| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-cell Lymphoma (DLBCL), Primary Mediastinal B cell lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancers of white blood cells, collectively known as 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 | HLT |
| E.1.2 | Classification code | 10036711 |
| E.1.2 | Term | Primary mediastinal large B-cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10012819 |
| E.1.2 | Term | Diffuse large B-cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of phase 1 study is to evaluate the safety of axicabtagene ciloleucel regimens.
The primary objective of phase 2 pivotal study is to evaluate the efficacy of axicabtagene ciloleucel, as measured by objective response rate (ORR) in subjects with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL).
The primary objective of the Phase 2 safety management study is to assess the impact of a prophylactic regimen or earlier interventions and tumor debulking on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of phase 2 pivotal study will include assessing the safety and tolerability of axicabtagene ciloleucel and additional efficacy endpoints.
Secondary objectives of the Phase 2 safety management study include assessment of efficacy, levels of anti-CD19 chimeric antigen receptor (CAR) T cells, cytokines in blood/serum, and the change in European Quality of Life-5 Dimensions (EQ-5D) scores from baseline to Month 6. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
101. Histologically confirmed aggressive B cell NHL, including the following types defined by WHO 2008 (Campo et al, 2011):
- DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; OR
- primary mediastinal (thymic) large B cell lymphoma
- transformation of follicular lymphoma to DLBCL will also be included
102. Chemotherapy-refractory disease, defined as one or more of the following:
- No response to first-line therapy (primary refractory disease); subjects who are intolerant to first-line therapy chemotherapy are excluded
- PD as best response to first-line therapy
- SD as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP) with SD duration no longer than 6 months from last dose of therapy
OR
- No response to second or greater lines of therapy
- PD as best response to most recent therapy regimen
- SD as best response after at least 2 cycles of last line of therapy with SD duration no longer than 6 months from last dose of therapy
OR
- Refractory post-ASCT
- Disease progression or relapsed ≤12 months of ASCT (must have biopsy proven recurrence in relapsed subjects)
- if salvage therapy is given post-ASCT, the subject must have had no response to or relapsed after the last line of therapy
103. Subjects must have received adequate prior therapy including at a minimum:
- anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and
- an anthracycline containing chemotherapy regimen;
- for subjects with transformed FL must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to DLBCL
104 .At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
105. MRI of the brain showing no evidence of CNS lymphoma
106. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists etc).
107. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia)
108. Age 18 or older
109. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
110. ANC ≥1000/uL
111. Platelet count ≥75,000/uL
112. Absolute lymphocyte count ≥100/uL
113. Adequate renal, hepatic, pulmonary and cardiac function defined as:
- Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
- Serum ALT/AST ≤2.5 ULN
- Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert’s syndrome.
- Cardiac ejection fraction ≥ 50% ,no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings
- No clinically significant pleural effusion
- Baseline oxygen saturation >92% on room air
114. 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)
Additional criteria specific for Phase 2 safety management study (cohorts 3, 4 and 5):
115. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy |
|
| E.4 | Principal exclusion criteria |
201. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years
202. History of Richter’s transformation of CLL
203. Autologous stem cell transplant with therapeutic intent within 6 weeks of planned axicabtagene ciloleucel infusion
204. History of allogeneic stem cell transplantation
205. Prior CD19 targeted therapy with the exception of subjects who received axicabtagene ciloleucel in this study and are eligible for re-treatment
206. Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
207. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
208. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.
209. History of HIV infection or acute or chronic active hepatitis B or C infection. Subjects with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or applicable country guidelines.
210. Presence of any indwelling line or drain (e.g., 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
211. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases
212. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
213. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
214. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment
215. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome)
216. Primary immunodeficiency
217. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment
218. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
219. History of severe immediate hypersensitivity reaction to any of the agents used in this study
220. Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen
221. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential
222. Subjects of both genders who are not willing to practice birth control from the time of consent through 6 months after the completion of conditioning therapy
223. 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
224. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1 Study: Incidence of adverse events defined as dose-limiting toxicities (DLT)
Phase 2 Pivotal Study: Objective response rate (complete response [CR] + partial response [PR]) per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma as determined by study investigators. All subjects who do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.
Phase 2 Safety Management Study: Assess the rate and severity of CRS and neurologic toxicities. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 Study: The primary analysis of Cohort 1 will occur after 72 subjects in the mITT set have had the opportunity to be assessed for response 6 months after the axicabtagene ciloleucel infusion.
Phase 2 Pivotal Study: The primary analysis of Cohorts 1 and 2 combined will be performed when 72 subjects in the mITT set of Cohort 1 and 20 subjects in the mITT set of Cohort 2 have had the opportunity to be evaluated for response at 6 months after the target axicabtagene ciloleucel infusion.
Phase 2 Safety Management Study:The primary analysis of Cohort 3, 4 and 5 will occur after all treated subjects in each cohort
have had the opportunity to be followed for 6 months, respectively. |
|
| E.5.2 | Secondary end point(s) |
Phase 1 Study:
• Objective response rate (CR + PR) per the revised IWG Response Criteria for Malignant Lymphoma
• Duration of Response (DOR)
• Overall Survival (OS)
• Progression Free Survival (PFS)
• Incidence of adverse events and clinical significant changes in safety lab values
• Levels of anti-CD19 CAR T cells in blood
• Levels of cytokines in serum
• Incidence of anti-axicabtagene ciloleucel antibodies
Phase 2 Pivotal Study:
• Objective response rate per Independent Radiology Review Committee (IRRC)
• DOR
• PFS
• OS
• Incidence of adverse events and clinical significant changes in safety lab values
• Levels of anti-CD19 CAR T cells in blood
• Levels of cytokines in serum
• Incidence of anti-axicabtagene ciloleucel antibodies
Phase 2 Safety Management Study:
• Objective response rate (complete response [CR] + partial response [PR]) per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma (Cheson et al, 2007) as determined by study investigators.
• DOR
• PFS
• OS
• Incidence of adverse events and clinically significant changes in safety lab values
• Levels of anti-CD19 CAR T cells in blood
• Levels of cytokines in blood
• Incidence of anti-axicabtagene ciloleucel antibodies
• Changes over time in the EQ-5D scale score and visual analogue scale (VAS) score (Phase 2 SMS only) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All enrolled subjects will be followed in the long term follow-up period for survival and disease status, if applicable. Subjects will begin the long term follow-up period after they have completed the Month 3 visit of the post treatment assessment period (whether they have responded to treatment or went straight to the month 3 visit due to disease progression)
• Every 3 months (± 2 weeks) through Month 18
• Every 6 months (± 1 month) between Month 24 - Month 60
• Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time annually up to 15 years. |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I to assess safety, Phase II to assess efficacy of KTE-C19 and safety management study |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Canada |
| France |
| Germany |
| Israel |
| Netherlands |
| United States |
|
| 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
|
| Defined as when the last subject is assessed or received an intervention for evaluation in the study, including survival assessments |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 15 |
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