Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma
Purpose
The goal of this clinical study is to assess whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Condition
- Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Histologically proven large B-cell lymphoma including the following types defined by World Health Organization (WHO) 2016. - Diffuse large B-cell lymphoma (DLBCL) not otherwise specified activated B-cell/ germinal center B-cell (ABC/GCB). - High-grade B-cell lymphoma (HGBL) with or without myelocytomatosis oncogene (MYC) and B-cell lymphoma (BCL) 2 and/or BCL6 rearrangement. - DLBCL arising from follicular lymphoma (FL). - T-cell/histiocyte rich large B-cell lymphoma. - DLBCL associated with chronic inflammation. - Primary cutaneous DLBCL, leg type. - Epstein-Barr virus (EBV) + DLBCL. - Relapsed or refractory disease after first-line chemoimmunotherapy. - Refractory disease defined as no complete remission to first-line therapy; individuals 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 of therapy. - Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven relapse ≤ 12 months of first-line therapy. - Individuals must have received adequate first-line therapy including at a minimum: - Anti-Cluster of Differentiation antigen (CD) 20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and - An anthracycline containing chemotherapy regimen. - No known history or suspicion of central nervous system involvement by lymphoma. - Eastern cooperative oncology group (ECOG) performance status of 0 or 1. - Adequate bone marrow function as evidenced by: - Absolute neutrophil count (ANC) ≥ 1000/uL - Platelet ≥ 75,000/uL - Absolute lymphocyte count ≥ 100/uL - Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by: - Creatinine clearance (Cockcroft Gault) ≥ 60 mL/min. - Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper limit of normal (ULN). - Total bilirubin ≤ 1.5 mg/dl - Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an Echocardiogram (ECHO), and no clinically significant Electrocardiogram (ECG) findings. - No clinically significant pleural effusion. - Baseline oxygen saturation > 92% on room air.
Exclusion Criteria
- History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years. - Received more than one line of therapy for DLBCL. - History of autologous or allogeneic stem cell transplant. - Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management. - 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. - Individuals with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases. - History or presence of non-malignant central nervous system (CNS) disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement. - Presence of any indwelling line or drain. Dedicated central venous access catheter such as a Port-a-Cath or Hickman catheter are permitted. - 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 diseases within 12 months of enrollment. - History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment. - History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years. - History of anti-CD19 or CAR-T therapy or history of prior randomization in ZUMA-7. Note: Other protocol defined Inclusion/Exclusion criteria may apply
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Intervention Model Description
- Two arms, SOC and experimental treatment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Axicabtagene Ciloleucel Treatment |
Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation antigen (CD) 19 CAR transduced autologous T cells/kg on Day 0. |
|
|
Active Comparator Standard of Care Therapy |
Participants will receive 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who will respond will get high dose therapy and autologous stem cell transplant. |
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More Details
- Status
- Active, not recruiting
- Sponsor
- Kite, A Gilead Company
Study Contact
Detailed Description
This is a phase 3 randomized, open-label, multicenter study evaluating the efficacy of axicabtagene ciloleucel versus standard of care therapy in participants with relapsed/refractory DLBCL. Adult participants with relapsed/refractory DLBCL after first-line rituximab and anthracycline-based chemotherapy will be randomized in a 1:1 ratio to receive axicabtagene ciloleucel or standard of care second-line therapy. Standard of care will consist of a protocol-defined, platinum-based salvage combination chemotherapy regimen followed by high-dose therapy and autologous stem cell transplant in those who respond to salvage chemotherapy. After completing the treatment period, all participants will be followed in the post-treatment follow-up period for up to 5 years. Thereafter, participants who received at least one dose of axicabtagene ciloleucel as protocol therapy will transition to a separate long term follow up (LTFU) study and complete the remainder of the 15-year follow-up assessments within KT-US-982-5968 (NCT05041309).