TRAC Locus-inserted CD19-targeting STAR-T Cell Therapy in r/r B-NHL
Autologous TRAC Locus-inserted CD19-targeting Synthetic T-cell Receptor Antigen Receptor T (STAR-T) Cells for Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma
1 other identifier
interventional
38
1 country
2
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Jun 2023
Typical duration for phase_1
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 21, 2022
CompletedFirst Posted
Study publicly available on registry
November 30, 2022
CompletedStudy Start
First participant enrolled
June 30, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 15, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
December 15, 2025
CompletedJuly 6, 2023
July 1, 2023
1.5 years
November 21, 2022
July 3, 2023
Conditions
Outcome Measures
Primary Outcomes (5)
Phase 1: Incidence of Adverse Events (AEs)
AE is defined as any adverse medical event from the date of randomization to 12 months after CD19-STAR-T cells infusion. Among them, CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.
12 months
Phase 1: Incidence of Dose-Limiting Toxicities (DLTs)
DLT was defined as CD19-STAR-T cells-related events with onset within first 28 days following infusion: The development of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; Any CD19-STAR-T cells-related AE requiring intubation; All G4 non-hematologic toxicities.
First infusion date of CD19-STAR-T cells up to 28 days
Phase 1: Maximum tolerated dose (MTD)
MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.
12 months
Phase 1: Recommended phase 2 dose (RP2D)
The recommended dose for phase 2 was determined through phase 1 study.
12 months
Phase 2: Best objective Response Rate
The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the Lugano 2014 assessment criterion.
12 months
Secondary Outcomes (7)
Phase 2: Overall Survival (OS)
12 months after the first infusion of CD19-STAR-T cells
Phase 2: Progression Free Survival (PFS)
12 months after the first infusion of CD19-STAR-T cells
Phase 2: Time to response (TTR)
12 months
Phase 2: Duration of Response (DOR)
12 months
Pharmacokinetics: Number and copy number of CD19-STAR-T cells (phase 1 and phase 2)
12 months
- +2 more secondary outcomes
Other Outcomes (2)
Relationship between infusion dose of CD19-STAR-T cells and efficacy
12 months
To analyze the dynamic changes of STAR-T cells after infusion
12 months
Study Arms (1)
Autologous TRAC locus-inserted CD19-targeting STAR-T cells
EXPERIMENTALA conditioning chemotherapy regimen of fludarabine and cyclophosphamide (FC regimen) will be administered followed by investigational treatment, autologous targeting CD19 synthetic T-cell receptor antigen receptor T cells. Post leukapheresis, administration of short half-life chemo-agents, Bruton tyrosine kinase inhibitor (BTKi) and/or dexamethasone should be considered to bridge the following FC regimen in patients with bulky tumor burden, rapidly aggressive progression, and/or indications of imperious symptom control.
Interventions
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
Intravenous fludarabine 25-30 mg/m\^2/day on days -5, -4, and -3.
Intravenous cyclophosphamide 300-500 mg/m\^2/day on days -5, -4, and -3.
Eligibility Criteria
You may qualify if:
- Age 18-75 (inclusive).
- 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.
- 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.
- Individuals must have received adequate prior therapy:
- +15 more criteria
You may not qualify if:
- No obvious hereditary diseases.
- Able to understand the requirements and matters of the trial, and willing to participate in clinical research as required.
- Informed consent must be signed.
- 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.
- Women who are pregnant or breastfeeding, or who do not agree to use effective contraception during treatment and during the subsequent 1 year.
- History of allogeneic hematopoietic stem cell transplantation, or organ transplantation.
- History of other malignancies that have not been in remission.
- Patients with primary immunodeficiency or autoimmune diseases requiring immunosuppressive therapy.
- Received radiotherapy within 3 months before enrollment.
- 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.
- Patients who received any immunocellular therapy within 6 months before enrollment.
- Confirmed evidence showing positiveness of anti-CD19 scFv reaction in patient serum.
- Patients who participated in other clinical trials within 4 weeks prior to enrollment.
- 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.
- The presence of uncontrollable serous membrane fluid, such as massive pleural effusion or ascites.
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (2)
Biotherapeutic Department, Chinese PLA General Hospital
Beijing, Beijing Municipality, 100853, China
School of medicine, Tsinghua University & Changping Laboratory
Beijing, Beijing Municipality, China
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Weidong Han, Ph.D
Biotherapeutic Department, Chinese PLA General Hospital
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Director of Biotherapeutic Department
Study Record Dates
First Submitted
November 21, 2022
First Posted
November 30, 2022
Study Start
June 30, 2023
Primary Completion
December 15, 2024
Study Completion
December 15, 2025
Last Updated
July 6, 2023
Record last verified: 2023-07
Data Sharing
- IPD Sharing
- Will not share