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

Phase 1
Terminated
Conditions
Relapsed/Refractory Large B-cell Lymphoma
Interventions
Drug: Cyclophosphamide
Drug: Fludarabine
Biological: Lenzilumab
Biological: Axicabtagene Ciloleucel
Registration Number
NCT04314843
Lead Sponsor
Kite, A Gilead Company
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.

Recruitment & Eligibility

Status
TERMINATED
Sex
All
Target Recruitment
6
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

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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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Lenzilumab and Axicabtagene CiloleucelLenzilumabPhase 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.
Lenzilumab and Axicabtagene CiloleucelAxicabtagene CiloleucelPhase 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.
Lenzilumab and Axicabtagene CiloleucelCyclophosphamidePhase 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.
Lenzilumab and Axicabtagene CiloleucelFludarabinePhase 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.
Primary Outcome Measures
NameTimeMethod
Phase 1: Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) Related to Sequenced Therapy With Lenzilumab and AxicabtageneFirst infusion of lenzilumab and axicabtagene ciloleucel up to 28 days.

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

Phase 2: Percentage of Participants Experiencing Grade 2 or Higher Neurologic Events Within 28 Days of Axicabtagene Ciloleucel AdministrationUp to 28 days
Secondary Outcome Measures
NameTimeMethod
Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse EventsEnrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.
Phase 1 and Phase 2: Percentage of Participants Experiencing Serious Adverse EventsEnrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.
Phase 1 and Phase 2: Percentage of Participants Experiencing Cytokine Release SyndromeEnrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.
Phase 1 and Phase 2: Percentage of Participants Experiencing Neurologic EventsEnrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.
Phase 1 and Phase 2: Axicabtagene Ciloleucel Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in BloodBaseline up to Month 3

Peak is defined as the maximum number of CAR T cells in blood measured after the axicabtagene ciloleucel infusion.

Phase 1 and Phase 2: Complete Response (CR) Rate Per Internal Working Group (IWG) Lugano Classification as Determined by the Study InvestigatorsFirst infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).

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.

Phase 1 and Phase 2: Objective Response Rate (ORR) Per IWG Lugano Classification as Determined by Study InvestigatorsFirst infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).

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.

Phase 1 and Phase 2: Duration of Response (DOR) in Participants Who Experience an Objective Response Per IWG Lugano Classification as Determined by Study InvestigatorsFirst infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).

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.

Phase 1 and Phase 2: Progression-Free Survival (PFS) Per IWG Lugano Classification as Determined by Study InvestigatorsFirst infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).

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.

Phase 1 and Phase 2: Overall Survival (OS)First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).

OS is defined as the time from axicabtagene ciloleucel infusion to the date of death.

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-1Baseline up to Week 4

Peak is defined as the maximum post-baseline level of the analyte from baseline to Week 4.

Trial Locations

Locations (10)

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

Oregon Health & Science University

🇺🇸

Portland, Oregon, United States

Stanford University

🇺🇸

Palo Alto, California, United States

Moffitt Cancer Center

🇺🇸

Tampa, Florida, United States

Northwestern University

🇺🇸

Evanston, Illinois, United States

Mayo Clinic

🇺🇸

Rochester, Minnesota, United States

Roswell Park Cancer Institute

🇺🇸

Buffalo, New York, United States

Levine Cancer Center

🇺🇸

Charlotte, North Carolina, United States

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