Clinical trial NCT06646666: ARTA-based Chemo-free Bridging/Maintenance Therapy in CAR-T Treatment for High-Risk R/R B-NHL Ineligible for HDCT and ASCT
Official title: Efficacy and Safety of All-trans Retinoic Acid (ATRA)-Based Chemo-free Bridging/Maintenance Therapy in CAR-T Treatment of High-risk Relapsed/Refractory B-NHL Ineligible for High-dose Chemotherapy （HDCT） and Autologous Stem Cell Transplantation （ASCT）
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: B-cell Non Hodgkin Lymphoma
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
First posted: 2024-10-17
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-center, open-label, prospective study enrolling high-risk (tumor diameter \> 4 cm) relapsed/refractory B-NHL patients ineligible for HDCT and ASCT. The treatment consists of ATRA combined with zanubrutinib ± radiotherapy and CAR-T therapy. Based on the efficacy at day 28 post-CAR-T infusion, patients achieving CR will receive 3 months of ATRA and zanubrutinib, while those with PR will receive 3 months of zanubrutinib plus 2 years of ATRA and a PD-1 inhibitor. Patients with stable disease or progression will discontinue. The primary endpoint is the 3-month CR rate following CAR-T infusion.


Eligibility criteria: Inclusion Criteria:

* Willingly sign the informed consent form.
* Age ≥ 18 years, any gender.
* Histologically confirmed as B-cell non-Hodgkin lymphoma, including:

  * Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (DLBCL-NOS)
  * Transformed follicular lymphoma (tFL)
  * High-grade B-cell lymphoma (HGBL) with MYC, BCL2, and/or BCL6 rearrangements
  * High-grade B-cell lymphoma not otherwise specified (HGBL-NOS)
  * Primary mediastinal large B-cell lymphoma (PMBL)
  * Follicular lymphoma grade 3b (FL3b)
* Patients must have experienced at least one line of treatment for relapsed or refractory disease, meeting the following definitions:

  * Refractory: At least partial response (PR) after the last chemotherapy or relapse within 12 months after autologous transplantation.
  * Relapsed: Complete response (CR) after the last chemotherapy, followed by relapse before enrollment, or relapse or progression 12 months or longer after autologous transplantation.
* Maximum tumor diameter (long axis) \> 4 cm.
* Evaluator determines that the patient does not meet HDCT/ASCT criteria and meets at least one of the following:

  * Age ≥ 60 years
  * ECOG score = 2
  * FEV1% or DLCO% ≤ 60%
  * LVEF \< 50%
  * Creatinine clearance \< 60 mL/min
  * ALT or AST \> 2× upper limit of normal (ULN)
  * Patient unwilling to receive high-dose chemotherapy and autologous stem cell transplantation.
* Measurable target lesions: lymph nodes ≥ 15 mm in longest diameter, or extranodal lesions \> 10 mm.
* Expected survival ≥ 12 weeks.
* Laboratory tests must meet the following requirements at screening:

  * Lymphocyte count ≥ 0.1 × 10\^9/L
  * Hemoglobin ≥ 80 g/L
  * Platelets ≥ 50 × 10\^9/L
  * ALT/AST ≤ 5 × ULN and total bilirubin \< 2 × ULN
  * Creatinine clearance ≥ 30 mL/min
  * Lung function: ≤ CTCAE grade 1 dyspnea, and oxygen saturation (SpO2) ≥ 92% in room air.
  * LVEF ≥ 40%
* Patients with primary central nervous system lymphoma are allowed (secondary CNS lymphoma is not allowed).
* Sufficient venous access for apheresis, and no other contraindications for blood cell separation; female participants of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

* History of allergy to any component of the cellular product or study treatment.
* History of allogeneic hematopoietic stem cell transplantation.
* History of organ transplantation.
* Patients with active viral hepatitis requiring treatment, including:

  * Chronic HBV carriers with HBV DNA ≥ 500 IU/mL.
  * Positive HCV RNA in patients with positive HCV antibodies.
  * Positive HIV antibodies (HIV-Ab).
  * Positive Treponema pallidum antibodies (TP-Ab).
  * Elevated CMV DNA or EBV DNA above normal limits.
* Clinical significance of CNS diseases
* Presence of active primary central nervous system lymphoma.
* Prior treatment with other genetically modified T-cell therapies or CAR-T therapies.
* Severe genetic diseases or autoimmune diseases (e.g., systemic lupus erythematosus).
* Thromboembolic events (e.g., myocardial infarction, pulmonary embolism, deep vein thrombosis) within 6 months prior to screening.
* History of malignancies other than the indication for this trial within the last 5 years, except for in situ cancers (e.g., cervical, bladder, breast) or non-melanoma skin cancer.
* Active infections requiring systemic treatment or uncontrolled infections.
* Received lenalidomide, calcineurin inhibitors, chemotherapy (e.g., methotrexate, cyclophosphamide, ifosfamide, nitrogen mustard, or melphalan), mycophenolate, thalidomide, immunosuppressive antibodies (e.g., anti-TNF, anti-IL6, or anti-IL6R), radiation therapy, or any drug that binds FKBP12 (e.g., rapamycin, tacrolimus, everolimus) within 4 weeks prior to PBMC collection.
* Pregnant or breastfeeding women, or men or women of childbearing potential unwilling to use contraception during the trial and for 2 years after RJ CAR-T 002 cell infusion.
* Participation in other drug clinical trials (e.g., new drug trials, registrational studies, investigator-initiated trials) within 4 weeks prior to PBMC collection.
* Researcher's judgment that the patient is unsuitable for the trial (e.g., poor compliance, drug abuse).
* Vaccination with live or attenuated vaccines within 3 months prior to PBMC collection, or expected vaccination during the trial.

Primary outcomes:
measure: Complete Response (CR) Rate at 3-month
timeFrame: 3 months post CAR-T infusion
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: 2 years post CAR-T infusion
measure: Overall Survival (OS)
timeFrame: 2 years post CAR-T infusion
measure: Adverse Events rate as assessed by CTCAE version 5.0
timeFrame: 2 years post CAR-T infusion
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Study officials:
References: