Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma (ZUMA-11)

A Phase 1/2 Multi-center Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Subjects With Relapsed/Refractory Large B-Cell Lymphoma

The primary objectives of this study are:

Phase 1: To evaluate the safety of axicabtagene ciloleucel in combination with utomilumab and to identify the most appropriate dose and timing of utomilumab to carry forward into Phase 2

Phase 2: To evaluate the efficacy of axicabtagene ciloleucel and utomilumab as measured by complete response rate in participants with refractory large B-cell lymphoma

Study Overview

• Status: Terminated
• Conditions: Relapsed/Refractory Large B-cell Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Detailed Description

This study was intended to be a Phase 1/2. Enrollment was stopped prior to completion of Phase 1 portion of the study based on the sponsor's decision to end the program. No participants were enrolled in Phase 1 Cohort 5 and Phase 2.

After the study ends, participants who received an infusion of axicabtagene ciloleucel and utomilumab will complete the remainder of the 15-year follow-up assessments in a separate Long-term Follow-up study, KT-US-982-5968 (NCT05041309).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford Cancer Institute
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/ Oncology
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Histologically proven large B-cell lymphoma including the following types:

  • Diffuse large B cell lymphoma (DLBCL) not otherwise specified Activated B cell / Germinal center B cell (ABC/GCB).
  • High grade B-cell lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6 rearrangement.
  • DLBCL arising from follicular lymphoma.
  • T cell/histiocyte rich large B-cell lymphoma.
  • DLBCL associated with chronic inflammation.
  • Primary cutaneous DLBCL, leg type.
  • Epstein-Barr virus (EBV) + DLBCL

• Relapsed or chemotherapy-refractory disease, defined as one or more of the following:

  • No response to first-line therapy (primary refractory disease); individuals who are intolerant to first-line systemic chemotherapy are excluded

    • Progressive disease (PD) as best response to first-line therapy.
    • Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP) with SD duration no longer than 6 months from last dose of therapy.

  • No response to second or greater lines of therapy.

    • PD as best response to most recent therapy regimen.
    • SD as best response after at least 2 cycles of last line of therapy with SD duration no longer than 6 months from last dose of therapy OR

  • Refractory post-autologous stem cell transplant (ASCT).

    • Disease progression or relapsed 12 months after ASCT (must have biopsy proven recurrence in relapsed individual).
    • if salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy .

  • Relapsed or refractory LBCL including DLBCL, Transformed follicular lymphoma (TFL), and HGBCL after 2 or more lines of systemic therapy that is defined by and aligns with currently approved indication:

    • Relapsed disease after 2 or more lines of systemic therapy.
    • Best response that is less than a complete response to second or greater line of systemic therapy.
• At least 1 measurable lesion according to the Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.

• Individual must have received adequate prior therapy including at a minimum:

  • Anti-cluster of differentiation (CD) 20 monoclonal antibody unless investigator determines that tumor is CD20-negative, and
  • An anthracycline containing chemotherapy regimen.
• No radiographic 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 (ANC) ≥ 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/aspartate aminotransferase (ALT/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% and no evidence of pericardial effusion within 180 days provided the individual did not receive an anthracycline-based treatment or experience a cardiac event or change in performance status.
  • No clinically significant pleural effusion.
  • Baseline oxygen saturation > 92% on room air.

Key Exclusion Criteria:

• Histologically proven primary mediastinal B-cell lymphoma (PMBCL).
• History of Richter's transformation of chronic lymphocytic lymphoma (CLL).
• Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
• History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or applicable country guidelines.
• Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or a history of 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.
• Individuals with cardiac atrial or cardiac ventricular lymphoma involvement.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• Requirement for urgent therapy due to tumor mass effects (eg, blood vessel compression, bowel obstruction, or transmural gastric involvement.
• Primary immunodeficiency.
• History of autoimmune disease (eg, Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Individuals with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and individuals with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
• Autologous stem cell transplant within 6 weeks of planned enrollment
• Prior organ transplantation including prior allogeneic stem cell transplant (SCT)
• Use of any standard or experimental anti-cancer therapy within 2 weeks prior to enrollment, including cytoreductive therapy and radiotherapy, immunotherapy, or cytokine therapy (except for erythropoietin) Prior treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137 (4-1BB), anti-OX40 or other immune checkpoint blockade or activator therapy
• History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
• In the investigator's judgment, the individual is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg; Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation (CD) 19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 10 mg on Day 1, IV infusion, once every 4 weeks (Q4W) for 6 months or until progressive disease, whichever came first.	Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously; Other Names: Yescarta®; Biological: Utomilumab; Administered as an IV infusion
Experimental: Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg; Participants will receive cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 30 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first.	Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously; Other Names: Yescarta®; Biological: Utomilumab; Administered as an IV infusion
Experimental: Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg; Participants will receive cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 100 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first.	Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously; Other Names: Yescarta®; Biological: Utomilumab; Administered as an IV infusion
Experimental: Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg; Participants will receive cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 200 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first.	Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously; Other Names: Yescarta®; Biological: Utomilumab; Administered as an IV infusion
Experimental: Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg; Participants will receive cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 400 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first. However, as the study was early terminated, no participants were enrolled in Cohort 5 of the study.	Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously; Other Names: Yescarta®; Biological: Utomilumab; Administered as an IV infusion
Experimental: Phase 2: Axicabtagene Ciloleucel + Utomilumab; Participants will receive cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel and utomilumab based on the dose and schedule selected to move forward from the Phase 1 portion of the study as recommended by the internal safety review team. However, as the study was early terminated, no participants were enrolled in Phase 2 of the study.	Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously; Other Names: Yescarta®; Biological: Utomilumab; Administered as an IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose Limiting Toxicities (DLTs)	DLTs are study drug-related events with onset within first 28 days following infusion of axicabtagene ciloleucel or utomilumab: Grade (GR) 4 hematologic toxicity lasting more than 30 days (except lymphopenia or B-cell aplasia); All study drug-related GR 3 lasting for > 7 days or 4 non-hematologic toxicities regardless of duration (except: aphasia/dysphasia or confusion/cognitive disturbance which resolves to at least GR 1 within 2 weeks or baseline within 4 weeks, fever of any grade, immediate study drug-related hypersensitivity reactions within 2 hours of drug infusion that are reversible to grade 2 or less within 24 hours, renal toxicity which requires dialysis for ≤ 7 days, intubation for airway protection if ≤ 7 days, tumor lysis syndrome, grade 3 liver function test elevation, provided there is resolution to ≤ GR 2 within 14 days, grade 4 transient serum hepatic enzyme abnormalities provided there is resolution to ≤ GR 3 within < 72 hours, grade 3 nausea and/or anorexia).	Up to 28 days
Phase 2: Complete Response (CR) Rate	CR Rate: 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.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 and Phase 2: Objective Response Rate (ORR)	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.	From first infusion date of axicabtagene ciloleucel until first occurrence of CR or PR (maximum duration: 42.6 months)
Phase 1 and Phase 2: Duration of Response (DOR)	DOR is time from first objective response (OR) to disease progression (PD)/death from any cause/up to last date known alive in the study. PD:score 4(uptake moderately>liver)/5(uptake markedly>liver and/or new lesions) with increase in intensity of uptake from baseline; new fluorodeoxyglucose (FDG)-avid foci consistent with lymphoma at interim/EOT assessment; new FDG-avid foci consistent with lymphoma rather than another etiology; new/recurrent FDG-avid foci in bone marrow; an individual node/lesion must be abnormal with: LDi >1.5 cm, increase by ≥50% from cross-product of LDi and perpendicular diameter (PPD) nadir, increase in LDi/shortest axis perpendicular to LDi from nadir, splenic length must increase by >50% of extent of its prior increase beyond baseline. If no prior splenomegaly, increase must be ≥2 cm from baseline; new/recurrent splenomegaly; new or clear progression of pre-existing NMLs; new lesion; new/recurrent bone marrow involvement. OR is defined in outcome measure 3.	From first documentation of CR or PR until first occurrence of PD or death from any cause or up to last date known alive in the study (maximum duration: 42.6 months)
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 PD per Lugano classification or death from any cause or up to last date known alive in the study. PD is defined in outcome measure 4.	From first infusion date of axicabtagene ciloleucel to the date of PD or death from any cause or up to last date known alive in the study (maximum duration: 43.5 months)
Phase 1 and Phase 2: Overall Survival (OS)	OS was defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause or up to last date known alive in the study.	From first infusion date of axicabtagene ciloleucel to date of death from any cause or up to last date known alive in the study (maximum duration: 43.5 months)
Phase 1 and Phase 2: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)	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. TEAEs were defined as any worsening of a pre-existing medical condition that occurred on or after axicabtagene ciloleucel infusion or any AE with onset on or after axicabtagene ciloleucel infusion.	From first dose up to 30 days post last dose (maximum duration: 23.0 months)
Phase 1 and Phase 2: 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. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.	From first dose up to 30 days post last dose (maximum duration: 23.0 months)
Phase 1 and Phase 2: Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value	Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.	From first dose up to 30 days post last dose (maximum duration: 23.0 months)
Phase 1 and Phase 2: Pharmacokinetics: Peak Levels of Axicabtagene Ciloleucel in Blood	Peak was defined as the maximum number of CAR T cells in blood measured after infusion.	Day 1 (Pre-utomilumab (UTO) Dose 1), Day 3 (Post-UTO Dose 1), Day 7, Day 10, Week 2, Week 3, Week 4 (Pre and Post-UTO Dose 2), Week 8 (Pre and Post-UTO Dose 3), Week 12 (Pre-UTO Dose 4), Week 16 (Pre-UTO Dose 5), Week 20 (Pre-UTO Dose 6), Week 24
Phase 1 and Phase 2: Pharmacodynamics: Peak Levels of Cytokines in Serum	Peak is defined as the maximum post-baseline level of cytokine in the blood.	Baseline, Day 0, Day 7, Week 2, Week 4 (Pre and Post-UTO Dose 2)

Collaborators and Investigators

• Sponsor: Kite, A Gilead Company
• Collaborators: Pfizer
• Investigators: Study Director: Kite Study Director, Kite, A Gilead Company

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2018
• Primary Completion (Actual): May 7, 2021
• Study Completion (Actual): December 15, 2022

Study Registration Dates

• First Submitted: October 10, 2018
• First Submitted That Met QC Criteria: October 10, 2018
• First Posted (Actual): October 12, 2018

Study Record Updates

• Last Update Posted (Actual): June 28, 2024
• Last Update Submitted That Met QC Criteria: June 26, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Fludarabine; Axicabtagene ciloleucel
• Other Study ID Numbers: KTE-C19-111

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gileadclinicaltrials.com/transparency-policy/
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No