Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.

Official Title
-----------------
A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
-----------------
Diffuse Large B-cell Lymphoma (DLBCL)

Intervention / Treatment
-----------------
* Biological: Tisagenlecleucel
* Drug: Lymphodepleting chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained prior to any screening procedures Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment. .- Relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT Measurable disease at time of enrollment Life expectancy ≥12 weeks Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening Adequate organ function: Renal function defined as: A serum creatinine of ≤1.5 x Upper Limit of Normal ULN OR Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m2 Liver function defined as: Alanine Aminotransferase (ALT) ≤ 5 times the Upper Limit of Normal (ULN) for age Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA) Adequate bone marrow reserve without transfusions defined as: Absolute neutrophil count (ANC) > 1.000/mm3 Absolute lymphocyte count (ALC) ≥ 300/mm3 Platelets ≥ 50.000//mm3 Hemoglobin > 8.0 g/dl Must have an apheresis product of non-mobilized cells accepted for manufacturing Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests Exclusion Criteria: Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy Treatment with any prior gene therapy product Active Central Nervous System (CNS) involvement by malignancy Prior allogeneic HSCT Eligible for and consenting to ASCT Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion Investigational medicinal product within the last 30 days prior to screening The following medications are excluded: Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m2/day hydrocortisone or equivalent Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to enrollment Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of infusion Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate) Prior radiation therapy within 2 weeks of infusion Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive ) HIV positive patients Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion) Unstable angina and/or myocardial infarction within 6 months prior to screening Previous or concurrent malignancy with the following exceptions: Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry) In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study A primary malignancy which has been completely resected and in complete remission for ≥ 5 years Investigational medicinal product within the last 30 days prior to screening Pregnant or nursing (lactating) women Intolerance to the excipients of the CTL019 cell product Cardiac arrhythmia not controlled with medical management Patients on oral anticoagulation therapy Prior treatment with any adoptive T cell therapy Patients with active neurological auto immune or inflammatory disorders(e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis) Other protocol-related inclusion/exclusion may apply.

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: Tisagenlecleucel<br>Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who will receive tisagenlecleucel. | Biological: Tisagenlecleucel<br>* A single infusion of 5 x 10^8 viable CTL019 transduced cells, which will be administered via intravenous infusion.<br>* Other names: CTL019;Drug: Lymphodepleting chemotherapy<br>* Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy cycle is planned. The use of any additional chemotherapy prior to the recommended lymphodepleting chemotherapy will be at the discretion of the investigator and dependent on the patient's disease burden. Lymphodepleting chemotherapy should be started 14 to 5 days before CTL019 infusion (D1) to allow for at least 48 hours from last dose of lymphodepleting chemotherapy to CTL019 infusion. The proposed lymphodepleting regimen is: Fludarabine (25 mg/m2 intravenously [i.v.] daily for 3 doses) and cyclophosphamide (250 mg/m2 i.v. daily for 3 doses starting with the first dose of fludarabine).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events (AEs) |  | 5 years | 
| Time to response (TTR) |  | 5 years | 
| Duration of overall response (DOR) |  | 5 years | 
| Event free survival (EFS) |  | 5 years | 
| Progression free survival (PFS) |  | 5 years | 
| Overall survival (OS) |  | 5 years | 
| In vivo cellular Pharmacokinetic (PK) profile of CTL019 transduced cells into target tissues |  | 5 years | 
| Incidence of immunogenicity to CTL019 |  | 5 years | 
| Number of Participants with presence of exposure to replication-competent lentivirus (RCL) as Assessed by quantitative polymerase chain reaction (qPCR) |  | 5 years | 
| Prevalence of immunogenicity to CTL019 |  | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diffuse large B-cell lymphoma,, DLBCL,, Relapsed/refractory,, CTL019, CART19, CART, CAR T cells, Chimeric antigen receptor