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

Status: Recruiting
Location: See all (2) locations...
Intervention Type: Drug, Biological
Study Type: Interventional
Study Phase: Phase 1/Phase 2
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.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Maximum Age: 75
Healthy Volunteers: f
View:

• 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:

‣ 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.

• The estimated survival time is over 3 months.

• The Eastern Cooperative Oncology Group (ECOG) score is 0-2.

• 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).

• 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.

• 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.

⁃ 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.

⁃ 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.

⁃ 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).

⁃ 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.

Locations
Other Locations
China
Biotherapeutic Department, Chinese PLA General Hospital
RECRUITING
Beijing
School of medicine, Tsinghua University & Changping Laboratory
RECRUITING
Beijing
Contact Information
Primary
Weidong Han, Ph.D
hanwdrsw@sina.com
+86-010-55499341
Backup
Yang liu, M.D
liuyang301blood@163.com
+86-010-66937463
Time Frame
Start Date: 2023-06-30
Estimated Completion Date: 2025-12-15
Participants
Target number of participants: 38
Treatments
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.
Related Therapeutic Areas
Sponsors
Leads: Chinese PLA General Hospital

This content was sourced from clinicaltrials.gov

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