| Eligibility |
Inclusion Criteria:
1. Volunteer to participate in the clinical study; fully understand and be informed of
the information on this study, and sign the written Informed Consent Form (ICF);
willing to follow and able to complete all trial procedures.
2. According to the criteria for B-cell lymphoma defined in the National Comprehensive
Cancer Network (NCCN) Guidelines for Lymphoma (5th edition 2018), and with CD19-
and/or CD22-positive lymphoma cells detected by flow cytometry or
immunohistochemistry;
3. Must have at least 1 evaluable or measurable lesion meeting Lugano 2014 criteria
[Evaluable lesions: Fluorodeoxyglucose/positron emission tomography (FDG/PET) showed
increased local uptake in lymph nodes or extranodal sites (higher than the liver), and
PET and/or computed tomography (CT) findings are consistent with lymphoma
manifestations. Measurable lesions: defined as nodule lesions with a long diameter
greater than 15 or extranodal lesions with a long diameter greater than 10 mm (if the
only measurable lesion has been previously treated with radiation therapy, the
evidence of radiographic progression after radiation therapy is required), with
increased FDG uptake). Absence of measurable lesion and diffuse increase of hepatic
FDG uptake should be excluded.
4. Relapsed/refractory BCL (meet one of the following conditions):
1. Subjects in this category had received at least two cycles of two or more lines
of standard of care and had been evaluated for best clinical response per Lugano
2014 at the time of enrollment: (one of the following conditions are met)
- The subject had a best clinical response of PD after the most recent
standard chemotherapy;
- The subject had a best clinical response of SD after the most recent
standard chemotherapy, but PD occurred when SD persisted for less than 6
months;
2. Recurrence or progression within = 12 months after autologous hematopoietic stem
cell transplantation;
3. In one of the following situations, the benefit of the subject may outweigh the
risk as judged jointly by the investigator and the partner:
- The subject had received at least two lines of standard of care, and the
best response after the most recent standard chemotherapy was SD, which
persisted for less than 6 months, and the evaluable or measurable disease
was larger than before but did not achieve PD;
- The subject had received at least two lines of standard of care, and the
best response after the most recent standard chemotherapy was partial
response (PR) or higher, but persisted for less than 6 months before
progression;
- The subject had received at least two lines of standard of care and was
intolerant to the most recent chemotherapy.
5. All subjects must have received standardized treatment regimens with anti-CD20
monoclonal antibodies (except for those with CD20-negative tumors as determined by the
investigator) and anthracyclines. For standardized treatment regimens, please refer to
the criteria in the NCCN Guidelines for B-cell Lymphoma (version 5, 2018);
6. Male or female, aged 18-75 years at the time of signing the ICF;
7. Primary laboratory test values met the following criteria to demonstrate adequate
organ and bone marrow function without severe hematopoietic abnormalities and heart,
lung, liver, renal dysfunction and immunodeficiency:
Serum albumin =30g/L Haemoglobin = 8.0 g/dL (no red blood cell [RBC] infusion within 7
days prior to laboratory tests; recombinant human erythropoietin is allowed) *
Absolute neutrophil count = 0.75 × 109/L (growth factor support is allowed but must
not have received supportive care within 7 days prior to laboratory tests) Platelet =
40 × 109/L (must not have received blood transfusion support within 7 days prior to
laboratory tests) Creatinine clearance = 40 mL/min/1.73 m2, calculated according to
Modified Dietary Formula for Renal Disease (Attachment 11) or 24-hour urine collection
results.
ALT and AST = 3.0 x upper limit of normal (ULN) Total bilirubin = 2.0 × ULN; except
for subjects with congenital bilirubinemia, such as Gilbert's syndrome (in this case,
direct bilirubin = 1.5 x ULN is required) Coagulation PT and APTT <2ULN SpO2 =95%
* For subjects who meet the inclusion criteria at screening, red blood cell infusion
after the first hematology test at screening is allowed to maintain hemoglobin levels
= 8.0 g/dL.
8. ECOG performance status of 0-1;
9. Estimated survival time of patients > 90 days;
10. A highly sensitive serum pregnancy test (beta human chorionic gonadotropin [beta-HCG])
must be negative at screening and prior to first treatment with cyclophosphamide and
fludarabine in women of childbearing potential.
11. Women of childbearing potential must comply with the following requirements:
- Subjects must agree to use a highly effective method of contraception (annual
failure rate < 1% for continuous and correct use) and agree to use a highly
effective method of contraception from signing the informed consent form (ICF)
until at least 1 year after receiving infusion of LCAR-L10D cell formulation.
Highly effective methods of contraception include:
- User-independent methods: 1) implantable progesterone contraceptives that
inhibit ovulation; 2) intra-uterine devices (IUDs); intrauterine
hormone-releasing systems; 3) vasectomies in sexual partners;
- User-dependent methods: 1) compound (estrogen- and progestogen-containing)
hormonal contraceptives that inhibit ovulation: oral, vaginal and
transdermal; 2) progesterone contraceptives (oral or injectable) that
inhibit ovulation.
In addition to highly effective methods of contraception, male subjects should:
- Agree to use barrier contraception (e.g. condoms plus spermicidal
foam/gel/film/emulsion/suppository) upon sexual intercourse with a woman of
childbearing potential from signing the ICF to at least 1 year after receiving
infusion of the LCAR-L10D cell formulation.
- Use condoms when having sex with a pregnant woman Women and men must agree not to
donate ova (oocytes, oocytes) or sperm during the study and within 1 year after
infusion of LCAR-L10D cell formulation.
Note: Hormonal contraceptives may interact with study treatment, resulting in decreased
contraceptive efficacy.
Exclusion Criteria:
1. Subjects who have received any CART cell therapy or other genetically modified T cell
therapy;
2. Previous allogeneic stem cell transplantation.
3. Have been diagnosed or treated with other aggressive malignancies other than B-cell
lymphoma, with the following exceptions:
1. Malignant tumors that have been treated radically, and no known active disease
within = 2 years prior to enrollment; or
2. Non-melanoma skin cancers have been adequately treated without symptom of
disease.
4. Previous anti-tumor therapy (prior to apheresis) as follows:
1. Targeted therapy, epigenetic therapy, or investigational drug within 14 days or
at least 5 half-lives (whichever is shorter), or has used an invasive
investigational medical device.
2. Cytotoxic drugs within 14 days.
3. Immunomodulator within 7 days.
4. Monoclonal antibodies to treat BCL within 21 days.
5. Radiation therapy within 14 days.
5. Positive for any one of hepatitis B surface antigen (HBsAg), hepatitis B virus
deoxyribonucleic acid (HBV DNA), hepatitis C antibody (HCV-Ab), hepatitis C virus
ribonucleic acid (HCV RNA), or human immunodeficiency virus antibody (HIV-Ab)
6. The following cardiac disorders occurred:
1. New York Heart Association (NYHA) phase III or IV congestive heart failure;
2. Myocardial infarction or coronary artery bypass graft (CABG) = 6 months prior to
enrollment;
3. History of clinically significant ventricular arrhythmia or unexplained syncope
(non-vasovagal or caused by dehydration);
4. History of severe nonischemic cardiomyopathy;
5. Impaired cardiac function (LVEF < 50%) as assessed by echocardiogram or multiple
gated acquisition scan (MUGA) (performed = 8 weeks prior to apheresis).
6. Clinically significant pericardial effusion
7. Clinically significant pleural effusion(Excluding caused by lymphoma mass compression
or pleural involvement);
8. Except alopecia or peripheral neuropathy, other toxicity of prior anti-tumor therapy
must have improved to baseline or = Grade 1.
9. Patients with serious underlying diseases, such as:
1. Documented serious active viral or bacterial infection, or uncontrolled systemic
fungal infections;
2. Active auto-immune diseases or medical history of auto-immune diseases within 3
years;
3. Clear clinical evidence of dementia or altered mental status.
10. Female subjects who become pregnant, are breastfeeding, or plan to become pregnant
while participating in the study or within 1 year after receiving study treatment;
11. Male subjects who plan to have a baby while participating in the study or within 1
year after receiving study treatment;
12. Subjects with marked bleeding tendency, e.g, digestive tract hemorrhage, coagulation
disorder, hypersplenism (diagnosed by splenomegaly noted by palpation or
ultrasonography, cytopenia, and hematopoietic cell hyperplasia in the bone marrow);
13. The equivalent dose of corticosteroids used cumulatively within 7 days prior to
apheresis was = 70 mg prednisone;
14. Concomitant anticancer drugs or therapies (including radiotherapy);
15. Occurrence of a stroke or epileptic seizure within 6 months prior to signing the ICF;
16. Administration of live attenuated vaccine within 4 weeks prior to apheresis;
17. Major surgery within 2 weeks prior to apheresis, or scheduled surgery during the study
or within 2 weeks after administration of study treatment. (Note: Subjects who plan to
undergo surgery under local anesthesia may participate in the study.)
18. Any condition that is not conducive to the subject's ability to receive or tolerate
the planned treatment at the study site, or understand the informed consent form, or
any condition that, in the opinion of the investigator, is not in the best interest of
the subject (e.g., impairing health), or any condition that may prevent, limit, or
confound protocol-specified assessments.
19. Known life threatening allergic reactions, hypersensitivity reactions, or intolerance
to LCAR-L10D cell formulation or their excipients, including DMSO (see Investigator's
Brochure).
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