A Study to Compare the Efficacy and Safety of JCAR017 to Standard of Care in Adult Subjects With High-risk, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas

Study Overview
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Brief Summary
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The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is a randomized, open-label, parallel-group, multi-center trial in adult subjects with Relapsed or refractory (R/R) aggressive Non-Hodgkin lymphoma (NHL) to compare safety and efficacy between the standard of care (SOC) strategy versus JCAR017 (also known as lisocabtagene maraleucel or liso-cel). Subjects will be randomized to either receive SOC (Arm A) or to receive JCAR017 (Arm B). All subjects randomized to Arm A will receive Standard of care (SOC) salvage therapy (R-DHAP, RICE or R-GDP) as per physician's choice before proceeding to High dose chemotherapy (HDCT) and Hematopoietic stem cell transplant (HSCT). Subjects from Arm A may be allowed to cross over and receive JCAR017 upon confirmation of an EFS event. Subjects randomized to Arm B will receive Lymphodepleting (LD) chemotherapy followed by JCAR017 infusion.

Official Title
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A Global Randomized Multicenter Phase 3 Trial of JCAR017 Compared to Standard of Care in Adult Subjects With High-risk, Second-line, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas (TRANSFORM).

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Standard of Care
* Genetic: JCAR017


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the informed consent form (ICF). Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Histologically proven diffuse large B-cell lymphoma (DLBCL) NOS (de novo or transformed indolent NHL), high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma [DHL/THL]), primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T cell/histiocyte-rich large B-cell lymphoma (THRBCL) or follicular lymphoma grade 3B. Enough tumor material must be available for confirmation by central pathology. Refractory or relapsed within 12 months from CD20 antibody and anthracycline containing first line therapy. [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) positive lesion at screening. (Deauville score 4 or 5) Adequate organ function Participants must agree to use effective contraception Exclusion Criteria: Subjects not eligible for hematopoietic stem cell transplantation (HSCT). Subjects planned to undergo allogeneic stem cell transplantation. Subjects with, primary cutaneous large B-cell lymphoma, EBV (Epstein-Barr virus) positive DLBCL, Burkitt lymphoma or transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (Richter transformation). Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following noninvasive malignancies: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative. Other completely resected stage 1 solid tumor with low risk for recurrence Treatment with any prior gene therapy product. Subjects who have received previous CD19-targeted therapy. Subjects with active hepatitis B, or active hepatitis C are excluded. Subjects with negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are permitted. Subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy. Subjects with a history of or active human immunodeficiency virus (HIV) are excluded. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment. Active autoimmune disease requiring immunosuppressive therapy. History of any one of the following cardiovascular conditions within the past 6 months prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease. History or presence of clinically relevant central nervous system (CNS) pathology Pregnant or nursing (lactating) women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A - Standard of Care (SOC)<br>Subjects should receive SOC (R-DHAP, R-ICE or R-GDP) followed by HDCT (BEAM) and HSCT. Standard of care regimen will be administered as per investigator decision. | Drug: Standard of Care<br>* Standard of Care<br>|
| Experimental: Arm B - JCAR017<br>Lymphodepleting chemotherapy with intravenous (IV) fludarabine (30 mg/m2/day for 3 days) plus cyclophosphamide IV (300 mg/m2/day for 3 days) (flu/cy) concurrently followed by JCAR017 infusion. | Genetic: JCAR017<br>* JCAR017<br>* Other names: lisocabtagene maraleucel or liso-cel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | Time from randomization to death from any cause, progressive disease (PD), failure to achieve complete response (CR) or partial response (PR), or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CRR) | Percentage of subjects achieving a complete response (CR) | Approximately 3 years | 
| Progression-free survival (PFS) | Time from randomization to PD or death from any cause, whichever occurs first | Approximately 3 years | 
| Overall survival (OS) | Time from randomization to time of death due to any cause | Approximately 4.5 years | 
| Overall response rate (ORR) | Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification as assessed by IRC review | Approximately 3 years | 
| Duration of response (DOR) | Time from first response to disease progression, start of new antineoplastic therapy due to efficacy concerns or death from any cause | Approximately 3 years | 
| PFS on next line of treatment (PFS-2) | Time from randomization to second objective disease progression or death from any cause, whichever is first. | Approximately 3 years | 
| Adverse Events (AEs) | Type, frequency and severity of adverse events (AEs), serious adverse events (SAE), and laboratory abnormalities (overall and in clinical, histological and molecular subgroups) | Approximately 3 years | 
| HRQoL using European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC-QLQ-C30) | European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire: The EORTC QLQ-C30 questionnaire will be used as a measure of health-related quality of life, fatigue, physical and cognitive functions. | Approximately 3 years | 
| HRQoL parameters assessed by FACT-Lym Additional concerns subscale | Functional Assessment of Cancer Therapy-Lymphoma Additional concerns subscale: Only the LYM subscale will be administered in this study. This scale addresses symptoms and functional limitations (15 item) that are important to lymphoma patients. | Approximately 3 years | 
| Reasons for hospital resource utilization | Will be assessed based on reasons for hospitalization | Approximately 3 years | 
| Rate of hematopoietic stem cell transplant (HSCT) | Rate of completion of HDCT and HSCT | Approximately 3 years | 
| Frequency of hospital resource utilization | Will be assessed based on frequency of hospitalizations calculated as, inpatient days, intensive care unit (ICU) days, outpatient visits days | Approximately 3 years | 
| Hospital resource utilization (HRU) | Will be assessed based on frequency of hospitalizations calculated as, inpatient days, intensive care unit (ICU) days, outpatient visits days and reasons for hospitalization | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin Lymphomas, DLBCL, Efficacy, Safety, JCAR017, Liso-cel, High-Risk, Relapsed, Refractory, B-cell NHL