Clinical Trials /

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

NCT03704298

Description:

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

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
  • Transformed Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma
  • Official Title: A Phase 1/2 Multi-center Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Subjects With Refractory Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: KTE-C19-111
  • NCT ID: NCT03704298

Conditions

  • Refractory Large B-cell Lymphoma

Interventions

DrugSynonymsArms
CyclophosphamideAxicabtagene ciloleucel plus utomilumab
FludarabineAxicabtagene ciloleucel plus utomilumab
Axicabtagene CiloleucelYescarta®Axicabtagene ciloleucel plus utomilumab
UtomilumabAxicabtagene ciloleucel plus utomilumab

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Axicabtagene ciloleucel plus utomilumabExperimentalPhase 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.
  • Cyclophosphamide
  • Fludarabine
  • Axicabtagene Ciloleucel
  • Utomilumab

Eligibility Criteria

        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

          -  Chemotherapy-refractory disease, defined as one or more of the following:

               -  No response to second or greater lines of therapy

                    -  Progressive disease (PD) as best response to most recent therapy regimen

                    -  Stable disease (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

          -  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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:For Phase 1: Percentage of Participants Experiencing Adverse Events defined as Dose Limiting Toxicities (DLTs)
Time Frame:Up to 28 days
Safety Issue:
Description:Dose-limiting toxicity is defined as protocol-defined axicabtagene ciloleucel related events with onset within the first 28 days following axicabtagene ciloleucel infusion.

Secondary Outcome Measures

Measure:For Phase 1 and Phase 2: Objective Response Rate
Time Frame:Up to 15 years
Safety Issue:
Description: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.
Measure:For Phase 1 and Phase 2: Duration of Response
Time Frame:Up to 15 years
Safety Issue:
Description: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.
Measure:For Phase 1 and Phase 2: Progression Free Survival
Time Frame:Up to 15 years
Safety Issue:
Description: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.
Measure:For Phase 1 and Phase 2: Overall Survival
Time Frame:Up to 15 years
Safety Issue:
Description:Overall survival is defined as the time from axicabtagene ciloleucel infusion to the date of death.
Measure:For Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse Events
Time Frame:Up to 24 months plus 30 days
Safety Issue:
Description:
Measure:For Phase 1 and Phase 2: Percentage of Participants Experiencing Clinically Significant Changes in Safety Lab Values
Time Frame:Up to 24 months plus 30 days
Safety Issue:
Description:
Measure:For Phase 1 and Phase 2: Pharmacokinetics: Levels of Axicabtagene Ciloleucel in Blood
Time Frame:Days 0, 1, 3, 7, 14, and 21. Pre (1 day) and post (2 days) utomilumab for up to 6 months and every 3 months thereafter up to year 15
Safety Issue:
Description:
Measure:For Phase 1 and Phase 2: Pharmacodynamics: Levels of Cytokines in Serum
Time Frame:At enrollment; prior to axicabtagene ciloleucel infusion on Day 0, Days 3, 7, 14, and 21; prior to utomilumab infusion on Days 1, 29, and 57; and post utomilumab infusion on Days 3, 31, and 59
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Kite, A Gilead Company

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