Study of Lenzilumab and Axicabtagene Ciloleucel in Participants With Relapsed or Refractory Large B-Cell Lymphoma

Relapsed/Refractory Large B-cell Lymphoma Clinical Trial

— ZUMA-19  

Official title:

A Phase 1/2 Open-label, Multicenter Study of Lenzilumab and Axicabtagene Ciloleucel in Subjects With Relapsed or Refractory Large B-cell Lymphoma (ZUMA-19)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04314843
• Other study ID #: KT-US-471-0119
• Secondary ID: 2019-004568-23
• Status: Terminated
• Phase: Phase 1
• Start date: May 26, 2020
• Est. completion date: July 27, 2022

Study information

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

Clinical Trial Summary

The primary objectives of this study are:

Phase 1: To evaluate the safety of sequenced therapy with lenzilumab and axicabtagene ciloleucel in participants with relapsed or refractory large B-cell lymphoma and identify the most appropriate dose of lenzilumab for Phase 2.

Phase 2: To evaluate the incidence of neurologic events with sequenced therapy given at the recommended Phase 2 dose (RP2D) of lenzilumab in participants with relapsed or refractory large B-cell lymphoma.

Description:

This study was intended to be a Phase 1/2, but the planned Phase 2 part has been canceled.

All participants who received an infusion of lenzilumab and axicabtagene ciloleucel will be provided the opportunity to transition to a separate long-term follow-up (LTFU) study, KT-US-982-5968.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: July 27, 2022
• Est. primary completion date: March 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Individuals with large B-cell lymphoma, including Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, Primary mediastinal large B-cell lymphoma (PMBCL), High-grade B-cell lymphoma (HGBL), and DLBCL arising from Follicular lymphoma (FL)

• Individuals must have relapsed disease after 2 or more lines of systemic therapy, or chemorefractory disease defined as the following:

• No response to first-line therapy, including the following:

• Progressive disease (PD) as best response to first therapy

• Stable disease (SD) as best response after = 4 cycles of first-line therapy (eg, 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)), with SD duration no longer than 6 months from the last dose of therapy

• No response to = 2 lines of therapy, including the following:

• PD as best response to most recent therapy

• SD as best response after = 2 cycles of last line of therapy

• Individuals 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

• At least 1 measurable lesion according to the International Working Group Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.

• Magnetic resonance imaging of the brain showing no evidence of central nervous system (CNS) lymphoma

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

• Individuals with a known medical history of tuberculosis or a risk for tuberculosis exposure require negative tuberculosis testing by either tuberculin skin test or interferon gamma release assay.

• Adequate bone marrow function as evidenced by:

• Absolute neutrophil count = 1000/µL

• Platelets = 75,000/µL

• Absolute lymphocyte count = 100/µL

• Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:

• Creatinine clearance (Cockcroft-Gault) = 60 mL/min

• Serum alanine aminotransferase or aspartate aminotransferase = 2.5 upper limit of normal

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

• Cardiac ejection fraction = 50% with no evidence of clinically significant pericardial effusion as determined by 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 Richter's transformation of chronic lymphocytic leukemia

• Autologous stem cell transplant (SCT) within 6 weeks of planned axicabtagene ciloleucel infusion

• History of allogeneic stem cell transplantation

• Prior CD19 targeted therapy or prior CAR T cell therapy

• History of pulmonary alveolar proteinosis (PAP)

• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides

• Known history of human immunodeficiency virus (HIV) infection, hepatitis B (HBsAg positive) or hepatitis C (HCV) (anti-HCV positive) infection. A history of hepatitis B or hepatitis C infection is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.

• Individuals with detectable Cerebrospinal fluid (CSF) malignant cells, or brain metastases, or with a history of CNS lymphoma, CSF malignant cells or brain metastases

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

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Relapsed/Refractory Large B-cell Lymphoma

Intervention

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

Biological:
• Lenzilumab
Administered as an IV infusion
• Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously.

Locations

Country	Name	City	State
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Levine Cancer Center	Charlotte	North Carolina
United States	Northwestern University	Evanston	Illinois
United States	MD Anderson Cancer Center	Houston	Texas
United States	Vanderbilt University	Nashville	Tennessee
United States	Columbia University Medical Center, New York-Presbyterian Hospital	New York	New York
United States	Stanford University	Palo Alto	California
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Kite, A Gilead Company	Humanigen, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (2)

Kenderian, S. S., Oluwole, O. O., Mccarthy, P. L., Reshef, R., Shiraz, P., Ahmed, O., Le Gall, J., Nahas, M., Tang, L. And Neelapu, S. S. Zuma-19: A Phase 1/2 Multicenter Study of Lenzilumab Use With Axicabtagene Ciloleucel (Axi-Cel) In Patients (Pts) With Relapsed Or Refractory Large B Cell Lymphoma (R/R Lbcl). Blood 136(Supplement 1): 6-7, (2020). Conference Proceedings.

Olalekan O. Oluwole, MBBS, Saad S. Kenderian, MD, Parveen Shiraz, MD, Reem Karmali, MD, MSc, Ran Reshef, MD, MSc, Philip L. McCarthy, MD, Nilanjan Ghosh, MD, PhD, Aleksandr Lazaryan, MD, PhD, MPH, Simone Filosto, PhD, Soumya Poddar, PhD, Daqin Mao, PhD, Andrew Peng, MS, Adrian Kilcoyne, MD, MPH, Myrna Nahas, MD, Sattva S. Neelapu, MD. A Phase 1/2 Study of Axicabtagene Ciloleucel Plus Lenzilumab in Patients With Relapsed or Refractory Large B-Cell Lymphoma. American Society of Hemotology; Dec 10-13, 2022; New Orleans, LA. Abstract 4635

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) Related to Sequenced Therapy With Lenzilumab and Axicabtagene	A DLT was defined as the following sequenced therapy-related events with onset within the first 28 days following lenzilumab and axicabtagene ciloleucel infusions: Grade 4 neutropenia lasting longer than 21 days from the day of cell transfer; Grade 4 thrombocytopenia lasting longer than 28 days from the day of cell transfer; Any sequenced therapy-related AE requiring intubation, including Grade 4 encephalopathy requiring intubation for airway protection; Any sequenced therapy-related Grade 5 event	First infusion of lenzilumab and axicabtagene ciloleucel up to 28 days.
Primary	Phase 2: Percentage of Participants Experiencing Grade 2 or Higher Neurologic Events Within 28 Days of Axicabtagene Ciloleucel Administration		Up to 28 days
Secondary	Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse Events		Enrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.
Secondary	Phase 1 and Phase 2: Percentage of Participants Experiencing Serious Adverse Events		Enrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.
Secondary	Phase 1 and Phase 2: Percentage of Participants Experiencing Cytokine Release Syndrome		Enrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.
Secondary	Phase 1 and Phase 2: Percentage of Participants Experiencing Neurologic Events		Enrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.
Secondary	Phase 1 and Phase 2: Complete Response (CR) Rate Per Internal Working Group (IWG) Lugano Classification as Determined by the Study Investigators	CR rate: percentage of participants with CR (CMR;CRR). CMR: positron emission tomography(PET)5-point scale(5PS) scores of 1(no uptake above background), 2(uptake = mediastinum), 3(uptake > mediastinum but = liver) with/without a residual mass); no new sites; and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. CRR: target nodes/nodal masses regressed to = 1.5 cm in longest transverse diameter (LDi) of a lesion; no extra lymphatic sites; absent non-measured lesion;organ enlargement regress to normal; no new sites; and bone marrow normal by morphology.	First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
Secondary	Phase 1 and Phase 2: Objective Response Rate (ORR) Per IWG 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 1,2,3 with/without a residual mass;no new sites;no evidence of FDG-avid disease in bone marrow.CRR:target nodes/nodal masses regressed to = 1.5 cm in LDi of a lesion;no extra lymphatic sites;absent non-measured lesion;organ enlargement regress to normal;no new sites;bone marrow normal by morphology.PMR:5PS scores of 4(uptake moderately higher than liver),or 5(uptake markedly higher than liver and/or new lesions),with reduced uptake compared to baseline and residual masses of any size;no new sites;residual update > update in normal bone marrow but reduced compared with baseline.PRR:= 50% decrease in sum of the product of perpendicular diameters of up to 6 target measurable nodes and extranodal sites;absent/normal, regressed, but no increase of nonmeasured lesions;spleen regressed by > 50% in length beyond normal;no new sites.	First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
Secondary	Phase 1 and Phase 2: Duration of Response (DOR) in Participants Who Experience an Objective Response Per IWG Lugano Classification as Determined by Study Investigators	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) 7.	First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
Secondary	Phase 1 and Phase 2: Progression-Free Survival (PFS) Per IWG Lugano Classification as Determined by Study Investigators	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 axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
Secondary	Phase 1 and Phase 2: Overall Survival (OS)	OS is defined as the time from axicabtagene ciloleucel infusion to the date of death.	First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
Secondary	Phase 1 and Phase 2: Pharmacodynamics: Peak Serum Level of CXCL10, Granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-8, TNF Alpha, GM-CSF, and MCP-1	Peak is defined as the maximum post-baseline level of the analyte from baseline to Week 4.	Baseline up to Week 4
Secondary	Phase 1 and Phase 2: Axicabtagene Ciloleucel Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood	Peak is defined as the maximum number of CAR T cells in blood measured after the axicabtagene ciloleucel infusion.	Baseline up to Month 3

External Links

•   Gilead Clinical Trials Website