E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
B-Cell Non Hodgkin Lymphoma |
|
E.1.1.1 | Medical condition in easily understood language |
B-Cell Non Hodgkin Lymphoma |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025320 |
E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To compare progression free survival (PFS) of patients randomized to investigational point-of-care (PoC) ARI-0001 CAR T-cells versus PFS of patients randomized to commercial standard-of-care (SoC) (axicabtagene ciloleucel (Axi cel, Yescarta)) CAR T-cells inpatients with R/R DLBCL.
|
|
E.2.2 | Secondary objectives of the trial |
• To evaluate response rates • To evaluate safety and toxicity of ARI-0001 and Axi-cel • To assess overall survival • To evaluate quality of life • To assess costs associated with both treatment regimens (ARI-0001 vs Axi-cel) • To evaluate CAR T-cell expansion, persistence, and T-cell characteristics in both treatment arms (ARI-0001 vs Axi-cel) • To evaluate PoC CAR T-cell production characteristics (e.g. number of viable T-cells, transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)), including the functional characteristics between the different production sites. • To evaluate the association of the functional characteristics of ARI-0001 CAR T-cells with CAR T-cell expansion, persistence, adverse events, response rates and PFS. • To assess the proportion of successful batches between the different production sites • To evaluate the number of days between leukapheresis and infusion of CAR T-cells • To evaluate fludarabine pharmacokinetics. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016 classification: DLBCL not otherwise specified (NOS), High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B, T-cell/histocyte rich B-cell lymphoma, Primary mediastinal B-cell lymphoma, EBV+ DLBCL, transformed lymphoma (transformed follicular) and R/R after at least 2 lines of systemic therapy • Age ≥ 18 years • Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0-2 • Secondary central nervous system (CNS) involvement is allowed however, then he/she must have: - No signs or symptoms of CNS involvement that would hamper adequate ICANS assessment • Estimated life expectancy of >3 months other than primary disease • Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen • Signed and dated informed consent before conduct of any trial-specific procedure • Patient is capable of giving informed consent |
|
E.4 | Principal exclusion criteria |
• Absolute neutrophil count (ANC) <1.0x109/L • Platelet count <50x109/L • Absolute lymphocyte count <0.1x109/L • Primary CNS lymphoma • Known history of infection with hepatitis C or B virus unless treated and confirmed to be PCR negative • Active HIV infection with detectable viral load or CD4 T-cell count below 0.20x109/L • Known history or presence of seizure activities or on active anti- seizure medications within the previous 12 months • Known history of CVA within prior 12 months • Unstable neurological deficits • Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease • Active systemic autoimmune disease for which immunnosupressive therapy is required • Presence of CNS disease that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity, baseline dementia that would interfere with therapy or monitoring, determined using mini-mental status exam at baseline • Active systemic fungal, viral or bacterial infection • Clinical heart failure with NYHA class ≥2 or LVEF <40% • Resting oxygen saturation <92% on room air • Liver dysfunction as indicated by total bilirubin, AST and/or ALT >5 x institutional ULN, unless directly attributable to the lymphoma or Gilbert disease • GFR <40 mL/min calculated according to the modified formula of Cockcroft and Gault or by direct urine collection • Pregnant or breast-feeding woman • Active other malignancy requiring treatment • Medical condition requiring prolonged use of systemic immunosuppressives with exception of prednisolon<10mg/day • History of severe immediate hypersensitivity reaction against any drug or its Ingredients/ impurities that is scheduled to be given during trial participation e.g. as part of the mandatory lymphodepletion protocol, premedication for infusion, or rescue medication/salvage therapies for treatment related toxicities • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• PFS from date of IMP infusion (if applicable) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
When applicable data of evaluable patients are available |
|
E.5.2 | Secondary end point(s) |
• PFS from date of randomization • Safety and toxicity assessment of ARI-0001 CAR T-cells and Axi-cel per AE reporting classified according to CTCAE Version 5 and CRS and ICANS classified according to the ASTCT criteria • Overall response rate (ORR, sum of (metabolic) complete response [CR] and partial response [PR]), as well as CR, PR, stable disease (SD) and progressive disease (PD)/relapse at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells • Best overall response (BOR) rate at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells • Duration of response (DOR) • OS from date of randomization, and from date of CAR T-cell infusion (if applicable) • Patient Reported Outcome/Quality of Life (PRO/QOL) • CAR T-cell expansion, persistence, and T-cell characteristics in both treatment arms (ARI-0001 vs Axi-cel) • PoC CAR T-cell production characteristics (e.g. number of viable T-cells, transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)), including the functional characteristics (eg potency tests) between the different production sites. • The association of the functional characteristics (eg potency tests) of the CAR T-cell products (ARI-0001 CAR T-cells) with CAR T-cell expansion, persistence, adverse events, response rates and progression free survival. • Proportion of successful batches between the different production sites • Number of days between leukapheresis and infusion of CAR T-cells (vein-to-vein time) • Fludarabine pharmacokinetics. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
When applicable data of evaluable patients are available |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
registered CAR T-cel therapy (Axi-cel) |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |