Treatment for relapsed and refractory B-cell Non-Hodgkin's Lymphoma using CAR T cells

Decitabine-primed Tandem Targeting CD19 and CD20 Chimeric Antigen Receptor T Cells Treatment in Relapsed and/or Refractory Non-Hodgkin's Lymphoma Patients

This study is testing a new treatment using specially modified immune cells to see if it can help people with relapsed and hard-to-treat B-cell Non-Hodgkin's Lymphoma.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 33 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Chinese PLA General Hospital (other)
• Drugs / interventions: chemotherapy, immunotherapy, CART
• Locations: 1 site (Beijing, Beijing)
• Trial ID: NCT04697940 on ClinicalTrials.gov

What this trial studies

This open-label, phase 1/2 clinical trial aims to evaluate the safety and efficacy of decitabine-primed tandem CAR T cells targeting CD19 and CD20 in patients with relapsed and refractory B-cell Non-Hodgkin's Lymphoma. The study will enroll 19 to 33 patients, with phase 1 focusing on dose escalation to determine the maximum tolerated dose, while phase 2 will expand on the findings with additional participants. Patients will receive a series of infusions of engineered T cells, and their responses will be closely monitored for safety and effectiveness.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 75 with histologically confirmed CD20+ and/or CD19+ B-cell Non-Hodgkin's Lymphoma.

Not a fit: Patients with other types of lymphoma or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with difficult-to-treat B-cell Non-Hodgkin's Lymphoma.

How similar studies have performed: Other studies using CAR T cell therapies have shown promising results, indicating potential success for this novel approach.

Eligibility criteria

Inclusion Criteria:

Patients eligible for inclusion in this study had to meet all of the following criteria:

* Age ≥18 and ≤75 years.
* Eastern Cooperative Oncology Group (ECOG) performance status score between 0 and 2.
* Patients with histologically confirmed CD20+ and/or CD19+ 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.
* Successful leukapheresis assessment and preculture of T cells.
* Life expectancy \> 3 months.
* 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. 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.
* 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.

Exclusion Criteria:

Patients eligible for this study must not meet any of the following criteria:

* 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 and/or anti-CD20 scFv reactions 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.
* A history of stroke or intracranial hemorrhage within 3 months prior to enrollment.
* Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
* History of allergies to any of the ingredients in cell products.
* 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.
* 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.
* Inability to understand or unwillingness to sign informed consent.
* Researchers believe that other reasons are not suitable for clinical trials.

Where this trial is running

Beijing, Beijing

• Biotherapeutic Department of Chinese PLA General Hospital — Beijing, Beijing, China (RECRUITING)

Study contacts

• Principal investigator: Weidong Han, M.D. — Chinese PLA Hospital
• Study coordinator: Weidong Han, M.D.

Conditions: Relapsed and Refractory B-cell Non-Hodgkin's Lymphoma, Decitabine-primed Tandem CD19/CD20 CAR T Cells