A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting (TRANSCEND-OUTREACH-007)

Study Overview
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Brief Summary
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This is an open-label, multicenter, Phase 2 study to determine the safety, PK, and efficacy of lisocabtagene maraleucel (JCAR017) in subjects who have relapsed from, or are refractory to, two lines of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) in the outpatient setting. Subjects will receive treatment with JCAR017 and will be followed for up to 2 years.

Detailed Description
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This is an open-label, multicenter, Phase 2 study to assess the safety and antitumor activity in adult patients with relapsed or refractory B-cell non-Hodgkin Lymphoma when administered with lisocabtagene maraleucel (JCAR017) in the outpatient setting. Upon the successful product generation of lisocabtagene maraleucel, subjects will enter the treatment phase of the study. Treatment will include lymphodepleting chemotherapy followed by lisocabtagene maraleucel administration. Subjects will then enter the post-treatment follow-up phase of the study and will be followed for approximately 24 months for safety, disease status, health-related quality of life (HRQoL), and survival. Long-term follow-up will continue under a separate long-term follow-up protocol, per health regulatory authority guidelines, currently up to 15 years after the last lisocabtagene maraleucel administration.

Official Title
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A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting

Conditions
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Lymphoma, Non-Hodgkin, Lymphoma, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Neoplasms, Neoplasms by Histologic Type, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Disorder

Intervention / Treatment
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* Biological: lisocabtagene maraleucel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of consent Relapsed or refractory B-cell NHL of the following histologies: diffuse large B cell lymphoma (DLBCL) not otherwise specified; includes biopsy-confirmed transformed DLBCL from indolent histologies, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, primary mediastinal B-cell lymphoma(PMBCL), and follicular lymphoma Grade 3B. Subjects must have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have relapsed or refractory disease after at least 2 systemic lines of therapy for DLBCL or after auto-HSCT. Positron-emission tomography-positive disease by Lugano Classification Eastern Cooperative Oncology Group performance status of 0 to 1 Adequate bone marrow, renal, hepatic, pulmonary, cardiac organ function Adequate vascular access for leukapheresis procedure Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy Subjects must agree to use appropriate contraception. Exclusion Criteria: Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study) History of prior allogeneic hematopoietic stem cell transplant Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis History of another primary malignancy that has not been in remission for at least 2 years.The following are examples of exceptions from the 2-year limit: nonmelanoma skin cancer, definitively-treated stage 1 solid tumor with a low risk of recurrence, curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on a Papanicolau smear. Active hepatitis B or hepatitis C infection at the time of screening History of or active human immunodeficiency virus infection at the time of screening Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate anti-infection treatment at the time of leukapheresis or lisocabtagene maraleucel administration Presence of acute or chronic graft-versus-host disease History of clinically significant cardiac conditions within the past 6 months History or presence of clinically relevant CNS pathology such as epilepsy/seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis Pregnant or nursing women Subject does not meet protocol-specified washout periods for certain prior treatments Prior CAR T-cell or other genetically modified T-cell therapy Progressive vascular tumor invasion, thrombosis, or embolism Venous thrombosis or embolism not managed on stable regimen of anticoagulation Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lisocabtagene maraleucel<br>Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of lisocabtagene maraleucel. During lisocabtagene maraleucel production, subjects may receive low-dose chemotherapy for disease control. Upon successful generation of lisocabtagene maraleucel product, subjects will receive treatment which will include lymphodepleting chemotherapy followed by one dose of lisocabtagene maraleucel administered by intravenous (IV) injection. | Biological: lisocabtagene maraleucel<br>* lisocabtagene maraleucel will be administered as single dose intravenous (IV) injection<br>* Other names: liso-cel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Cytokine Release Syndrome (CRS) Adverse Events Grade ≥ 3 | Cytokine release syndrome is characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, rigors, hypotension, hypoxia, myalgia/arthralgia, and anorexia. Incidence of Grade ≥ 3 CRS, based on the TEAE with MedDRA PT Cytokine release syndrome, graded according to the grading scale adapted from Lee (Lee 2014). | From first dose to 90 days following first dose (up to approximately 90 days) | 
| Percentage of Participants With Neurotoxicity (NT) Adverse Events Grade ≥ 3 | NT events have also been reported and may include neurologic symptoms such as altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like activity. Incidence of Grade ≥ 3 NT, defined as an Investigator-identified TEAE considered neurotoxicity related to JCAR017. | From first dose to 90 days following first dose (up to approximately 90 days) | 
| Percentage of Participants With Infection Adverse Events Grade ≥ 3 | Incidence of treatment-emergent Grade ≥ 3 infections, defined using MedDRA SOC. | From first dose to 90 days following first dose (up to approximately 90 days) | 
| Percentage of Participants With Prolonged Grade ≥ 3 Cytopenia at Day 29. | Prolonged cytopenia is defined as the occurrence of Grade ≥ 3 cytopenia not resolved by the Day 29 visit, based on laboratory results of low hemoglobin, absolute neutrophil count decreased, and platelet count decreased. The frequency of subjects experiencing each individual laboratory abnormality and the total number with at least 1 abnormality will be summarized, as will recovery from prolonged cytopenia after Day 29. | At Day 29 after first treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events |  | From first dose to 90 days following first dose (up to approximately 90 days) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities- Hematology |  | From first dose to up to 41 months | 
| Number of Participants With Clinically Significant Laboratory Abnormalities- Chemistry |  | From first dose to up to 41 months | 
| Number of Participants With Adverse Events Grade ≥ 3 |  | From first dose to 90 days following first dose (up to approximately 90 days) | 
| Time to Onset and Time to Resolution of Grade ≥ 3 Cytokine Release Syndrome (CRS) |  | From first dose to up to approximately 41 months | 
| Time to Onset and Time to Resolution of Grade ≥ 3 Neurotoxicity (NT) |  | From first dose to up to approximately 41 months | 
| Number of Participants Administered Tocilizumab and Corticosteroid for Management of Cytokine Release Syndrome (CRS) |  | From first dose to up to approximately 41 months | 
| Number of Participants Administered Tocilizumab and Corticosteroid for Management of Neurotoxicity (NT) |  | From first dose to up to approximately 41 months | 
| Objective Response Rate (ORR) | The Percentage of participants with a best overall response (BOR) of either CR or PR based on the Lugano 2014 criteria. Disease response will be determined according to the Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification Complete response is defined as: Score 1, 2, or 3a with or without residual mass No evidence of FDG-avid disease in marrow Partial Response is defined as: Score 4 or 5a with reduced uptake compared with baseline and residual masses of any size Bone marrow with residual uptake higher than in normal marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed). If there are persistent focal changes in marrow in the context of a nodal response, should consider further evaluation with MRI, biopsy, or interval scan. | From first dose to up to approximately 41 months | 
| Complete Response Rate (CRR) | The Percentage of participants with a best overall response (BOR) with CR based on the Lugano 2014 criteria. Disease response will be determined according to the Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification Complete response is defined as: Score 1, 2, or 3a with or without residual mass No evidence of FDG-avid disease in marrow | From first dose to up to approximately 41 months | 
| Duration of Response (DoR) and Duration of Complete Response (DoCR) | Duration of response (DOR) is defined as the time from the first documentation of response (CR or PR) after JCAR017 infusion to disease progression or death from any cause, whichever occurs first. Duration of response (DOR) if BOR is CR is defined for subjects with a BOR of CR as the time from the first documentation of response (CR or PR) after JCAR017 infusion to earlier of disease progression or death from any cause. | From first dose to up to approximately 41 months | 
| Progression Free Survival (PFS) | Progression-free survival is defined as the time from infusion of JCAR017 to progressive disease or death, whichever is earlier. If a subject does not have an event for the PFS analysis, the subject will be censored. Progressive Disease is defined as: Score 4 or 5a with an increase in intensity of uptake from nadir New FDG-avid foci consistent with lymphoma (may need biopsy or repeat scan if uncertain about etiology of foci). Investigator assessed clinical progression | From first dose to up to approximately 41 months | 
| Overall Survival (OS) | Overall survival is defined as the time from infusion of JCAR017 to the date of death. For assessment of OS, data from surviving participants will be censored at the last time that the participant is known to be alive. The OS analysis will include all available survival information from the long-term follow-up study if applicable. | From first dose to up to approximately 41 months | 
| Area Under the Blood Concentration-time Curve From Time to Zero to 28 Days After Dosing AUC (0-28) |  | 28days after first dose | 
| Maximum Observed Blood Concentration (Cmax) |  | 28days after first dose | 
| Time of Maximum Observed Blood Concentration (Tmax) |  | 28days after first dose | 
| European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning; a high score for the global health status/HRQoL represents a high HRQoL, but a high score for a symptom scale/item represents a high level of symptomatic problem. | From Enrollment to end of follow up, approximately 26 months | 
| EuroQol Instrument EQ-5D-5L. | EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue scale (EQ VAS). The descriptive system comprises dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). | Enrollment to end of follow up, approximately 26 months | 
| Number of Intensive Care Unit (ICU) Inpatient Days and Non-ICU Inpatient Days and Reasons for Hospitalization | Length of initial ICU and non-ICU stay from liso-cel administration | From first hospitalization to the last. Approximately 31 days | 
| Number of Participants Transfused and the Number of Transfusions Per Participant. |  | From first dose to end of treatment period approximately 24 months | 
| Number of Participants Requiring Growth Factor Support. |  | From first dose to end of treatment period approximately 24 months | 
| Number of Participants Requiring Intravenous Immunoglobulin (IVIG) Support |  | From first dose to end of treatment period approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lisocabtagene maraleucel, liso-cel, JCAR017, relapse, refractory, B-Cell Non-Hodgkin Lymphoma, NHL, chimeric antigen receptor, CAR, CAR T cell, autologous T cell therapy, immunotherapy, cell therapy, B-cell malignancies