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

Study Overview
=================
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.

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) Therapy in Patients With Relapsed or Refractory B-cell Lymphoma

Conditions
-----------------
Diffuse Large B Cell Lymphoma, Primary Mediastinal Large B Cell Lymphoma, Large B-cell Lymphoma, Follicular Lymphoma Grade 3A, Follicular Lymphoma Grade 3B

Intervention / Treatment
-----------------
* Biological: CD19-targeted chimeric antigen receptor T-cell


Participation Criteria
=================
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. (Non-primary CNS lymphoma with CNS involvement is eligible). Primary intra-ocular lymphoma. Prior CD19 targeted therapy, such as CAR-T, Bi-specific T-cell engagers (BiTE), or monoclonal antibody. 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. 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. 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). 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 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). 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.

Ages Eligible for Study
-----------------
Minimum Age: 14 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD19-targeted chimeric antigen receptor T-cell<br>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<br>* 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.<br>* Other names: PL001;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Dose-limiting toxicities | Dose-limiting toxicities through 30 days after PL001 infusion | 30 days | 
| Phase 2: best overall response (BOR) | The BOR comprising of patients with partial and complete responses according to Lugano criteria assessed by the Independent Central Review. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and Phase 2: Treatment-related adverse events | 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. | 12 months | 
| Phase 1 and Phase 2: Best overall response (BOR) | The BOR of patients with partial and complete responses according to Lugano criteria assessed by the Investigator. | 12 months | 
| Phase 1 and Phase 2: Median duration of response (mDOR) | Median duration of response (mDOR) measured from the time of initial documented response (complete response or partial response) until documented disease progression or death. | 12 months | 
| Phase 1 and Phase 2: Progression-free survival (PFS) | Progression-free survival (PFS) defined as the time from the infusion of PL001 until objective disease progression or death, whichever occurs first. | 12 months | 
| Phase 1 and Phase 2: Overall survival (OS) | Overall survival (OS) defined as the time from the infusion of PL001 until death from any cause. | 12 months | 
| Phase 1 and Phase 2: the health-related quality of life (HRQoL) | Change in the health-related quality of life (HRQoL) by FACT-Lym (the Functional Assessment of Cancer Therapy-Lymphoma)® version 4 | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DLBCL, FL, PMLBCL