The Safety and Efficacy of BRL-201 in the Treatment of r/r B Lymphocyte Non-Hodgkin Lymphoma

Official title

A Phase I/II Clinical Study of the Safety and Efficacy of CD19-targeted Non-viral PD1 Site-specific Integrated CAR-T Cell Injection (BRL-201) in the Treatment of Relapsed or Refractory B Lymphocyte Non-Hodgkin Lymphoma

Overview

This is a multi-center, single-arm, open-label clinical study, and the sample size is set to 12-18 subjects.

Detailed description

This is a multi-center, single-arm, open-label clinical study, and the sample size is set to 12-18 subjects. Based on the "3 + 3" dose escalation design principle, subjects will be divided into 3 groups from low dose to high dose in sequence (Group A; Group B; Group C. Additional subjects will be enrolled into the RP2D group to ensure that 6-9 efficacy-evaluable subjects are available in the RP2D group before entering the phase II study.

Interventions

• Drug CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection
  CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection

Primary outcome measures

• DLT [Time frame: Within 28 Days After BRL-201 Infusion]
• AEs [Time frame: Up to 24 Months After BRL-201 Infusion]
• RP2D [Time frame: Within 28 Days After BRL-201 Infusion]

Eligibility criteria

Inclusion criteria

• Willing to participate in this clinical study and sign an informed consent form;
• Age ≥ 18 years old;
• Estimated survival time ≥ 3 months;
• Presence of at least one measurable lesion as assessed according to Lugano Classification 2014 for response assessment in lymphomas (i.e., the cross-sectional images obtained by CT show that the long diameter of lymph node lesions is > 15 mm or the long diameter of extranodal lesions is > 10 mm, and FDG-PET scan results are positive). Lesions, for which radiotherapy was provided, can be regarded as measurable lesions only if there is an unequivocal progression after radiotherapy;
• Histopathologically confirmed aggressive B-NHL; positive expression of CD19 in tumors detected by immunohistochemistry or flow cytometry; pathological types of B-NHL (according to WHO Lymphoma Classification 2016);
• Relapsed or refractory diseases;
• Subjects who must receive adequate prior therapy;
• Absence of invasion of central nervous system (CNS) lymphoma by cranial magnetic resonance imaging (MRI);
• Hematological parameters meeting the requirements;
• Blood biochemistry meeting the requirements;
• LVEF ≥ 55%;
• No severe pulmonary disorders;
• Toxic reactions induced by prior anti-lymphoma therapy must be stable and resolved to grade ≤ 1;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;
• Patients with physical conditions for apheresis of peripheral blood; 16 . Willing to abide by the rules formulated in the study protocol.

Exclusion criteria

• Pregnant or lactating women;
• Subjects who previously received allogeneic cell therapies, including allogeneic stem cell transplant;
• Subjects who previously received anti-CD19 targeted therapy, except those who receive BRL-201 and are eligible to receive reinfusion in this study;
• Prior treatment with any CAR-T cell product or other genetically modified T cell therapies;
• History of Richter's transformation of chronic lymphocytic leukemia (CLL);
• Presence of uncontrollable fungal, bacterial, viral, or other infections requiring systemic therapy. Patients can be enrolled if the simple urinary tract infection or pharyngitis responds to treatment;
• Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and peripheral blood HBV DNA titer higher than the upper limit of detection; hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive; human immunodeficiency virus (HIV) antibody positive; syphilis test positive;
• Severe mental disorders; history of CNS disorders (e.g., epileptic seizure, cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases, or any CNS-involved autoimmune disorders);
• Active autoimmune disorders requiring immunotherapy, including but not limited to end organ damages caused by autoimmune disorders (e.g., Crohn's disease, rheumatoid arthritis, and systemic lupus erythematosus) in the past 2 years, or requiring systemic application of immunosuppressive drugs or other drugs for systemic control of diseases;
• Primary immunodeficiency;
• History of other malignancies;
• Patients with severe cardiovascular disorders, including but not limited to those with lymphoma infiltration in the cardiac atrium or ventricles and those with a history of myocardial infarction, cardioangioplasty or stent implantation, unstable angina, or other clinically significant heart diseases within 12 months before enrollment;
• History of deep venous thrombosis or pulmonary embolism within 6 months before enrollment;
• Patients who are receiving oral anticoagulant therapy; prothrombin time (PT), activated partial thromboplastin time (APTT), or international normalized ratio (INR) > 1.5 × ULN without anticoagulant therapy;
• Presence of any indwelling tube or catheter (e.g., tube or catheter for percutaneous nephrostomy, indwelling catheter, or catheter in pleural cavity/peritoneal cavity/pericardium). Dedicated central venous access catheters (e.g., Port-a-Cath or Hickman catheter) are permitted;
• Lymphoma cells detected in cerebrospinal fluid, presence of brain metastases, history of CNS lymphoma, or history of lymphoma cells detected in cerebrospinal fluid or brain metastases;
• Conditions (e.g., intestinal obstruction or vascular compression) requiring emergency treatment due to tumor masses;
• History of severe immediate hypersensitivity to any drug to be used in this study;
• Vaccination of live vaccines, excluding corona virus disease 2019 (COVID-19) vaccines, within ≤ 6 weeks before the start of the pretreatment regimen;
• Any circumstances that possibly increase the risk of subjects or interfere with the study results as judged by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 3 centers

• Wuhan Union Hospital — Wuhan
• Tianjin Institute of Hematology — Tianjin
• The First Affiliated Hospital of Zhejiang University — Hangzhou

Identifiers

NCT: NCT05741359 · 2022-BRL-201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗