Diffuse Large B-cell Lymphoma (DLBCL), Primary Mediastinal B cell lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL). MedDRA version: 20.0 Level: HLT Classification code 10036711 Term: Primary mediastinal large B-cell lymphomas System Organ Class: 100000004851 MedDRA version: 20.0 Level: HLT Classification code 10012819 Term: Diffuse large B-cell lymphomas System Organ Class: 100000004851 MedDRA version: 21.0 Level: PT Classification code 10012818 Term: Diffuse large B-cell lymphoma S
Conditions
Sponsors
Kite Pharma, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 childbe
Exclusion criteria
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 requiring systemic anticoagulation 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 investigator's 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 au
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the phase 1 study is to evaluate the safety of axicabtagene ciloleucel regimens. The primary objective of the 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, earlier interventions, debulking therapy on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities.;Secondary Objective: 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.;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 incidence and severity of CRS and neurologic toxicities.;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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);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 annual | — |
Countries
Canada, France, Germany, Israel, Netherlands, United States
Contacts
Public ContactRegulatory Affairs
Kite Pharma, Inc.
Outcome results
None listed