Clinical trial NCT04314843: Study of Lenzilumab and Axicabtagene Ciloleucel in Participants With Relapsed or Refractory Large B-Cell Lymphoma
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Relapsed/Refractory Large B-cell Lymphoma
Keywords: Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF)
GM-CSF antibody
Chimeric Antigen Receptor (CAR)
CD19
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
Collaborators: name: Humanigen, Inc.
First posted: 2020-03-19
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) Related to Sequenced Therapy With Lenzilumab and Axicabtagene
timeFrame: First infusion of lenzilumab and axicabtagene ciloleucel up to 28 days.
measure: Phase 2: Percentage of Participants Experiencing Grade 2 or Higher Neurologic Events Within 28 Days of Axicabtagene Ciloleucel Administration
timeFrame: Up to 28 days
Secondary outcomes:
measure: Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse Events
timeFrame: Enrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.
measure: Phase 1 and Phase 2: Percentage of Participants Experiencing Serious Adverse Events
timeFrame: Enrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.
measure: Phase 1 and Phase 2: Percentage of Participants Experiencing Cytokine Release Syndrome
timeFrame: Enrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.
measure: Phase 1 and Phase 2: Percentage of Participants Experiencing Neurologic Events
timeFrame: Enrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.
measure: Phase 1 and Phase 2: Complete Response (CR) Rate Per Internal Working Group (IWG) Lugano Classification as Determined by the Study Investigators
timeFrame: First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
measure: Phase 1 and Phase 2: Objective Response Rate (ORR) Per IWG Lugano Classification as Determined by Study Investigators
timeFrame: First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
measure: 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
timeFrame: First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
measure: Phase 1 and Phase 2: Progression-Free Survival (PFS) Per IWG Lugano Classification as Determined by Study Investigators
timeFrame: First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
measure: Phase 1 and Phase 2: Overall Survival (OS)
timeFrame: First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).
measure: 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
timeFrame: Baseline up to Week 4
measure: Phase 1 and Phase 2: Axicabtagene Ciloleucel Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood
timeFrame: Baseline up to Month 3
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center, New York-Presbyterian Hospital
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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