Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma
- Conditions
- Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
- Interventions
- Drug: Platinum-containing salvage chemotherapy (eg, R-ICE) followed by high dose therapy (eg, BEAM) and autologous stem cell transplant in responders.
- Registration Number
- NCT03391466
- Lead Sponsor
- Kite, A Gilead Company
- Brief Summary
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).
- 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 359
-
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.
Key
- 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
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard of Care Therapy Platinum-containing salvage chemotherapy (eg, R-ICE) followed by high dose therapy (eg, BEAM) and autologous stem cell transplant in responders. 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. Axicabtagene Ciloleucel Treatment Axicabtagene Ciloleucel 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. Axicabtagene Ciloleucel Treatment Cyclophosphamide 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. Axicabtagene Ciloleucel Treatment Fludarabine 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.
- Primary Outcome Measures
Name Time Method Event Free Survival (EFS) Per Blinded Central Assessment From randomization date up to a median follow-up: 24.9 months EFS:Time from randomization to disease progression (PD), best response of SD up to and including Day 150, commencement of subsequent new anti-lymphoma therapy including stem cell transplant, or death from any cause. PD=score 4 (uptake moderately\>liver)/5 (uptake markedly \>liver and/or new lesions) with an increase in intensity of uptake from baseline;new fluorodeoxyglucose (FDG)-avid foci consistent with lymphoma at interim/EOT assessment, rather than another etiology or in bone marrow;an individual node/lesion must be abnormal with LDi \>1.5 cm, increase by ≥50% from cross-product of LDi and perpendicular diameter nadir, increase in LDi or shortest axis perpendicular to LDi from nadir, splenic length must increase by \>50% of extent of its prior increase beyond Baseline. If no prior splenomegaly, increase must be ≥2 cm from baseline;new/recurrent splenomegaly;new/clear progression of pre-existing NMLs;new lesion;new/recurrent bone marrow involvement. KM estimates was used for analysis.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) From randomization date up to a median follow-up: 47.2 months Overall survival is defined as the time from randomization to death from any cause. Kaplan-Meier (KM) estimates was used for analysis.
Objective Response Rate (ORR) Per Blinded Central Assessment From randomization date up to a median follow-up: 24.9 months ORR: Percentage of participants with CR \[CMR;CRR\] or PR \[partial metabolic response (PMR); partial radiologic response (PRR)\].CMR: PET 5PS scores of 1 (no uptake above background, 2(uptake≤mediastinum), 3(uptake\>mediastinum but≤liver) with/without a residual mass;no new lesions; no evidence of FDG-avid disease in BM. CRR:target nodes/nodal masses regressed to ≤ 1.5 cm in LDi;no extralymphatic sites of disease;absent non-measured lesions (NMLs);organ enlargement regress to normal;no new sites;bone marrow morphology normal. PMR:scores 4 (uptake moderately\>liver),5(uptake markedly \> liver, new lesions) with reduced uptake compared with baseline and residual mass;no new lesions;responding disease at interim/residual disease at end of treatment (EOT).PRR: ≥50% decrease in sum of the product of perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites;absent/normal, regressed, but no increase of NMLs;spleen regressed by \>50% in length beyond normal;no new sites.
Duration of Response (DOR) Per Blinded Central Assessments From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (Up to 37.8 months) DOR is defined only for participants who experience an objective response after axicabtagene ciloleucel infusion and is the time from the first objective response per Lugano classification to disease progression or death from any cause. Objective response is defined in outcome measure 2 and disease progression is defined in outcome measure 1. KM estimates were used for analysis.
Modified Event Free Survival (mEFS) Per Blinded Central Assessment From randomization date up to a median follow-up: 24.9 months Modified event free survival is defined the same way as EFS, except that a best response of SD up to and including Day 150 assessment post randomization was not considered an event. KM estimates were used for analysis.
Event Free Survival Per Investigator Disease Assessments From randomization date up to a median follow-up: 47.2 months EFS was defined as the time from randomization to the earliest date of disease progression per the IWG Lugano Classification, best response of stable disease (SD) up to and including Day 150, commencement of new lymphoma therapy, or death from any cause. Disease progression is defined in outcome measure 1.
Progression-Free Survival (PFS) Per Investigator Disease Assessments From randomization date up to a median follow-up: 47.2 months PFS is defined as the time from the randomization date to the date of disease progression per Lugano classification or death from any cause. Disease progression is defined in outcome measure 1. KM estimates was used for analysis.
Modified Event Free Survival (mEFS) Per Investigator Assessment From randomization date up to a median follow-up: 47.2 months Modified event free survival is defined the same way as EFS, except that a best response of SD up to and including Day 150 assessment post randomization was not considered an event. KM estimates were used for analysis.
Change From Baseline in Global Health Status Scores Baseline, Days 50, 100, and 150; Months 9, 12, 15, 18, 21 and 24 Global health status was measured using European Organization for Research and Treatment of Cancer (EORTC) Quality Life Questionnaire (QLQ) C-30. This health related quality of life (HRQoL) questionnaire was comprised of 15 questions on functional scales, 13 questions on symptom scales and 2 on global health status scale. Global Health Status used a 7 point Likert-type scale of 1 (Very poor) to 7 (Excellent). All scores were transformed to 0-100. Higher scores for Global Health Status indicated better HRQoL.
Change From Baseline in EORTC QLQ-C30 Physical Functioning Score Baseline, Days 50, 100, 150, Months 9, 12, 15, 18, 21 and 24 The EORTC QLQ-C30 is composed of global health status/QoL scale; five functional domains (physical, role, emotional, cognitive, and social); three symptom domains (fatigue, nausea and vomiting, and pain); and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
The Physical Functioning domain includes 5 questions in which participants were asked to rate their overall health and overall quality of life as it relates to physical functioning during the past week on a scale from 1 (very poor) to 7 (excellent). The 5 scores were transformed to a scale from 0 to 100, where a high score indicated better QoL. A positive change from baseline indicates better QoL.Changes From Baseline in the European Quality of Life Five Dimensions Five Levels Scale (EQ-5D-5L) Index Score Baseline, Days 50, 100, 150; Months 9, 12, 15, 18, 21 and 24 The Euro-QOL, Five Dimensions, Five Levels (EQ-5D-5L) questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L comprises 2 components: a questionnaire covering 5 dimensions and a tariff of values based upon direct valuations of health states using a visual analog scale (VAS). The total score for EQ-5D-5L index- is presented on a range from 0 to 1 where higher scores indicate better outcome. A positive change from Baseline indicates improvement.
Change From Baseline in EQ-5D-5L VAS Scale Score Baseline, Days 50, 100, 150; Months 9, 12, 18, 21 and 24 The EQ-5D-5L VAS is a 20-cm VAS for recording self-rated current HRQoL state and is used to describe the participants' health status on the day of the assessment. The EQ-5D-5L VAS score is recorded by each participant for his or her current HRQoL state and scored 0 ("the worst health you can imagine") to 100 ("the best health you can imagine"). The value 100 indicates improvement.
Number of Participants With Anti-Axicabtagene Ciloleucel Antibodies From first dose of axicabtagene up to a median follow-up: 24 months Percentage of Participants Experiencing Treatment-emergent Adverse Events Up to 5 years A TEAE is defined as any AE that begins on or after the first dose of study treatment (axicabtagene ciloleucel infusion or SOC), excluding bridging therapy. Participant incidence rates of TEAEs, including all, serious, fatal, CTCAE Grade 3 or higher, and treatment related AEs reported will be tabulated by preferred term and system organ class coded with the Medical Dictionary for Regulatory Activities (MedDRA).
Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs Up to 5 years Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.
Trial Locations
- Locations (72)
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
The University of Texas, MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Swedish Cancer Institute
🇺🇸Seattle, Washington, United States
University of Miami Hospital and Clinics/Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
University of Iowa Hospitals and Clinincs
🇺🇸Iowa City, Iowa, United States
University of Maryland, Greenbaum Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Mayo Clinic, Patient Location
🇺🇸Rochester, Minnesota, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
Stanford Cancer Institute
🇺🇸Stanford, California, United States
Medizinische Universitat Innsbruck, Innere Medizin V - Hamatologie und Onkologie
🇦🇹Innsbruck, Austria
IRCCS Ospedale San Raffaele di Milano
🇮🇹Milano, Italy
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Henry-Joyce Cancer Center
🇺🇸Nashville, Tennessee, United States
Peter MacCallum Cancer Center
🇦🇺Melbourne, Victoria, Australia
Centre Hospitalier Universitaire de Rennes - Hopital Pontchaillou
🇫🇷Rennes, France
Universitäts-klinikum Dresden
🇩🇪Dresden, Germany
Academic Medical Center
🇳🇱Amsterdam, Netherlands
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Erasmus Medical Center
🇳🇱Rotterdam, Netherlands
UZ Gasthuisberg
🇧🇪Leuven, Belgium
Instituto di Ematologia "L. e A. Seragnoli" - Dipartimento di Medicina Specialistica Diagnostica e Sperimentale
🇮🇹Bologna, Italy
CHRU de Lille - Hopital Claude Huriez
🇫🇷Lille cedex, France
Institut Catala d'Oncologia
🇪🇸Barcelona, Spain
Centre Hospitalier Lyon-Sud - Service d'Hematologie clinique
🇫🇷Pierre Benite, France
Universitatsmedizin Gottingen
🇩🇪Göttingen, Germany
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Germany
University Medical Center Groningen
🇳🇱Groningen, Netherlands
Universitäts-klinikum Würzburg
🇩🇪Würzburg, Germany
Universitatsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
The University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
Barbara Ann Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Cliniques Universiaires Saint-Luc
🇧🇪Brussels, Belgium
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
University Hospital Zurich
🇨🇭Zürich, Switzerland
QEII Health Sciences Centre
🇨🇦Halifax, Canada
Uninversity Health Network - Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
Centre Integre Universitaire de Sante et Services Sociaux de l'Est-de-l'lle-de-Montreal / Hopital Maisonneuve-Rosemont
🇨🇦Montréal, Canada
CHU de Quebec-Universite Laval, Hopital de L'Enfante-Jesus
🇨🇦Québec, Canada
Barts Health NHS Trust
🇬🇧London, United Kingdom
Mayo Clinic Hospital
🇺🇸Phoenix, Arizona, United States
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
UCLA
🇺🇸Santa Monica, California, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
John Theurer Cancer Center at Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University of Utah, Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Universitatsklinikum Graz, Division of Hematology
🇦🇹Graz, Austria
McGill University Health Center
🇨🇦Montreal, Quebec, Canada
The Ottawa Hospital - General Campus
🇨🇦Ottawa, Canada
Hopital Saint-Louis
🇫🇷Paris, France
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Clinica Universidad de Navarra
🇪🇸Pamplona, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
IOSI, OSpedale Regionale Bellinzona e Valli
🇨🇭Bellinzona, Switzerland
Uppsala Akademiska Sjukhus
🇸🇪Uppsala, Sweden
University Hospitals Birmingham NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom
The Royal Marsden NHS Foundation Trust
🇬🇧Sutton, United Kingdom
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands