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

Gilead Sciences

Status and phase: Terminated; Phase 1

Conditions: Relapsed/Refractory Large B-cell Lymphoma

Treatments: Biological: Utomilumab; Drug: Cyclophosphamide; Biological: Axicabtagene Ciloleucel; Drug: Fludarabine

Study type: Interventional

Funder types: Industry

Identifiers

NCT03704298

KTE-C19-111

Details and patient eligibility

About

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

Full 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).

Enrollment: 15 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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15 participants in 6 patient groups

Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Biological: Utomilumab

Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Biological: Utomilumab

Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Biological: Utomilumab

Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Biological: Utomilumab

Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Biological: Utomilumab

Phase 2: Axicabtagene Ciloleucel + Utomilumab

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Biological: Utomilumab