A Dose Escalating Study of CD19/CD22/BCMA CAR-T Therapy in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma(NHL)

Официальное название

A Dose Escalating Study of CD19/CD22/BCMA Three Targets Autologous Chimeric Antigen Receptor T (CAR-T) Cell Therapy in Subjects With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma(NHL)

Обзор

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.

Подробное описание

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).

Вмешательства

• Биопрепарат CD19/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

Первичные конечные точки

• Dose-limiting toxicity(DLT) [Срок оценки: Day0-Day28]
• Maximum tolerated dose (MTD) [Срок оценки: Day0-Day28]

Вторичные конечные точки (7)

• Maximum Plasma Concentration(Cmax) [Срок оценки: Day0-Day28，Day0-undetectable for CAR positive T cells]
• Maximum Plasma Concentration Time (Tmax) [Срок оценки: Day0-Day28，Day0-undetectable for CAR positive T cells]
• Area Under Curve (AUC) [Срок оценки: Day0-Day28，Day0-undetectable for CAR positive T cells]
• CAR positive T cells [Срок оценки: Day0-Day28，Day0-undetectable for CAR positive T cells]
• 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) [Срок оценки: Day0-Day28]
• Overall survival (OS) [Срок оценки: Day28,Month2,Month3,Month6,Month9,Month12,Month18,Month24]
• Progression-free survival (PFS) [Срок оценки: Day28,Month2,Month3,Month6,Month9,Month12,Month18,Month24]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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/exclusion criteria may apply.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Mengchao Cancer Hospital — Шанхай

Идентификаторы

NCT: NCT06446128 · BZE2204-A-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗