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This study is a phase I multicenter, single arm, open, dose increasing, single treatment clinical study. This study plans to recruit a total of about 10-16 adult patients with CD19 positive recurrent or refractory DLBCL for a single autologous car-t cell therapy. There are three dose groups in the study. The first dose group has one patient. If there is no dose limiting toxicity (DLT), it can be increased to the second dose group, otherwise it will continue to be enrolled according to the "3 + 3" method; The follow-up dose group is conducted according to the traditional "3 + 3" design, that is, three subjects are first enrolled in a dose group. If there is no dose limiting toxicity (DLT) in the three patients in the dose group, it can be increased to the next higher dose after completing the DLT observation period; If DLT occurs in 1 of the 3 patients in the dose group, it is necessary to continue to enroll 3 patients in the dose group for DLT observation. The highest dose level of DLT in less than or equal to 1 of the last 6 confirmed patients will be defined as MTD. The safety of car-t treatment was evaluated by observing the adverse events after cell therapy; Evaluate the effectiveness of car-t treatment compared with the results or historical data of the patient's own previous standard treatment regimen. Blood and bone marrow were collected before and 12 months after cell infusion, the number and activity of car-t cells were detected, and the pharmacokinetics (PK) of car-t cells was evaluated.
This study is a phase I multicenter, single arm, open, dose increasing, single treatment clinical study. This study plans to recruit a total of about 10-16 adult patients with CD19 positive recurrent or refractory DLBCL for a single autologous car-t cell therapy. There were three dose groups in the study, and one patient in the first dose group, If there is no dose limiting toxicity (DLT), it can be increased to the second dose group, otherwise it will continue to be included in the group according to the "3 + 3" method; the follow-up dose group is designed according to the traditional "3 + 3" design, that is, three subjects will be included in a dose group first, if there is no dose limiting toxicity in the three patients in the dose group (DLT), after completing the DLT observation period, it can be increased to the next higher dose; if one of the three patients in the dose group has DLT, it is necessary to continue to join the group of three patients in the dose group for DLT observation. The highest dose level of DLT in less than or equal to one of the six patients finally confirmed will be defined as MTD. By observing the adverse events after cell therapy, the patients will be evaluated Evaluate the safety of car-t treatment; Evaluate the effectiveness of car-t treatment compared with the results or historical data of the patient's own previous standard treatment regimen. Blood and bone marrow were collected before and 12 months after cell infusion to detect the number and activity of car-t cells, Evaluate the pharmacokinetics (PK) of car-t cells. During the study, the blood samples used for the production of car-t cells will be transported to Shenzhen xiankangda Life Sciences Co., Ltd. (sponsor). After the production of car-t cells is completed, the car-t cells will be sent to the research unit so that the researchers can infuse them to the corresponding subjects.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Autologous anti-CD19 CAR-T cell injection | Experimental | with 1.00×106 CAR+T cells/kg, 3.00×106 CAR+T cells /kg and 9.00×106 CAR+T cells/kg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Autologous anti-CD19 CAR-T cell injection | Other | According to preclinical research, existing preliminary clinical data and similar approved therapeutic products (kte-c19 of Kate company, the trade name is yescarta ®) According to the clinical trial results, three doses (the number of cells per unit body weight) were selected as the therapeutic dose of this study. Among the patients who increased the dose according to the "3 + 3" design, the number of target cells in each dose group was: (1) the first dose group was 1.00 × 106 Car + T cells / kg, 20% dose error is allowed. (2) the second dose group is 3.00 × 106 Car + T cells / kg, 20% dose error is allowed. (3) the third dose group is 9.00 × 106 Car + T cells / kg, 20% dose error is allowed. |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse event | Type, incidence and severity of adverse events | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Maximum tolerated dose | The maximum dose that does not cause death of the subject | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Recommended dose for phase II | Determine the recommended dose for phase II clinical trials | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Peak time,Tmax | Venous blood samples were collected once during the infusion period D1, D2, D4, D6, D8, D10, D12, D14, D16, D18, D21, D24, d27, d30 and follow-up period. The proportion and count of car-t cells in peripheral blood and bone marrow were detected by flow cytometry and RT-PCR, and the PK parameters, PK characteristics and distribution of car-t cells in bone marrow were evaluated. The probe method of fluorescence quantitative PCR was used to monitor the copy number of CAR. |
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Inclusion Criteria:
Exclusion Criteria:
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| ID | Term |
|---|---|
| D016403 | Lymphoma, Large B-Cell, Diffuse |
| ID | Term |
|---|---|
| D016393 | Lymphoma, B-Cell |
| D008228 | Lymphoma, Non-Hodgkin |
| D008223 | Lymphoma |
| D009370 | Neoplasms by Histologic Type |
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Single infusion of autologous anti-CD19 car-t cells
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| The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Maximum concentration, Cmax | Venous blood samples were collected once during the infusion period D1, D2, D4, D6, D8, D10, D12, D14, D16, D18, D21, D24, d27, d30 and follow-up period. The proportion and count of car-t cells in peripheral blood and bone marrow were detected by flow cytometry and RT-PCR, and the PK parameters, PK characteristics and distribution of car-t cells in bone marrow were evaluated. The probe method of fluorescence quantitative PCR was used to monitor the copy number of CAR. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Area Under Curve, AUC1-30d | Venous blood samples were collected once during the infusion period D1, D2, D4, D6, D8, D10, D12, D14, D16, D18, D21, D24, d27, d30 and follow-up period. The proportion and count of car-t cells in peripheral blood and bone marrow were detected by flow cytometry and RT-PCR, and the PK parameters, PK characteristics and distribution of car-t cells in bone marrow were evaluated. The probe method of fluorescence quantitative PCR was used to monitor the copy number of CAR. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Pharmacodynamics | The peak value of cytokines within 1 month after car-t cell infusion and the time to return to the baseline state or normal range. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Total remission rate | The total remission rate of each dose group and all patients evaluated at 1 month, 3 months, 6 months, 9 months and 12 months after car-t treatment.M3 was scanned with systemic CT ± head, neck, chest, abdomen and pelvis enhanced CT. For M6, M9 and M12, enhanced CT or MRI of head, neck, chest and abdominal basin was used. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Complete remission rate | The complete remission rate of each dose group and all patients evaluated at 1 month, 3 months, 6 months, 9 months and 12 months after car-t treatment.M3 was scanned with systemic CT ± head, neck, chest, abdomen and pelvis enhanced CT. For M6, M9 and M12, enhanced CT or MRI of head, neck, chest and abdominal basin was used. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Partial remission rate | The partial remission rate of each dose group and all patients evaluated at 1 month, 3 months, 6 months, 9 months and 12 months after car-t treatment.M3 was scanned with systemic CT ± head, neck, chest, abdomen and pelvis enhanced CT. For M6, M9 and M12, enhanced CT or MRI of head, neck, chest and abdominal basin was used. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Distribution of car-t cells in bone marrow | The proportion and count of car-t cells in peripheral blood and bone marrow were detected by flow cytometry and RT-PCR to evaluate the distribution of car-t cells in bone marrow. The probe method of fluorescence quantitative PCR was used to monitor the copy number of CAR. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| Survival of car-t cells | Survival of car-t cells in adult patients with recurrent or refractory DLBCL. | The follow-up visit within 2 months is allowed to have a time window of ± 2 days, and the follow-up visit from the 3rd to 12th months is allowed to have a time window of ± 5 days. |
| D009369 |
| Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |