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TRAC Locus-inserted CD19-targeting STAR-T Cell Therapy in r/r B-NHL

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ClinicalTrials.gov Identifier: NCT05631912
Recruitment Status : Recruiting
First Posted : November 30, 2022
Last Update Posted : November 30, 2022
Information provided by (Responsible Party):
Han weidong, Chinese PLA General Hospital

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.

Condition or disease Intervention/treatment Phase
Non-hodgkin Lymphoma,B Cell Biological: Autologous CD19-STAR-T cell Drug: Fludarabine Drug: Cyclophosphamide Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : December 15, 2022
Estimated Primary Completion Date : December 15, 2024
Estimated Study Completion Date : December 15, 2025

Arm Intervention/treatment
Experimental: Autologous TRAC locus-inserted CD19-targeting STAR-T cells

A 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.

Biological: Autologous CD19-STAR-T cell
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
Other Name: Autologous CD19-targeting synthetic T-cell receptor antigen receptor T cells

Drug: Fludarabine
Intravenous fludarabine 25-30 mg/m^2/day on days -5, -4, and -3.
Other Name: Fludarabine Phosphate for Injection

Drug: Cyclophosphamide
Intravenous cyclophosphamide 300-500 mg/m^2/day on days -5, -4, and -3.
Other Name: Cyclophosphamide for Injection

Primary Outcome Measures :
  1. Phase 1: Incidence of Adverse Events (AEs) [ Time Frame: 12 months ]
    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.

  2. Phase 1: Incidence of Dose-Limiting Toxicities (DLTs) [ Time Frame: First infusion date of CD19-STAR-T cells up to 28 days ]
    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.

  3. Phase 1: Maximum tolerated dose (MTD) [ Time Frame: 12 months ]
    MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.

  4. Phase 1: Recommended phase 2 dose (RP2D) [ Time Frame: 12 months ]
    The recommended dose for phase 2 was determined through phase 1 study.

  5. Phase 2: Best objective Response Rate [ Time Frame: 12 months ]
    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.

Secondary Outcome Measures :
  1. Phase 2: Overall Survival (OS) [ Time Frame: 12 months after the first infusion of CD19-STAR-T cells ]
    OS is defined as the time from CD19-STAR-T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.

  2. Phase 2: Progression Free Survival (PFS) [ Time Frame: 12 months after the first infusion of CD19-STAR-T cells ]
    PFS is defined as the time from the CD19-STAR-T cells infusion date to the date of disease progression assessed by investigators and based on the Lugano 2014 assessment criterion, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date.

  3. Phase 2: Time to response (TTR) [ Time Frame: 12 months ]
    TTR is defined as the time from CD19-STAR-T infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion.

  4. Phase 2: Duration of Response (DOR) [ Time Frame: 12 months ]
    DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators and based on the Lugano 2014 assessment criterion for r/r B-cell NHL, or death regardless of cause.

  5. Pharmacokinetics: Number and copy number of CD19-STAR-T cells (phase 1 and phase 2) [ Time Frame: 12 months ]
    Number and copy number of CD19-STAR-T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CD19-STAR-T cells were not detected for two consecutive times) to detect the number and copy number of CD19-STAR-T cells, and to evaluate the pharmacokinetics of CD19-STAR-T.

  6. Pharmacokinetics: Persistence of CD19-STAR-T (phase 1 and phase 2) [ Time Frame: 12 months ]
    Persistence of CD19-STAR-T cell assessed by number in peripheral blood.

  7. Pharmacodynamics: Peak level of cytokines in serum (phase 1 and phase 2) [ Time Frame: Up to 28 days after infusion ]
    The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.

Other Outcome Measures:
  1. Relationship between infusion dose of CD19-STAR-T cells and efficacy [ Time Frame: 12 months ]
    Peripheral blood was collected at the day of infusion (day 1), day 4, day 7, day 11, day 14, day 28, at least once every month after 28 days, at least once every three months after half a year, and at least once every six months after a year. The researchers will analyze the relationship between the number of CD19-STAR-T cells, copy number, cytokines level, and efficacy of CD19-STAR-T cells. The number of STAR-T cells was detected by flow cytometry, and the copy number was detected by quantitative PCR (qPCR).

  2. To analyze the dynamic changes of STAR-T cells after infusion [ Time Frame: 12 months ]
    The dynamic changes of the number and copy number of STAR-T cells in patients after CD19-STAR-T treatment were analyzed. To summarize the characteristic of the peak, expansion pattern, continuous expansion time and evolution of STAR-T cells in vivo.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05631912

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Contact: Weidong Han, Ph.D +86-010-55499341 hanwdrsw@sina.com
Contact: Yang liu, M.D +86-010-66937463 liuyang301blood@163.com

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China, Beijing
Biotherapeutic Department, Chinese PLA General Hospital Recruiting
Beijing, Beijing, China, 100853
Contact: Weidong Han, Ph.D    +86-010-66937463    hanwdrsw@sina.com   
Contact: Yang Liu, M.D.    +86-010-66937463    liuyang301blood@163.com   
Sub-Investigator: Yang Liu, M.D.         
Sub-Investigator: Qingming Yang, M.D.         
Sub-Investigator: Chunmeng Wang, M.S         
Sub-Investigator: Jinhong Shi, M.S         
School of medicine, Tsinghua University & Changping Laboratory Recruiting
Beijing, Beijing, China
Contact: Xin Lin, Ph.D    +86-010-62796319    linxin307@mail.tsinghua.edu.cn   
Sub-Investigator: Xin Lin, Ph.D         
Sponsors and Collaborators
Chinese PLA General Hospital
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Principal Investigator: Weidong Han, Ph.D Biotherapeutic Department, Chinese PLA General Hospital
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Responsible Party: Han weidong, Director of Biotherapeutic Department, Chinese PLA General Hospital
ClinicalTrials.gov Identifier: NCT05631912    
Other Study ID Numbers: CHN-PLAGH-BT-073
First Posted: November 30, 2022    Key Record Dates
Last Update Posted: November 30, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic