Clinical trial NCT04657965: LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies
Official title: Clinical Trial for the Safety and Efficacy of Sequential of LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: EARLY_PHASE1
Conditions: Infectious Diseases
Hematological Malignancies
Keywords: Infectious diseases
Hematological Malignancies
CAR T-cell therapy
LMP1
Lead sponsor: Zhejiang University
Sponsor class: OTHER
Collaborators: name: Yake Biotechnology Ltd.
First posted: 2020-12-08
Enrollment: 144
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A study of LMP1 CAR-T for patients with LMP1 positive infectious diseases and hematological malignancies

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Only applicable to the inclusion criteria of CAEBV

1. 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;
2. All CAEBV patients who have not achieved complete remission, including:

   1. 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;
   2. inactive phase: EBV-DNA level in PBMC is higher than 1×10\^2.5 copies/μg DNA, without symptoms and signs of active diseases;
3. The disease has not yet progressed to hematopoietic lymphohistiocytosis (HLH);

Only applicable to the inclusion criteria of LMP1-positive ENKTL:

1. 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;
2. R/R ENKTL (meets one of the following prerequisites)

   1. Without remission or with progression after receiving second-line or higher-line chemotherapy/chemotherapy + radiotherapy;
   2. Primary drug resistance;
   3. With recurrence after receiving autologous/allogeneic hematopoietic stem cell transplantation;
3. According to 2014 Lugano standard, there should be at least one evaluable tumor lesion.

Only applicable to the inclusion criteria for LMP1-positive HL:

1. According to the 2016 WHO classification criteria for lymphocytic tumors, subjects with Hodgkin lymphoma diagnosed by histopathology (HD) and LMP1 positive in tumor tissue;
2. R/R HD (meets one of the following prerequisites):

   1. Without remission or with progression after receiving second-line or higher-line chemotherapy;
   2. Primary resistance Drugs;
   3. With recurrence after receiving autologous hematopoietic stem cell transplantation;
3. 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:

1. Only PTLD after hematopoietic stem cell transplantation;
2. According to the 2016 WHO classification criteria for lymphocytic tumors, subjects with PTLD diagnosed by histopathology and LMP1 positive in tumor tissue;
3. Excluding PTLD of early-stage
4. R/R PTLD (meets one of the following prerequisites):

   1. Without remission or with progression after receiving rituximab-based standard treatment;
   2. Primary drug resistance;
5. 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:

1. History of craniocerebral trauma, conscious disturbance,epilepsy,cerebrovascular ischemia, and cerebrovascular, hemorrhagic diseases;
2. Electrocardiogram shows prolonged QT interval, severe heart diseases such as severe arrhythmia in the past;
3. Pregnant (or lactating) women;
4. Patients with severe active infections (excluding simple urinary tract infection and bacterial pharyngitis);
5. Active infection of hepatitis B virus or hepatitis C virus;
6. Concurrent therapy with systemic steroids within 2 weeks prior to screening, except for the patients recently or currently receiving in haled steroids;
7. Previously treated with any CAR-T cell product or other genetically modified T cell therapies;
8. Creatinine\>2.5mg/dl, or ALT / AST \> 3 times of normal amounts, or bilirubin\>2.0 mg/dl;
9. Other uncontrolled diseases that were not suitable for this trial;
10. Patients with HIV infection;
11. Any situations that the investigator believes may increase the risk ofpatients or interfere with the results of study

Primary outcomes:
measure: Dose-limiting toxicity (DLT)
timeFrame: Baseline up to 28 days after LMP1 targeted CAR T-cells infusion
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: Up to 2 years after LMP1 targeted CAR T-cells infusion
Secondary outcomes:
measure: Chronic active EB virus infection (CAEBV), Overall response rate (ORR)
timeFrame: At Month 1, 3, 6, 12, 18 and 24
measure: CAEBV，Duration of remission（DOR）
timeFrame: Up to 2 years after LMP1 CAR-T cells infusion
measure: CAEBV, Overall survival (OS)
timeFrame: Up to 2 years after LMP1 CAR-T cells infusion
measure: CAEBV, Relapse rate(RR)
timeFrame: At Month 6, 12, 18 and 24
measure: CAEBV, Event-free survival (EFS)
timeFrame: Up to 2 years after LMP1 CAR-T cells infusion
measure: 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)
timeFrame: At Month 1, 3, 6, 12, 18 and 24
measure: HL, ENKTL, PTLD, OS
timeFrame: Up to 2 years after LMP1 CAR-T cells infusion
measure: HL, ENKTL, PTLD, EFS
timeFrame: Up to 2 years after LMP3 CAR-T cells infusion
measure: Quality of life
timeFrame: At Baseline, Month 1, 3, 6, 9 and 12
measure: Activities of Daily Living (ADL) score
timeFrame: At Baseline, Month 1, 3, 6, 9 and 12
measure: Instrumental Activities of Daily Living (IADL) score
timeFrame: At Baseline, Month 1, 3, 6, 9 and 12
measure: Hospital Anxiety and Depression Scale (HADS) score
timeFrame: At Baseline, Month 1, 3, 6, 9 and 12
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: The First Affiliated Hospital，College of Medicine, Zhejiang University
state: Zhejiang
Study officials:
References: