Non-Hodgkin Lymphoma, B-cell
Conditions
Keywords
B cell non-hodgkin lymphoma, CAR-T, CD19, CD22, BCMA
Brief summary
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous chimeric antigen receptor T (CAR-T) cells targeting CD19/CD22/BCMA in patients with relapsed or refractory B cell non-Hodgkin lymphoma.
Detailed description
This is a single arm, open-label, dose escalation investigator initiated (IIT) study, the primary objective is to evaluate the safety and tolerability of CD19/CD22/BCMA CAR-T therapy in patients with B cell non-Hodgkin lymphoma, and determine the maximum tolerated dose (MTD). For the secondary objectives, pharmacokinetics(PK), survival of CAR-T cells in vivo, pharmacodynamics (PD) and efficacy in R/R B cell NHL will be evaluated. This study flow comprises of a screening phase( ≤28 days prior to apheresis), apheresis phase (occur upon enrollment, ≤10 days prior to infusion), lymphodepletion phase (from Day -5 to Day -3) ,infusion of CD19/CD22/BCMA CAR-T cells on Day0, DLT assessments phase from Day1 to Day 28 and post-treatment follow-up phase (Day 29 and up to end of the study).
Interventions
BIOLOGICALCD19/CD20/BCMA CAR T cells
Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of CD19/CD20/BCMA CAR T cells. Cyclophosphamide and fludarabine will be given from day-5 to day-3 before the infusion for lymphodepletion. On day0 subjects will receive one dose treatment with CD19/CD20/BCMA CAR T cells by intravenous (IV) injection
Sponsors
Shanghai Cell Therapy Group Co.,Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Patients who are diagnosed with relapsed/refractory B cell non-Hodgkin lymphoma , especially * Diffuse Large B Cell Lymphoma, not other specified (DLBCL,NOS), * Primary Mediastinal Large B Cell Lymphoma (PMBCL) * Transformation Follicular Lymphoma (TFL) * High grade B-cell lymphoma(HGBCL) * High grade B-cell lymphoma (HGBCL) with MYC(myelocytomatosis oncogene) and BCL2(B-cell lymphoma2) /BCL6 (B-cell lymphoma6) rearrangement * Refractory diseases are defined as one of the following * No response to last line of therapy: i. Progressive disease (PD) as best response to most recent therapy regimen; ii. Stable disease (SD) as best response to most recent therapy regimen * Not candidate for autologous stem cell transplant (ASCT) or refractory post-ASCT: i. Disease progression (PD) or relapsed ≤12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy * Individuals must have received adequate prior therapy including at a minimum: * anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20-negative and * an anthracycline containing chemotherapy regimen * Immunohistochemical staining shows at least two of B cell surface receptor antigen CD19,CD20, BCMA are positive(including weak, medium and strong positive) * At least one measurable lesion during the screening based on the recommendation for initial evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma. * Life expectancy ≥ 12 weeks * Eastern cooperative oncology group (ECOG) performance status of 0 or 1 * Adequate renal, hepatic, pulmonary and cardiac function defined as: * Renal function: Serum creatinine ≤ 1.5 upper limit of normal(ULN), or eGFR ≥ 60 mL/min/1.73m2 \[eGFR(estimated glomerular filtration rate)=186×age\^-0.203×SCr\^-1.154（mg/dl）,female×0.742\] * Hepatic function: i: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 5 ULN and ii: total bilirubin ≤ 2 ULN, except in individuals with Gilbert syndrome (in Gilbert's syndrome patients, those with total bilirubin ≤ 3 ULN and direct bilirubin ≤ 1.5 ULN can be enrolled).iii: International normalized ratio (INR) or prothrombin time (PT) ≤1.5 ULN Pulmonary: Have the minimum level of pulmonary reserve, defined as ≤ CTCAE (Common Terminology Criteria for Adverse Events) grade 1 dyspnea and the SaO2(oxygen saturation)≥ 91% on room air * Cardiac: left ventricular ejection fraction (LVEF) ≥50% determined by echocardiogram(ECG) or multigated acquisition scan (MUGA) * Adequate bone marrow function, define as: * absolute neutrophil count (ANC) ≥1 ×10\^9/L * absolute lymphocyte count (ALC)≥ 0.5 ×10\^9/L * Platelets ≥50 ×109/L； * Hemoglobulin ≥80 g/L; patients with bone marrow involvement can be enrolled if globulin\>60 g/L * Female of child-bearing age and male participants must agree to use effective contraceptive methods until no CAR-T cells can be detected by PCR(polymerase chain reaction) test. Key
Exclusion criteria
* Individuals who have antiCD45 or antiCD3 therapy * Individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of primary or secondary CNS (central nervous system) lymphoma, cerebrospinal fluid malignant cells or brain metastases * Presence or history of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement * History of allogeneic stem cell transplantation * Any of the following situations: • HBsAg/ HBeAg positive; HBeAb/HBcAb positive and HBV(hepatitis B virus) DNA copies above the lower test limit; * HCV(hepatitis C virus) RNA positive * HIV(human immunodeficiency virus) positive or treponema pallidum positive * Presence of active or life-threatening fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. * Individuals presence of unstable angina or myocardial infarction within 6 months of screening, or other severe/uncontrolled diseases during the screening (eg. Unstable or uncompensated respiratory, cardiac, hepatic or renal disease) * Presence of uncontrolled arrhythmia with treatment * Pregnancy or breastfeeding women Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity(DLT) | Day0-Day28 | Safety |
| Maximum tolerated dose (MTD) | Day0-Day28 | Tolerability |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Curve (AUC) | Day0-Day28，Day0-undetectable for CAR positive T cells | Pharmacokinetics(PK) |
| CAR positive T cells | Day0-Day28，Day0-undetectable for CAR positive T cells | Pharmacokinetics(PK) |
| Maximum Plasma Concentration(Cmax) | Day0-Day28，Day0-undetectable for CAR positive T cells | Pharmacokinetics (PK) |
| Overall survival (OS) | Day28,Month2,Month3,Month6,Month9,Month12,Month18,Month24 | Clinical response assessed by Lugano Response Criteria for non-Hodgkin Lymphoma |
| Progression-free survival (PFS) | Day28,Month2,Month3,Month6,Month9,Month12,Month18,Month24 | Clinical response assessed by Lugano Response Criteria for non-Hodgkin Lymphoma |
| Cytokines ( IL(interleukin)-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN(interferon)-γ, TNF(tumor necrosis factor)-α and MCP( monocyte chemoattractant protein)-1) | Day0-Day28 | Pharmacodynamics (PD) |
| Maximum Plasma Concentration Time (Tmax) | Day0-Day28，Day0-undetectable for CAR positive T cells | Pharmacokinetics (PK) |
Countries
China
Contacts
Primary ContactJinxing Lou
Outcome results
None listed