Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma

Study Overview
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Brief Summary
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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
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This is a phase 3 randomized, open-label, multicenter study evaluating the efficacy of axicabtagene ciloleucel versus standard of care therapy in subjects with relapsed/refractory DLBCL. Adult subjects 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 subjects will be followed in the post-treatment follow-up period for up to 5 years. Thereafter, subjects 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.

Official Title
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A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel Versus Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma

Conditions
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Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Intervention / Treatment
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* Biological: Axicabtagene Ciloleucel
* Drug: Platinum-containing salvage chemotherapy (eg, R-ICE) followed by high dose therapy (eg, BEAM) and autologous stem cell transplant in responders.
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically proven large B-cell lymphoma including the following types defined by WHO 2016 (Swerdlow et al, 2016) DLBCL not otherwise specified (ABC/GCB) HGBL with or without MYC and BCL2 and/or BCL6 rearrangement DLBCL arising from 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-CD20 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two arms, SOC and experimental treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axicabtagene Ciloleucel Treatment<br> | Biological: Axicabtagene Ciloleucel<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously following a conditioning chemotherapy regimen of fludarabine and cyclophosphamide<br>* Other names: Yescarta ®;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|
| Active Comparator: Standard of Care Therapy<br> | Drug: Platinum-containing salvage chemotherapy (eg, R-ICE) followed by high dose therapy (eg, BEAM) and autologous stem cell transplant in responders.<br>* Platinum-containing salvage chemotherapy (R-ICE, R-DHAP, R-ESHAP, or R-GDP as selected by treating investigator) followed by high dose therapy (eg, BEAM) and autologous stem cell transplant in responders.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival (EFS) | Event free survival is defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause as determined by blinded central review. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective response rate is defined as the incidence of either a complete response or a partial response by the Lugano Classification, as determined by blinded central review. | Up to 5 years | 
| Overall Survival (OS) | Overall survival is defined as the time from randomization to death from any cause | Up to 5 years | 
| Modified Event Free Survival (mEFS) | Modified event free survival is defined the same way as EFS, except that failure to attain CR or PR by Day 150 assessment is not considered an event. mEFS will be analyzed per blinded central review and per investigator disease assessments. | Up to 5 years | 
| Progression-Free Survival (PFS) | Progression Free Survival is defined as the time from randomization to disease progression per Lugano Classification or death from any cause. | Up to 5 years | 
| Duration of Response (DOR) | Duration of response is derived only among subjects who experience an objective response per Lugano Classification, as determined by blinded central review and is defined as the time from first response to disease progression per the Lugano Classification or death from any cause. | Up to 5 years | 
| Duration of Complete Response | Duration of complete response is derived only among subjects who experience a complete response per Lugano Classification as determined by blinded central review and is defined as the time from first response to disease progression per the Lugano Classification or death from any cause. | Up to 5 years | 
| Event Free Survival (EFS) Per Investigator Disease Assessments | Event free survival is defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause as determined by investigator disease assessments. | Up to 5 years | 
| Changes in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 (EORTC QLQ-C30) Domains | The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 (EORTC QLQ-C30) is a multi-item questionnaire measuring the following content five (5) multi-item functional scales, three (3) multi-item symptom scales, one (1) global health status scale, and one (1) global health-related quality of life (HRQoL) each scale is measured from 0 to 100 after a linear transformation. Higher scores for functioning scales and for the Global Health Status or Global HRQoL scales indicate a higher level of functioning and a better HRQoL respectively, whereas higher scores in symptom scales represent a higher level of symptoms. | Up to 5 years | 
| Percentage of Participants Experiencing Adverse Events and Clinical Significant Changes in Safety Lab Values, Including Antibodies to Axicabtagene Ciloleucel. |  | Up to 5 years | 
| Changes Over Time in the European Quality of Life Five Dimensions Five Levels Scale (EQ-5D-5L) | 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). | Up to 5 years | 
| Changes Over Time in the Visual Analog Scale (VAS) Scores | The EQ-5D-5L VAS is a 20-cm VAS for recording self-rated current HRQoL state and is used to describe the subjects' health status on the day of the assessment. The EQ-5D-5L VAS score is recorded by each subject for his or her current HRQoL state and scored 0 (the worst health you can imagine) to 100 (the best health you can imagine). | Up to 5 years |