Overview
TRAC Locus-inserted CD19-targeting STAR-T Cell Therapy in r/r B-NHL
Status:
Recruiting
Recruiting
Trial end date:
2025-12-15
2025-12-15
Target enrollment:
0
0
Participant gender:
All
All
Summary
The team has developed a chimeric antigen receptor (CAR) based on T cell receptor (TCR) complex, called synthetic TCR and antigen receptor (STAR). Further, the researchers disrupted the endogenous T-cell receptor α constant (TRAC) locus by CRISPR/cas9, and then knocked in the anti-CD19-STAR construct through TRAC endogenous promoter. In this single center, prospective, open-label, single-arm, phase 1/2 study, the safety and efficacy of autologous CD19-targeting STAR-T cell therapy will be evaluated in patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (B-NHL) . A total of 19 to 38 patients are planned to be enrolled and receive CD19-STAR-T cell infusion. Phase 1 (9 to 18 cases) is dose escalation part, and phase 2 (10 to 20 cases) is expansion cohort part.Phase:
Phase 1/Phase 2Accepts Healthy Volunteers?
NoDetails
Lead Sponsor:
Chinese PLA General HospitalTreatments:
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Criteria
Inclusion Criteria:1. Age 18-75 (inclusive).
2. Patients with histologically confirmed CD19-positive B-cell NHL, including the
following types defined by the World Health Organization (WHO) 2016:
- Diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), including
Activated B-cell type (ABC) / Germinal center B-cell Type (GCB);
- Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
- Transformed follicular lymphoma (TFL);
- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
- Follicular lymphoma (FL);
- Mantle cell lymphoma (MCL) [pathologically confirmed, with documentation of
monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or
overexpress cyclin D1];
- Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell
lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
3. Relapse after treatment with ≥2 lines systemic therapy for all the above disease
types, or refractory disease for aggressive types (DLBCL-NOS, PMBCL, TFL and HGBCL).
Relapse disease is defined as disease progression after last regimen. Refractory
disease is defined as no CR to first-line therapy:
- PD as best response to first-line therapy, or
- SD as best response after at least 4 cycles of first-line therapy (eg, 4 cycles
of R-CHOP), or
- PR as best response after at least 6 cycles and biopsy-proven residual disease or
disease progression ≤ 6 months of therapy, or
- Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or
relapsed less than or equal to 12 months of ASCT (must have biopsy proven
recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT,
the individual must have had no response to or relapsed after the last line of
therapy.
4. Individuals must have received adequate prior therapy:
- For MCL, prior therapy must have included:
- Anthracycline or bendamustine-containing chemotherapy and
- Anti-CD20 monoclonal antibody (unless investigator determines that tumor is
CD20-negative) and
- Bruton's tyrosine kinase inhibitor (BTKi)
- For other types, prior therapy must have included:
- Anti-CD20 monoclonal antibody (unless investigator determines that tumor is
CD20-negative) and
- Anthracycline containing chemotherapy regimen.
- For individual with transformed FL must have relapse or refractory disease after
transformation to DLBCL.
5. The estimated survival time is over 3 months.
6. The Eastern Cooperative Oncology Group (ECOG) score is 0-2.
7. According to Lugano response criteria 2014, there should be at least one evaluable
tumor focus. Evaluable tumor focus was defined as that with the longest diameter of
intranodal focus > 1.5cm, the longest diameter of extranodal focus > 1.0cm assessed by
computed tomography (CT) or magnetic resonance imaging (MRI).
8. Subjects must be willing to undergo either excised or large-needle lymph node or
tissue biopsy, or provide formalin-fixed paraffin-embedded (FFPE) tumor tissue block
or freshly cut unstained slides.
9. Functions of important organs meet the following requirements: Echocardiography showed
left ventricular ejection fraction ≥50%. Serum creatinine ≤1.5 × upper limit of normal
range (ULN) or endogenous creatinine clearance ≥45mL/min (cockcroft-gault formula);
Alanine ULN, Total bilirubin ≤1.5× ULN; Pulmonary function: ≤CTCAE grade 1 dyspnea and
oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
10. Blood routine (normal values shall not be obtained with growth factors, and
hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions
below): hemoglobin (Hgb) ≥80g/L, neutrophil count (ANC) ≥1×10^6/L, platelet (PLT)
≥75×10^9/L.
11. Pregnancy tests for women of childbearing age shall be negative; Both men and women
agreed to use effective contraception during treatment and during the subsequent 1
year.
12. Toxicity from previous antitumor therapy ≤ grade 1 (according to CTCAE version 5.0) or
to an acceptable level of inclusion/exclusion criteria (other toxicities such as
alopecia and vitiligo considered by the investigator to pose no safety risk to the
subject).
13. No obvious hereditary diseases.
14. Able to understand the requirements and matters of the trial, and willing to
participate in clinical research as required.
15. Informed consent must be signed.
Exclusion Criteria:
1. During the screening period, there was central nervous system (CNS) invasion or a
history of clinically significant central nervous system diseases, such as epilepsy
and cerebrovascular diseases.
2. Women who are pregnant or breastfeeding, or who do not agree to use effective
contraception during treatment and during the subsequent 1 year.
3. History of allogeneic hematopoietic stem cell transplantation, or organ
transplantation.
4. History of other malignancies that have not been in remission.
5. Patients with primary immunodeficiency or autoimmune diseases requiring
immunosuppressive therapy.
6. Received radiotherapy within 3 months before enrollment.
7. Received immunotherapy drugs within 4 weeks before enrollment, such as anti-programmed
death 1 (PD-1) antibody, anti-programmed death ligand 1 (PD-L1) antibody,
CD19/CD3-bispecific antibody, and so on.
8. Patients who received any immunocellular therapy within 6 months before enrollment.
9. Confirmed evidence showing positiveness of anti-CD19 scFv reaction in patient serum.
10. Patients who participated in other clinical trials within 4 weeks prior to enrollment.
11. Uncontrolled infectious diseases or other serious illnesses, including but not limited
to infections [e.g., human immunodeficiency virus (HIV) infection or acute or chronic
active hepatitis B (HBV) or C (HCV) infection], congestive heart failure, unstable
angina, arrhythmias, or that pose an unpredictable risk in the opinion of the
attending physician.
12. The presence of uncontrollable serous membrane fluid, such as massive pleural effusion
or ascites.
13. A history of stroke or intracranial hemorrhage within 3 months prior to enrollment.
14. Major surgery or trauma occurred within 28 days prior to enrollment, or major side
effects have not been recovered.
15. History of allergies to any of the ingredients in cell products.
16. Conditions in which a known mental or physical illness interferes with cooperation
with the requirements of the study or disrupts the results or interpretation of the
results and, in the opinion of the therapeutic investigator, makes the patient unfit
for study participation.
17. There is the situation that the researcher's judgment will interfere with the whole
study participation; Situations where there is significant risk to the subject; Or
interferes with the interpretation of research data.
18. Inability to understand or unwillingness to sign informed consent.
19. Researchers believe that other reasons are not suitable for clinical trials.