LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies

Study Overview
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Brief Summary
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A study of LMP1 CAR-T for patients with LMP1 positive infectious diseases and hematological malignancies

Detailed Description
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This is a single arm, open-label, single-center study. This study is indicated for LMP1 positive infectious diseases and hematological malignancies. The selections of dose levels and the number of subjects are based on clinical trials of similar foreign products. 144 patients will be enrolled. Primary objective is to explore the safety, main consideration is dose-related safety.

Official Title
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Clinical Trial for the Safety and Efficacy of Sequential of LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies

Conditions
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Infectious Diseases, Hematological Malignancies

Intervention / Treatment
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* Drug: LMP1 CAR T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Only applicable to the inclusion criteria of CAEBV Subjects who are diagnosed with CAEBV according to the Okano revised standard proposed by the Japanese Ministry of Health, Labour and Welfare Research Group for the Prevention of Refractory Diseases; All CAEBV patients who have not achieved complete remission, including: Active phase: EBV-DNA level in PBMC is higher than 1×10^2.5 copies/μg DNA, with symptoms and signs of active diseases such as fever, hepatomegaly, splenomegaly, abnormal liver function, decrease of blood three lines, lymphadenopathy, and progressive skin lesions with increased EBV titer in peripheral blood; inactive phase: EBV-DNA level in PBMC is higher than 1×10^2.5 copies/μg DNA, without symptoms and signs of active diseases; The disease has not yet progressed to hematopoietic lymphohistiocytosis (HLH); Only applicable to the inclusion criteria of LMP1-positive ENKTL: According to the 2016 WHO classification criteria for lymphocytic tumors: Subjects diagnosed by histopathology as extranodal NK/T cell lymphoma, nasal type (ENKTL) with LMP1 positive in tumor tissue; R/R ENKTL (meets one of the following prerequisites) Without remission or with progression after receiving second-line or higher-line chemotherapy/chemotherapy + radiotherapy; Primary drug resistance; With recurrence after receiving autologous/allogeneic hematopoietic stem cell transplantation; According to 2014 Lugano standard, there should be at least one evaluable tumor lesion. Only applicable to the inclusion criteria for LMP1-positive HL: According to the 2016 WHO classification criteria for lymphocytic tumors, subjects with Hodgkin lymphoma diagnosed by histopathology (HD) and LMP1 positive in tumor tissue; R/R HD (meets one of the following prerequisites): Without remission or with progression after receiving second-line or higher-line chemotherapy; Primary resistance Drugs; With recurrence after receiving autologous hematopoietic stem cell transplantation; According to the Lugano 2014 standard, there should be at least one evaluable tumor lesion; Only applicable to the inclusion criteria for LMP1-positive PTLD: Only PTLD after hematopoietic stem cell transplantation; According to the 2016 WHO classification criteria for lymphocytic tumors, subjects with PTLD diagnosed by histopathology and LMP1 positive in tumor tissue; Excluding PTLD of early-stage R/R PTLD (meets one of the following prerequisites): Without remission or with progression after receiving rituximab-based standard treatment; Primary drug resistance; According to the Lugano 2014 standard, there should be at least one evaluable tumor lesion Exclusion Criteria: Subjects with any of the following exclusion criteria were not eligible for this trial: History of craniocerebral trauma, conscious disturbance,epilepsy,cerebrovascular ischemia, and cerebrovascular, hemorrhagic diseases; Electrocardiogram shows prolonged QT interval, severe heart diseases such as severe arrhythmia in the past; Pregnant (or lactating) women; Patients with severe active infections (excluding simple urinary tract infection and bacterial pharyngitis); Active infection of hepatitis B virus or hepatitis C virus; Concurrent therapy with systemic steroids within 2 weeks prior to screening, except for the patients recently or currently receiving in haled steroids; Previously treated with any CAR-T cell product or other genetically modified T cell therapies; Creatinine>2.5mg/dl, or ALT / AST > 3 times of normal amounts, or bilirubin>2.0 mg/dl; Other uncontrolled diseases that were not suitable for this trial; Patients with HIV infection; Any situations that the investigator believes may increase the risk ofpatients or interfere with the results of study
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of LMP1 CAR T-cells<br>Each subject receive LMP1 CAR T-cells by intravenous infusion | Drug: LMP1 CAR T-cells<br>* Each subject receive LMP1 CAR T-cells by intravenous infusion<br>* Other names: LMP1 CAR-T cells injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Adverse events assessed according to NCI-CTCAE v5.0 criteria | Baseline up to 28 days after LMP1 targeted CAR T-cells infusion | 
| Incidence of treatment-emergent adverse events (TEAEs) | Incidence of treatment-emergent adverse events [Safety and Tolerability] | Up to 2 years after LMP1 targeted CAR T-cells infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic active EB virus infection (CAEBV), Overall response rate (ORR) | Assessment of ORR (ORR = CR + PR) at Month 1, 3, 6, 12, 18 and 24 | At Month 1, 3, 6, 12, 18 and 24 | 
| CAEBV，Duration of remission（DOR） | From the first remission after LMP1 CAR-T cells to relapse, death or the last visit | Up to 2 years after LMP1 CAR-T cells infusion | 
| CAEBV, Overall survival (OS) | From the first infusion of LMP1 CAR-T cells to death or the last visit | Up to 2 years after LMP1 CAR-T cells infusion | 
| CAEBV, Relapse rate(RR) | From the first remission after LMP1 CAR-T cells to relapse or the last visit | At Month 6, 12, 18 and 24 | 
| CAEBV, Event-free survival (EFS) | From the first infusion of LMP1 CAR-T cells to the occurrence of any event, including death, relapse or gene relapse, disease progression (any one occurs first), and the last visit | Up to 2 years after LMP1 CAR-T cells infusion | 
| Hodgkin's lymphoma(HL), Extranodal NK/T cell lymphoma(ENKTL),Nasal type, Lymphoproliferative disease after hematopoietic stem cell transplantation, (post-HSCT PTLD),Overall response rate (ORR) | Assessment of ORR (ORR = CR + PR) at Month 1, 3, 6, 12, 18 and 24 | At Month 1, 3, 6, 12, 18 and 24 | 
| HL, ENKTL, PTLD, OS | From the first infusion of LMP1 CAR-T cells to death or the last visit | Up to 2 years after LMP1 CAR-T cells infusion | 
| HL, ENKTL, PTLD, EFS | From the first infusion of LMP1 CAR-T cells to the occurrence of any event, including death, relapse or gene relapse, disease progression (any one occurs first), and the last visit | Up to 2 years after LMP3 CAR-T cells infusion | 
| Quality of life | Assessment using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale [For item1-28: max score: 112, min score: 28, higher scores mean a better outcome; for item 28-29: max score: 14, min score: 2, higher scores mean a worse outcome] to measure Quality of life at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| Activities of Daily Living (ADL) score | Assessment using Activities of Daily Living (ADL) scale (Barthel Index) [max score: 100, min score: 0, higher scores mean a better outcome] at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| Instrumental Activities of Daily Living (IADL) score | Assessment of Instrumental Activities of Daily Living (IADL) scale [max score: 56, min score: 14, higher scores mean a worse outcome] at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| Hospital Anxiety and Depression Scale (HADS) score | Assessment using Hospital Anxiety and Depression Scale (HADS) [max score: 42, min score: 0, higher scores mean a worse outcome] at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infectious diseases, Hematological Malignancies, CAR T-cell therapy, LMP1