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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Relapsed/Refractory Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: Axicabtagene Ciloleucel
* Biological: Utomilumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axicabtagene ciloleucel plus utomilumab<br>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<br>* Administered according to package insert<br>Drug: Fludarabine<br>* Administered according to package insert<br>Biological: Axicabtagene Ciloleucel<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously<br>* Other names: Yescarta®;Biological: Utomilumab<br>* Administered as an IV infusion<br>|

What is the study measuring?
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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 |