Trial Title:
TRAC Locus-inserted CD19-targeting STAR-T Cell Therapy in r/r B-NHL
NCT ID:
NCT05631912
Condition:
Non-hodgkin Lymphoma,B Cell
Conditions: Official terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Autologous CD19-STAR-T cell
Description:
Phase 1 dose escalation (3+3) : dose 1 (1×10^6 cells/kg) ,dose 2 (3×10^6 cells/kg) ,dose
3 (1×10^7 cells/kg); Phase 2 : Appropriate dose
Arm group label:
Autologous TRAC locus-inserted CD19-targeting STAR-T cells
Other name:
Autologous CD19-targeting synthetic T-cell receptor antigen receptor T cells
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Intravenous fludarabine 25-30 mg/m^2/day on days -5, -4, and -3.
Arm group label:
Autologous TRAC locus-inserted CD19-targeting STAR-T cells
Other name:
Fludarabine Phosphate for Injection
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Intravenous cyclophosphamide 300-500 mg/m^2/day on days -5, -4, and -3.
Arm group label:
Autologous TRAC locus-inserted CD19-targeting STAR-T cells
Other name:
Cyclophosphamide for Injection
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.
Detailed description:
[Introduction]
At present, CAR-T cell therapy targeting CD19 has achieved remarkable efficacy in the
treatment of r/r B-NHL. However, at the same time, CAR-T cell treatment has a high
incidence of cytokine release syndrome (CRS), immune cell-associated neurotoxicity
syndrome (ICANS) and other toxicities. TCR-T is another adoptive T cell therapy, which
recognizes the surface and intracellular antigens of target cells presented by major
histocompatibility complex (MHC) molecules and engage CD3 signaling machinery, triggering
a wide range of TCR-CD3 signaling to kill tumors. TCR-T is characterized by high affinity
with target antigen, low toxicity, but difficulty in preparation.
Here, the researchers connected the murine TCR constant regions α and β with the light
chain and heavy chain of the murine FMC63 single-chain variable fragment (scFv)
respectively to construct a human leukocyte antigen (HLA)-independent antibody TCR
chimera, called synthetic T cell receptor and antigen receptor (STAR). Then, researchers
introduced an additional interchain disulfide bond by making cysteine mutations within
TCRα/β constant regions, and employed hydrophobic substitutions to the TCR-α chain
transmembrane domain to improve the receptor's stability on plasma membrane.
Further, the team disrupted the endogenous TRAC locus by CRISPR/cas9, and then knocked in
the CD19-STAR construct to this locus, and transcription of CD19-STAR triggered by the
TRAC endogenous promoter. TRAC locus knockout can prevent endogenous TCR assembly, and
avoid the harm caused by graft-versus host disease (GVHD) as well as random insertion.
This specific integration of "two in one" technology can give rise to highly efficient
expression of CD19-STAR chimeric molecule on T cell surface, and the subsequent assembly
of complete TCR signaling structure.
The molecular structure of STAR in this study: the variable region of TCRα/β chain is
replaced with the heavy chain and light chain of FMC63 antibody respectively, the
intracellular region of α/β chain is connected with an OX40 costimulatory molecule
respectively.
STAR integrates the advantages of TCR and CAR, and is close to the natural TCR-antigen
action mode with high affinity, high sensitivity, and low T cell exhaustion. Compared
with TCR-T, it is easier to obtain and prepare. The researchers confirmed that the
CD19-STAR-T cells, by in vitro and in vivo assays, had lower cytokine release but more
efficient anti-tumor activities when compared to canonical CAR-T cells. In this study, we
would like to evaluate the safety and efficacy of autologous TRAC locus-inserted
CD19-STAR-T cell in r/r patients with r/r B-NHL . The completion of this trial will
provide a research foundation for potential universal allogeneic adoptive T cell therapy.
[Study design]
Phase 1 (dose escalation)
In phase 1, 9 to 18 subjects will be enrolled. Subjects will receive 3 doses of
CD19-STAR-T cell therapy (1 × 10^6 cells/kg, 3 × 10^6 cells/kg, 1 × 10^7 cells/kg) from
low dose to high dose according to the "3 + 3" principle:
1. Three patients were enrolled in the lowest dose group.
2. Subsequent patients were enrolled according to the following rules:
1. If the incidence of dose limiting toxicity (DLT) was 0/3, 3 patients were
enrolled in the next high-dose group.
2. If the incidence of DLT was 1/3, 3 patients were enrolled at the same dose; If
the incidence of DLT was 1/3 + 0/3, 3 patients were enrolled in the next
high-dose group. If the incidence of DLT was 1/3 + 1/3, this dose was defined
as maximum tolerated dose (MTD); If the incidence of DLT was 1/3 + 2/3 or 1/3 +
3/3, the previous dose was MTD.
3. If the incidence of DLT was 2/3 or 3/3, the previous dose was MTD.
To ensure the safety of the subjects, the first subject in each dose group was observed
for at least 28 days after the cell infusion. If no DLT occurred, the remaining two
subjects could be enrolled and treated at the same dose level. The safety data of all
subjects in each dose group until day 28 should be reviewed and tolerated before
proceeding to the next dose group trial. No dose escalation was allowed for the same
subject during the trial. If a subject drop out during the observation period due to
non-DLT reasons, new subjects should be enrolled to make up for the number of subjects
who drop out.
Phase 2 (expansion cohort)
In phase 2, 10 to 20 subjects will be enrolled and receive CD19-STAR-T cell infusion at
dose of RP2D, which will be determined based on the MTD, occurrence of DLT, the obtained
efficacy results, pharmacokinetics / pharmacodynamics and other data according to the
phase 1.
[Objectives]
The primary objectives of the phase 1 were to evaluate the tolerability, safety, and
determine recommended phase 2 dose (RP2D). The primary purpose of the phase 2 study was
to evaluate the efficacy.
Criteria for eligibility:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Biotherapeutic Department, Chinese PLA General Hospital
Address:
City:
Beijing
Zip:
100853
Country:
China
Status:
Recruiting
Contact:
Last name:
Weidong Han, Ph.D
Phone:
+86-010-66937463
Email:
hanwdrsw@sina.com
Contact backup:
Last name:
Yang Liu, M.D.
Phone:
+86-010-66937463
Email:
liuyang301blood@163.com
Investigator:
Last name:
Yang Liu, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Qingming Yang, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Chunmeng Wang, M.S
Email:
Sub-Investigator
Investigator:
Last name:
Jinhong Shi, M.S
Email:
Sub-Investigator
Facility:
Name:
School of medicine, Tsinghua University & Changping Laboratory
Address:
City:
Beijing
Country:
China
Status:
Recruiting
Contact:
Last name:
Xin Lin, Ph.D
Phone:
+86-010-62796319
Email:
linxin307@mail.tsinghua.edu.cn
Investigator:
Last name:
Xin Lin, Ph.D
Email:
Sub-Investigator
Start date:
June 30, 2023
Completion date:
December 15, 2025
Lead sponsor:
Agency:
Chinese PLA General Hospital
Agency class:
Other
Source:
Chinese PLA General Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05631912
