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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Relapsed/Refractory Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: Lenzilumab
* Biological: Axicabtagene Ciloleucel


Participation Criteria
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Eligibility Criteria
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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.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenzilumab and Axicabtagene Ciloleucel<br>Phase 1: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab and axicabtagene ciloleucel on Day 0 to determine a recommended Phase 2 dose (RP2D) of lenzilumab. Phase 2: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab, at the RP2D, and axicabtagene ciloleucel on Day 0. | Drug: Cyclophosphamide<br>* Administered according to package insert<br>Drug: Fludarabine<br>* Administered according to package insert<br>Biological: Lenzilumab<br>* Administered as an IV infusion<br>* Other names: Humaneered® anti-human GM-CSF monoclonal antibody;Biological: Axicabtagene Ciloleucel<br>* A single infusion of chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously.<br>* Other names: Yescarta®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose Limiting Toxicities (DLTs) Related to Sequenced Therapy with Lenzilumab and Axicabtagene | Dose-limiting toxicity is defined as protocol-defined sequenced therapy-related events with onset within the first 28 days following lenzilumab and axicabtagene ciloleucel infusion. | Up to 28 days | 
| For Phase 2: Percentage of Participants Experiencing Grade 2 or Higher Neurologic Events Within 28 days of Axicabtagene Ciloleucel Administration |  | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse Events |  | Up to 12 months | 
| For Phase 1 and Phase 2: Percentage of Participants Experiencing Serious Adverse Events |  | Up to 24 months | 
| For Phase 1 and Phase 2: Percentage of Participants Experiencing Cytokine Release Syndrome |  | Up to 24 months | 
| For Phase 1 and Phase 2: Percentage of Participants Experiencing Neurologic Events |  | Up to 24 months | 
| For Phase 1 and Phase 2: Objective Response Rate (ORR) | ORR is defined as the incidence of either a Complete Response (CR) or a Partial Response (PR) per the International Working Group (IWG) Lugano Classification as determined by the study investigators. | Up to 2 years | 
| For Phase 1 and Phase 2: Complete Response (CR) Rate | CR rate is defined as the incidence of CR per the IWG Lugano Classification as determined by the study investigators | Up to 2 years | 
| For Phase 1 and Phase 2: Duration of Response (DOR) in Participants who Experience an Objective Response | Among participants who experience an objective response, DOR is defined as the date of participants' first objective response to disease progression per the IWG Lugano Classification as determined by study investigators or death from any cause. | Up to 2 years | 
| For Phase 1 and Phase 2: Progression-Free Survival (PFS) | PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the IWG Lugano Classification as determined by study investigators or death from any cause. | Up to 2 years | 
| For Phase 1 and Phase 2: Overall Survival (OS) | OS is defined as the time from axicabtagene ciloleucel infusion to the date of death. | Up to 2 years | 
| For Phase 1 and Phase 2: Pharmacodynamics: Levels of Cytokines in Blood |  | Up to 3 months | 
| For Phase 1 and Phase 2: Axicabtagene Ciloleucel Pharmacokinetics: Levels of anti-CD19 CAR T Cells in Blood |  | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), GM-CSF antibody, Chimeric Antigen Receptor (CAR), CD19