A Study to Evaluate the Efficacy and Safety of JCAR017 in Adult Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphoma (NHL)

Study Overview
=================
Brief Summary
-----------------
This is a global Phase 2, open-label, single-arm, multicohort, multicenter study to evaluate efficacy and safety of JCAR017 in adult subjects with r/r FL or MZL. The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This study is divided into three periods: Pretreatment, which consists of screening assessments, leukapheresis and the Pretreatment evaluation; Treatment, which starts with the administration of lymphodepleting (LD) chemotherapy and continues through JCAR017 administration at Day 1 with follow-up through Day 29; Posttreatment, which includes follow-up assessments for disease status and safety for 5 years.

Official Title
-----------------
A Phase 2, Open-label, Single Arm, Multicohort, Multicenter Trial to Evaluate the Efficacy and Safety of JCAR017 in Adult Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphoma (NHL)

Conditions
-----------------
Lymphoma, Non-Hodgkin

Intervention / Treatment
-----------------
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: JCAR017


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Relapsed or refractory follicular lymphoma (FL) (Grade 1, 2 or 3a) or marginal zone lymphoma (MZL) histologically confirmed within 6 months of screening, as assessed by local pathology Patients should have received at least one prior therapy that includes anti-CD20 and alkylating agent Follicular lymphoma patients: Received at least one prior line of systemic therapy. Patients that received one prior line of systemic therapy are eligible if they present with high risk features. Patients that received two or more prior lines of systemic therapy are eligible, assuming one of the prior lines includes anti-CD20 and alkylating agent (as listed in criterion 2) Marginal zone lymphoma patients: Received two or more prior lines of systemic therapy, assuming one of the prior lines includes anti-CD20 and alkylating agent (as listed in criterion 2) or relapsed after hematopoietic stem cell transplant Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ function Adequate vascular access for leukapheresis procedure Exclusion Criteria: Evidence or history of composite Diffuse large B-cell lymphoma (DLBCL) and FL, or of transformed FL WHO subclassification of duodenal-type FL Central nervous system-only involvement by malignancy (subjects with secondary central nervous system (CNS) involvement are allowed on study) History of another primary malignancy that has not been in remission for at least 2 years, with the exception of non-invasive malignancies Prior CAR T-cell or other genetically-modified cell therapy History of or active human immunodeficiency virus (HIV) Active hepatitis B or active hepatitis C Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment Active autoimmune disease requiring immunosuppressive therapy Presence of acute or chronic graft-versus-host=disease History of significant cardiovascular disease History or presence of clinically relevant central nervous system pathology Allogenic-hematopoietic stem cell transplant (Allo-HSCT) within 90 days of leukapheresis

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: Administration of JCAR017<br>Subjects will be treated with fludarabine IV (30 mg/m2/day for 3 days) and cyclophosphamide IV (300 mg/m2/day for 3 days) prior to JCAR017 infusion. Refer to the most recent package inserts for further details on administration of these agents. JCAR017 will be infused on Day 1 at a target dose of 100 × 10^6 CAR-positive viable T cells (CAR+ T cells), 2 to 7 days after completion of LD chemotherapy. Each JCAR017 dose includes CD4+ CAR+ T cells and CD8+ CAR+ T cells. | Drug: Fludarabine<br>* Fludarabine<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>Drug: JCAR017<br>* JCAR017<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Is defined as the percentage of participants achieving either a partial response (PR) or complete response (CR) at any time up to 60 months after JCAR017 treatment as assessed by PET-CT and/or CT using The Lugano classification | Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CRR) as assessed but PET-CT and/or CT using The Lugano Classification | Is defined as the percentage of subjects achieving a CR at any time up to 60 months after JCAR017 treatment | Up to 60 months | 
| Duration of Response (DOR) if Best Overall Response (BOR) is CR, as assessed by PET-CT and/or CT using The Lugano Classification | is defined for subjects with a BOR of CR as the time from first response (CR or PR) to disease progression or death from any cause up to 60 months after JCAR017 treatment | Up to 60 months | 
| Duration of Response (DOR) as assessed by PET-CT and/or CT using The Lugano Classification | is defined as the time from first response (CR or PR) to disease progression or death from any cause, whichever occurs first up to 60 months after JCAR017 treatment | Up to 60 months | 
| Progression-Free Survival (PFS) as assessed by PET-CT and/or CT using The Lugano Classification | is defined as the time from start of JCAR017 to disease progression or death from any cause, whichever occurs first up to 60 months after JCAR017 treatment | Up to 60 months | 
| Overall Survival (OS) | is defined as the time from start of JCAR017 to time of death due to any cause up to 60 months after JCAR017 treatment | Up to 60 months | 
| Adverse Events (AEs) | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. | Up to 60 months | 
| Pharmacokinetics - Cmax | Maximum concentration | Up to 60 months | 
| Pharmacokinetics - Tmax | Time to maximum concentration | Up to 60 months | 
| Pharmacokinetics - AUC | Area under the curve | Up to 60 months | 
| European Organization for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC QLQ-C30) | is questionnaire that will be used as a measure of health-related quality of life. The EORTC QLQ-C30 is composed of both multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/health-related quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. | Up to 24 months | 
| Functionality Assessment of Cancer Therapy Lymphoma Subscale (FACT-LymS) | is a 15-item lymphoma-specific additional concerns subscale. This subscale addresses symptoms and functional limitations are important to lymphoma patients. The FACT-LymS items are scored on a 0 (Not at all) to 4 (Very much) response scale. Items are aggregated to a single score on a 0-60 scale. High scores indicate lower symptom burden. | Up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
B-cell Non-Hodgkin Lymphoma (NHL), JCAR017, Relapsed or Refractory, Follicular Lymphoma, Marginal Zone Lymphoma