E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/Refractory Diffuse Large B cell Lymphoma (r/r DLBCL). |
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E.1.1.1 | Medical condition in easily understood language |
Cancers of white blood cells |
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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 | PT |
E.1.2 | Classification code | 10012822 |
E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine if axicabtagene ciloleucel is superior to SOC as measured by event-free survival (EFS), as determined by blinded central review |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on objective response rate (ORR)
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on overall survival (OS)
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on progression-free survival (PFS)
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on duration of response (DOR) and duration of complete response among responding subjects as determined by blinded central review
- To evaluate the safety of axicabtagene ciloleucel compared to SOC
- To evaluate the effect of axicabtagene ciloleucel on patient reported outcomes (PROs) and quality of life (QoL) compared to SOC
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
101. Histologically proven DLBCL including transformation from FL
102. Relapsed or refractory disease after first-line chemoimmunotherapy o Refractory disease defined as no complete remission to first- line therapy; subjects who are intolerant to first-line therapy are excluded Progressive disease (PD) as best response to first-line therapy Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP) Partial response (PR) as best response after at least 6 cycles, and biopsy-proven residual disease or disease progression ≤ 12 months from initiation of therapy o Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease relapse ≤ 12 months of initiating first-line therapy
103. Subjects must have received adequate first-line therapy including at a minimum: o Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and o An anthracycline containing chemotherapy regimen
104. Intent to proceed to HDT and ASCT if response to second-line therapy
105. Subjects must have radiographically documented disease
106. No known history or suspicion of central nervous system (CNS) involvement by lymphoma
107. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic cancer therapy at the time the subject provides consent
108. Age 18 years or older at the time of informed consent
109. ECOG performance status of 0 or 1
110. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function defined as: o Absolute neutrophil count (ANC) ≥1000/µL o Platelet count ≥ 75,000/µL o Absolute lymphocyte count ≥ 100/µL o Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min o Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 upper limit of normal (ULN) o Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert’s syndrome o Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings o No clinically significant pleural effusion o Baseline oxygen saturation > 92% on room air
111. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
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E.4 | Principal exclusion criteria |
201. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years
202. History of Richter’s transformation of CLL or PMBCL
203. History of autologous or allogeneic stem cell transplant
204. Received more than one line of therapy for DLBCL
205. Prior CD19 targeted therapy
206. Treatment with systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first dose of axicabtagene ciloleucel or SOC
207. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy, or prior randomization into ZUMA-7
208. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
209. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
210. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
211. Active tuberculosis
212. Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted.
213. Subjects with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases
214. History or presence of non-malignant CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
215. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
216. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months of enrollment
217. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression
218. History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years.
219. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
220. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment
221. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
222. History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study
223. Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
224. Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant. Subjects of either sex who are not willing to practice birth control from the time of consent and at least 6 months after the last dose of axicabtagene ciloleucel or SOC chemotherapy
225. In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
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E.5 End points |
E.5.1 | Primary end point(s) |
Event Free Survival (EFS): EFS is defined as the time from randomization to the earliest date of disease progression per the Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Subjects not meeting the criteria for these events by the analysis data cutoff date will be censored. For the primary analysis of EFS, disease progression events and censoring times will be determined by blinded central review. Events of new therapy and death will be based on the clinical trial database. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of EFS will be conducted when all subjects have had the opportunity to be followed to the Day 150 disease assessment and a minimum of 270 EFS events as determined by blinded central review have been observed. If more than 270 EFS events are observed at the time of the data cutoff for the primary analysis, all observed events will be used in the analysis. |
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E.5.2 | Secondary end point(s) |
Key secondary endpoints (in order of hierarchical testing) • Objective response rate • Overall survival
Secondary endpoints • EFS based on investigator disease assessments • Modified EFS based on blinded central review and on investigator disease assessments • Progression-free survival • Duration of response and complete response • Incidence of adverse events and clinically significant changes in safety lab values including antibodies to axicabtagene ciloleucel • Changes from screening to post baseline in the global health status QoL scale and the physical functioning domain of the EORTC QLQ-C30 • Changes from screening to post baseline in the EQ-5D-5L index and VAS scores
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall response rate (ORR) is defined as the incidence of either a complete response or a partial response by the Lugano Classification as determined by the study investigators.
Modified EFS is defined the same way as EFS, except that failure to attain CR or PR by Day 150 assessment is not considered as an event.
OS is defined as the time from randomization to death from any cause. Subjects who have not died by the analysis data cutoff date will have survival time censored at their last date known to be alive. For subjects alive or dead after the data cutoff date, survival time will be censored at the data cutoff date.
EFS, progression free survival (PFS), duration of response (DOR) timepoints of evaluation can be found in section 10.2.3. of the protocol. |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Germany |
Israel |
Italy |
Netherlands |
Spain |
United Kingdom |
United States |
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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
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Defined as when the last subject is assessed or received an intervention for evaluation in the study, including survival assessments |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 15 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 15 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |