Relmacabtagene Autoleucel As Second-Line Therapy in Adult Patients with Aggressive B-cell NHL

This is an open-label, multicenter, Phase 2 study to determine the antitumor activity, PK, and safety of JWCAR029(Relmacabtagene autoleucel ) in subjects who have relapsed within 12 months from, or are refractory to, a single line of immunochemotherapy for aggressive Bcell NHL and are ineligible for HSCT (as defined in the eligibility criteria). Subjects will be treated with lymphodepleting chemotherapy and JWCAR029.

• Relmacabtagene Autoleucel (Biological), also known as JWCAR029: A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells
• Fludarabine (Drug): Administered according to package insert
• Cyclophosphamide (Drug): Administered according to package insert

Primary outcomes

• ORR at 3 month [3 months]: Percentage of participants with CR \[CMR;CRR\] or PR \[partial metabolic response (PMR);

Secondary outcomes

• CRR at 3 month [3 months]: Complete response rate in subjects at 3 month
• Duration of response (DOR) [up to 2 years after Relmacabtagene Autoleucel infusion]: Time from first response(PR or CR) to disease progression or death from any cause.
• Duration of complete remission (DoCR) [up to 2 years after Relmacabtagene Autoleucel infusion]: Time from complete response (CR) to disease progression or death from any cause.
• Duration of partial remission (DoPR) [up to 2 years after Relmacabtagene Autoleucel infusion]: Time from partial response (PR) to disease progression or death from any cause.
• Time to response (TTR) [up to 2 years after Relmacabtagene Autoleucel infusion]: Time from JWCAR029 infusion to first documentation of CR or PR
• Progression-Free Survival (PFS) [up to 2 years after Relmacabtagene Autoleucel infusion]: PFS is defined as the time from the Relmacabtagene Autoleucel infusion date to the date of disease progression per Lugano classification or death from any cause.
• Overall Survival (OS) [up to 2 year after Relmacabtagene Autoleucel infusion]: OS is defined as the time from Relmacabtagene Autoleucel infusion to the date of death from any cause.
• Adverse events (AEs) [up to 2 year after Relmacabtagene Autoleucel infusion]: Types, frequency, and severity of adverse events and laboratory anomalies Physiological parameter
• Pharmacokinetic (PK)- Cmax of Relmacabtagene Autoleucel [up to 1 year after Relmacabtagene Autoleucel infusion]: Maximum observed concentration of Relmacabtagene Autoleucel in peripheral blood
• Pharmacokinetic (PK)- Tmax of Relmacabtagene Autoleucel [up to 1 year after Relmacabtagene Autoleucel infusion]: Time to maximum concentration of Relmacabtagene Autoleucel in peripheral blood
• Pharmacokinetic (PK)- AUC of Relmacabtagene Autoleucel [up to 1 year after Relmacabtagene Autoleucel infusion]: Area under the concentration vs time curve of Relmacabtagene Autoleucel
• The concentration of Car-T cell [up to 1 year after Relmacabtagene Autoleucel infusion]: The concentration of Car-T cell in peripheral blood

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age≥18 years;
2. Signed written informed consent obtained prior to any study procedures;
3. Histologically confirmed relapsed or refractory (R/R) aggressive B-cell NHL of the following histologiesLBCL as defined by the World Health Organization (WHO) Classification 2022:Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), high-grade B-cell lymphoma (HGL) with MYC and BCL2 rearrangements,HGL-NOS, Primary mediastinal large B-cell lymphoma, Follicular lymphoma Grade 3B (FL3B),Indolent B-NHL-transformed large B-cell lymphoma with adequate prior treatment with anthracycline-containing agents and rituximab or other CD20-targeted agents;
4. Subjects must meet the definition of refractory or relapsed;
5. Subjects were not eligible for HDCT/ASCT based on the investigator's assessment ;
6. Adequate organ function;
7. Presence of positive PET assessable lesions as determined by the Lugano criteria ;
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
9. Expected survival greater than 12 weeks;
10. Adequate vascular access for leukapheresis procedure;
11. Women of childbearing potential must agree to use highly effective methods of contraception for at least 28 days prior to lymphocyte clearance chemotherapy through 2 year after Relmacabtagene Autoleucel infusion; Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method for 2 year after Relmacabtagene Autoleucel infusion;

Exclusion Criteria:

1. Subjects with non-Hodgkin's lymphoma who have received second or more line therapy;
2. Lymphoma of the primary center (subjects with secondary central nervous system lymphoma are allowed to enroll;
3. History of another primary malignancy that has not been in remission for at least 2 years;
4. Subjects has active HBV, HCV, HIV or syphilis infection at the time of screening;
5. Deep venous thrombosis (DVT)/Pulmonary embolism (PE), or DVT/PE requires anti-coagulation within 3 months prior to signing the ICF;
6. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection;
7. Uncontrolled diabetes and hypertension;
8. Presence of acute or chronic graft-versus-host disease (GVHD);
9. Active autoimmune disease requiring immunosuppressive therapy;
10. History of any serious cardiovascular disease or presence of clinically relevant CNS pathology;
11. Pregnant or nursing women;
12. Subjects Received an autologous or allogeneic hematopoietic stem cell transplant;
13. Uncontrolled conditions or unwillingness or inability to follow the procedures required in the protocol;
14. Received CAR T-cell or other genetically-modified T-cell therapy previously;
15. Received live vaccination within 6 weeks prior to lymphocyte clearance chemotherapy;
16. History of severe hypersensitivity reactions to any of the drug ingredients used in this study product.

• Weili Zhao, PhD, Principal investigator, Ruijin Hospital
• Depei Wu, PhD, Principal investigator, The First Affiliated Hospital of Soochow University