Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma

B-cell Lymphoma Clinical Trial

— ZUMA-12  

Official title:

A Phase 2 Multicenter Study Evaluating the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Subjects With High-Risk Large B-Cell Lymphoma (ZUMA-12)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03761056
• Other study ID #: KTE-C19-112
• Secondary ID: 2019-002291-13
• Status: Completed
• Phase: Phase 2
• Start date: January 29, 2019
• Est. completion date: October 12, 2023

Study information

• Verified date: October 2023
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to estimate the efficacy of axicabtagene ciloleucel in participants with high-risk large B-cell lymphoma.

After the end of KTE-C19-112 (ZUMA-12), participants who received an infusion of axicabtagene ciloleucel will complete the remainder of the 15-year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: October 12, 2023
• Est. primary completion date: May 17, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Histologically confirmed large B-cell lymphoma

• High-grade large B-cell lymphoma

• Individuals must have a positive interim positron emission tomography (PET) per Cheson, 2014 (Deauville PET score of 4 or 5) after 2 cycles (PET2+) of chemoimmunotherapy

• No evidence, suspicion and/or history of central nervous system (CNS) involvement of lymphoma

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Absolute neutrophil count = 1000/µL

• Platelet count = 75,000/µL

• Absolute lymphocyte count = 100/µL

• Adequate renal, hepatic, pulmonary, and cardiac function defined as:

• Creatinine clearance (as estimated by Cockcroft Gault) = 60 mL/min

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 upper limit of normal (ULN)

• Total bilirubin =1.5 mg/dL, except in individuals with Gilbert's syndrome

• 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

• History of Richter's transformation of chronic lymphocytic leukemia or primary mediastinal B-cell lymphoma

• History of autologous or allogeneic stem cell transplant

• Prior CD19-targeted therapy

• Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy

• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management

• History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection

• Presence of any indwelling line or drain dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted

• Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or active CNS lymphoma

• History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment

• History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years

• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Related Conditions & MeSH terms

• B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell

Intervention

Biological:
• Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells

Drug:
• Fludarabine
Administered according to package insert
• Cyclophosphamide
Administered according to package insert

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
France	Hopital Saint Louis	Paris
United States	City of Hope	Duarte	California
United States	Banner Health MD Anderson Cancer Center	Gilbert	Arizona
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Kite, A Gilead Company

Countries where clinical trial is conducted

United States,  Australia,  France, 

References & Publications (4)

Neelapu SS, Chavez JC, Lin Y, Munoz J, Ujjani CS, Riedell P, et al. ZUMA-12: A Phase 2 Multicenter Study of Axicabtagene Ciloleucel (Axi-Cel) as a First-Line Therapy in Patients (Pts) with High-Risk Large B-Cell Lymphoma (LBCL) [Abstract]. J Clin Oncol 2019;37 (15).

Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, Thieblemont C, Oluwole OO, et al. 739 Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL) [Abstract]. 63rd American Society of Hematology (ASH) Annual Meeting and Exposition; 2021 11-14 December.

Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, Thieblemont C, Oluwole OO, Herrera AF, Ujjani CS, Lin Y, Riedell PA, Kekre N, de Vos S, Lui C, Milletti F, Dong J, Xu H, Chavez JC. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022 Apr;28(4):735-742. doi: 10.1038/s41591-022-01731-4. Epub 2022 Mar 21. — View Citation

Neelapu SS, Dickinson M, Ulrickson ML, Oluwole OO, Herrera AF, Thieblemont C, et al. 405 Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B-Cell Lymphoma (LBCL) [Abstract]. 62nd American Society of Hematology (ASH) Annual Meeting and Exposition Virtual; 2020 05-08 December.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators	Complete Response Rate (CRR): percentage of participants with CR [complete metabolic response (CMR); complete radiological response (CRR)]. CMR: positron emission tomography (PET) 5-point scale (5-PS) scores of 1 (no uptake above background), 2 (uptake = mediastinum), 3 (uptake > mediastinum but = liver) with/without a residual mass); no new lesions; and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow (BM). CRR: target nodes/nodal masses regressed to = 1.5 cm in longest transverse diameter of lesion (LDi); no extralymphatic sites of disease; absent non-measured lesion (NMLs); organ enlargement regress to normal; no new sites; and bone marrow normal by morphology.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months)
Secondary	Objective Response Rate (ORR) Per the Lugano Classification as Determined by Study Investigators	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 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.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months)
Secondary	Duration of Response (DOR) Per the Lugano Classification	DOR is defined only for participants who experience an objective response after axicabtagene ciloleucel infusion and is the time from the first objective response to disease progression or death from any cause. Objective response is defined in outcome measure (OM) 2.	From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (up to approximately 26.2 months)
Secondary	Event-Free Survival (EFS)	EFS was defined as time from axicabtagene ciloleucel infusion date to earliest date of disease progression (Lugano classification), commencement of subsequent new anti-lymphoma therapy including stem cell transplant, or death from any cause.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Progression-Free Survival (PFS)	PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per Lugano classification or death from any cause.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Overall Survival (OS)	OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Serious Adverse Events (SAE)	An AE was any untoward medical occurrence in a participant in a clinical trial participant, which did not necessarily have a causal relationship with the treatment. Treatment-emergent adverse events were defined as any adverse event with onset on or after the axicabtagene ciloleucel infusion. Serious adverse event was defined as an event that resulted in the following: death; life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; and medically important event or reaction.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value	Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value	Grading categories were determined by CTCAE version 5.0.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Relapse With Central Nervous Disease (CNS) Disease	Relapse with CNS disease was defined as the time from the axicabtagene ciloleucel infusion date to the earliest date of CNS involvement with lymphoma as determined by typical symptoms, cerebrospinal fluid (CSF) evaluation, and/or diagnostic imaging.	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
Secondary	Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood	Peak was defined as the maximum number of CAR T cells in blood measured after infusion.	From enrollment up to Month 24
Secondary	Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8	Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.	From enrollment up to Week 4
Secondary	Peak Serum Level of C-Reactive Protein (CRP)	Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.	From enrollment up to Week 4
Secondary	Peak Serum Level of Ferritin	Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.	From enrollment up to Week 4
Secondary	Time to Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8, CRP, and Ferritin	Time to peak is defined as the number of days from axicabtagene ciloleucel infusion to the date when the cytokine first reached the maximum post-baseline level.	From enrollment up to Week 4

External Links

•   Gilead Clinical Trials Website