Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma

Обзор

To find the highest tolerable dose of dualCAR-NK19/70 (a type of cell therapy) that can be given to patients who have B-cell lymphoma that is relapsed or refractory.

Подробное описание

Primary Objectives:

--The primary objective is to determine the safety and identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of dualCAR-NK19/70 in patients with r/r B-cell lymphomas.

Hypothesis: DualCAR-NK19/70 will be safe, well-tolerated, and effective in patients with r/r B-cell lymphomas.

Secondary Objectives:

--The secondary objective is to determine the efficacy in adults with r/r LBCL and FL grade 3B treated at the MTD or RP2D of dualCAR-NK19/70. Although the clinical benefit of dualCAR-NK19/70 has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. Secondary endpoints include overall response rate (ORR; including CR + PR) and CR rate as defined by the Lugano Classification response criteria for malignant lymphoma, DOR, PFS, and OS.

Exploratory Objectives:

--The exploratory objectives are to assess the cellular kinetics and pharmacodynamic effects of dualCAR-NK19/70 and to evaluate biomarkers associated with response, resistance, and toxicity after administration of dualCAR-NK19/70 in blood and tumor samples.

Вмешательства

• Препарат dualCAR-NK19/70 cell
  Given by IV (vein)

Первичные конечные точки

• incidence of dose limiting toxicity(DLTs) [Срок оценки: up to 28 days]

Вторичные конечные точки (5)

• Objective Response Rate（ORR） [Срок оценки: 6 months]
• Complete Remission Rate(CRR) [Срок оценки: 3 months]
• Overall survival(OS) [Срок оценки: Up to 3 years]
• Duration of Response(DOR) [Срок оценки: Up to 3 years]
• progression-free survival(PFS) [Срок оценки: Up to 3 years]

Критерии участия

Критерии включения

• Voluntarily participate in the study and sign the informed consent;
• Age 18-75, male and female;
• Histologically confirmed diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and other Indolent B-cell NHL transforming types:

（A） Relapsed or Refractory DLBCL and tFL after 2 lines Immunotherapy or chemotherapy ; （B） Definition of Refractory large B cell lymphoma (SCHOLAR - 1 Research Standard) : disease progression after more than 4 courses of standard Immunotherapy or chemotherapy; Or the time of disease stabilization ≤ 6 months; Or disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation (auto-HSCT); （C） Relapsed or Refractory MCL must be 1 line with immune chemotherapy; BTK inhibitors are resistant or intolerant as 2-line therapy; （D） Relapsed or Refractory disease after chemotherapy including rituximab and anthracycline.

• There was at least one measurable lesion with the longest diameter ≥ 1.5cm;
• Estimated life expectancy of more than 12 weeks other than primary disease;
• Previously confirmed diagnosis as CD19+ or CD70+ B-NHL.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3.
• Adequate reserve of organ function:

（A） Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤2.5 times the Upper Limit of Normal (ULN) for age; （B） A creatinine clearance (as estimated either by a direct urine collection or Cockcroft-Gault Equation) > 60mL/min; （C） Total bilirubin and alkaline phosphatase ≤1.5 times the Upper Limit of Normal (ULN) for age; （D） glomerular filtration rate > 50 ml/min （E） Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA); （F） Baseline oxygen saturation >92% on room air （G） Absolute neutrophil count > 1000/μL, Platelet count > 45,000/μL ,Hemoglobin > 80g/L;

• Once previous autologous hematopoietic stem cell transplantation (auto-HSCT) is allowed;
• For systemic therapy(Such as systemic chemotherapy, systemic radiotherapy and immunotherapy), at least 3 weeks，for Targeted drug therapy alone，at least 2 weeks，must have elapsed at the time of cell infusion;
• Either having failed or Relapsed after CAR-T therapy at 3 months of assessment;
• Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study. Women of childbearing potential must have a negative serum or urine pregnancy test.
• The viral load of severe coronavirus disease 2019 (COVID-19) is undetectable per quantitative PCR and/or nucleic acid testing for two tests.

Критерии исключения

• Allergic to any of the components of cell products;
• Previous or concurrent of other type of maligant tumors;
• Acute GvHD or generalized chronic GvHD with grade II-IV (Glucksberg standard) after previous autologous hematopoietic stem cell transplantation (auto-HSCT); Or receiving of anti-GVHD therapy;
• Known history of systemic gene therapy within the prior 3 months;
• Active systemic fungal, viral, or bacterial infection (except for simple urinary tract infections and bacterial pharyngitis), however, Preventive treatment is permitted;
• Known history of infection with hepatitis B (HBsAg positive, but HBV-DNA<1000 is not excluded) or hepatitis C virus (including virus carriers), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to HIV infection;
• Class III or IV heart failure as defined by the New York Heart Association;
• Persisting toxicities (>grade 1, except for clinically non-significant toxicities such as alopecia, fatigue, and anorexia) due to prior trerapy;
• Known history of active seizures or presence of seizure activities or other central nervous system disease;
• Have evidence of central nervous system lymphoma(CNS lymphoma) on CT or MRI;
• Breast-feeding woman;
• Any circumstances that possibly increase the risk of subjects or interfere with study results, which judged by investigator.

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

• Shanghai Tongji Hospital, Tongji University School of Medicine — Шанхай

Идентификаторы

NCT: NCT05842707 · 2023-008

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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