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 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, but the planned Phase 2 part has been canceled.

After the study, 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.

• 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
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

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

  • Diffuse large B cell lymphoma (DLBCL) not otherwise specified (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); subjects 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 participant)
    • if salvage therapy is given post-ASCT, the participant must have had no response to or relapsed after the last line of therapy

  • Relapsed or refractory LBCL including DLBCL, 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 CR to second or greater line of systemic therapy
• At least 1 measureable lesion according to the Lugano Classification (Cheson et al, 2014). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.

• Participant 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
• 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 subject 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 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. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and patients 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 CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed
• In the investigator's judgment, the subject 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Axicabtagene ciloleucel plus utomilumab; Phase 1: Participants will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by axicabtagene ciloleucel treatment on Day 0 plus utomilumab on study Day 1 or study Day 21 and continuing once every 4 weeks (Q4W) for 6 months or until Progressive Disease, whichever comes first. Phase 2: Participants will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by axicabtagene ciloleucel and utomilumab based on the dose/regimen selected to move forward from the Phase 1 portion of the study as recommended by the internal Safety Review Team.

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
For Phase 1: Percentage of Participants Experiencing Adverse Events defined as Dose Limiting Toxicities (DLTs)	Dose-limiting toxicity is defined as protocol-defined axicabtagene ciloleucel related events with onset within the first 28 days following axicabtagene ciloleucel infusion.	Up to 28 days
For Phase 2: Complete Response Rate	Complete response rate is defined as the incidence of a complete response per the Lugano Classification (Cheson et al, 2014), as determined by study investigators.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For Phase 1 and Phase 2: Objective Response Rate	Objective response rate is defined as the incidence of either a complete response (CR) or a partial response (PR) per Lugano Classification as determined by study investigators.	Up to 15 years
For Phase 1 and Phase 2: Duration of Response	Among participants who experience an objective response, duration of response is defined as the date of their first objective response to disease progression per Lugano Classification as determined by study investigators or death from any cause.	Up to 15 years
For Phase 1 and Phase 2: Progression Free Survival	Progression free survival is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per Lugano Classification as determined by study investigators or death from any cause.	Up to 15 years
For Phase 1 and Phase 2: Overall Survival	Overall survival is defined as the time from axicabtagene ciloleucel infusion to the date of death.	Up to 15 years
For Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse Events		Up to 24 months plus 30 days
For Phase 1 and Phase 2: Percentage of Participants Experiencing Clinically Significant Changes in Safety Lab Values		Up to 24 months plus 30 days
For Phase 1 and Phase 2: Pharmacokinetics: Levels of Axicabtagene Ciloleucel in Blood		Up to 2 years
For Phase 1 and Phase 2: Pharmacodynamics: Levels of Cytokines in Serum		Up to 2 years

Collaborators and Investigators

• Sponsor: Kite, A Gilead Company
• Collaborators: Pfizer

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 (Estimate): December 22, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2022
• Last Verified: December 1, 2022

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; Cyclophosphamide; Fludarabine
• 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; Statistical Analysis Plan (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