Relmacabtagene Autoleucel as Second-Line Therapy in Adult Patients With Aggressive B-cell NHL

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to asess the efficacy of Relmacabtagene autoleucel as second-line therapy in adult patients with aggressive B-cell Non-Hodgkins Lymphoma who are ineligible for haematopoietic stem cell transplantation.

Detailed Description
-----------------
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.

Official Title
-----------------
Relmacabtagene Autoleucel as Second-Line Therapy in Adult Patients With Aggressive B-cell NHL: a Single-arm, Multicenter, Open, Phase II Study

Conditions
-----------------
Lymphoma, Large B-Cell, Diffuse, Follicular Lymphoma Grade 3B, High-grade B-cell Lymphoma, Mediastinal B-Cell Diffuse Large Cell Lymphoma

Intervention / Treatment
-----------------
* Biological: Relmacabtagene Autoleucel
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age≥18 years; Signed written informed consent obtained prior to any study procedures; 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; Subjects must meet the definition of refractory or relapsed; Subjects were not eligible for HDCT/ASCT based on the investigator's assessment ; Adequate organ function; Presence of positive PET assessable lesions as determined by the Lugano criteria ; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; Expected survival greater than 12 weeks; Adequate vascular access for leukapheresis procedure; 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: Subjects with non-Hodgkin's lymphoma who have received second or more line therapy; Lymphoma of the primary center (subjects with secondary central nervous system lymphoma are allowed to enroll; History of another primary malignancy that has not been in remission for at least 2 years; Subjects has active HBV, HCV, HIV or syphilis infection at the time of screening; Deep venous thrombosis (DVT)/Pulmonary embolism (PE), or DVT/PE requires anti-coagulation within 3 months prior to signing the ICF; Subjects with uncontrolled systemic fungal, bacterial, viral or other infection; Uncontrolled diabetes and hypertension; Presence of acute or chronic graft-versus-host disease (GVHD); Active autoimmune disease requiring immunosuppressive therapy; History of any serious cardiovascular disease or presence of clinically relevant CNS pathology; Pregnant or nursing women; Subjects Received an autologous or allogeneic hematopoietic stem cell transplant; Uncontrolled conditions or unwillingness or inability to follow the procedures required in the protocol; Received CAR T-cell or other genetically-modified T-cell therapy previously; Received live vaccination within 6 weeks prior to lymphocyte clearance chemotherapy; History of severe hypersensitivity reactions to any of the drug ingredients used in this study product.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relmacabtagene Autoleucel<br>Experimental: Relmacabtagene Autoleucel Participants will receive cyclophosphamide250 mg/m^2/day intravenously (IV) and fludarabine 25 mg/m^2/day IV conditioning chemotherapy for 3 days followed by Relmacabtagene Autoleucel administered as a single IV infusion at a target dose of 1 x 10^8 anti-cluster of differentiation (CD)19 chimeric antigen receptor (CAR) transduced autologous T cells on Day1. | Biological: Relmacabtagene Autoleucel<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells<br>* Other names: JWCAR029;Drug: Fludarabine<br>* Administered according to package insert<br>Drug: Cyclophosphamide<br>* Administered according to package insert<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR at 3 month | Percentage of participants with CR [CMR;CRR] or PR [partial metabolic response (PMR); | 3 months | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Relmacabtagene Autoleucel, aggressive B-cell non-Hodgkin lymphoma, Chimeric antigen receptor T cells, second-line