/µL without transfusion support within 3 days
- Baseline O2 saturation <92% by pulse oximetry on room air
- Significant CNS diseases such as dementia, major stroke, seizure while under antiepileptic drug
- Aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) and alanine aminotransferase (ALT) >5 × ULN, or total bilirubin >2 × ULN (except for constitutional jaundice)
- Estimated glomerular filtration rate (eGFR) <60 mL/min as calculated by Cockcroft-Gault formula with overweight adjustment
- 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.
- 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.)
- Active hepatitis C virus (HCV) infection defined as positive anti- HCV antibody plus detectable HCV RNA.
- Positive for human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV) infection.
- 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).
- 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.
- Patient who had severe course of COVID-19 (extracorporeal membrane oxygenation [ECMO, extracorporeal membrane oxygenation], mechanically ventilated).
- 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:
Inadequate major organ functions at Screening which were defined as any of below:
- ANC <500/µL
- Hb <8.0 g/dL
- Platelet count <50,000/µL, without transfusion support within 3 days
- Baseline O2 saturation <92% by pulse oximetry on room air
- 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
- 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.
- 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).
- 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.
Sites / Locations
- Kaohsiung Medical University Chung-Ho Memorial HospitalRecruiting
- National Taiwan University HospitalRecruiting
- Taipei Veterans General HospitalRecruiting
Arms of the Study
Arm 1
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.