A Phase 2 Trial of Anakinra for the Prevention of CAR-T Cell Mediated Neurotoxicity

Study Overview
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Brief Summary
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This research study is studying the combination of anakinra and axicabtagene ciloleucel to reduce the occurrence of the side effects Cytokine Release Syndrome (CRS) and neurologic toxicities with relapsed or refractory Non-Hodgkin lymphoma (NHL). Relapsed NHL is the condition of returned Non-Hodgkin lymphoma. Refractory NHL is the condition of previous treatment resistant Non-Hodgkin lymphoma. Cytokine Release Syndrome (CRS) is a group of side effect symptoms that can include nausea, headache, rapid heartbeat, shortness of breath, kidney damage, and rash. Neurologic toxicity is nervous system disorder characterized by confusion This research study involves two drugs: Anakinra Axicabtagene Ciloleucel.

Detailed Description
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This Phase 2, single center, open-label research study is studying the combination of Anakinra and Axicabtagene Ciloleucel to reduce the occurrence of the side effects Cytokine Release Syndrome (CRS) and neurologic toxicities in people with relapsed or refractory Non-Hodgkin lymphoma (NHL). The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. This research study involves two drugs: Anakinra Axicabtagene Ciloleucel A total of 20 participants will be enrolled to this trial The U.S. Food and Drug Administration (FDA) has not approved anakinra for use in treatment of Non-Hodgkin lymphoma (NHL).

Official Title
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A Phase 2 Trial of Anakinra for the Prevention of CAR-T Cell Mediated Neurotoxicity

Conditions
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Non Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Relapsed Non Hodgkin Lymphoma, Neurotoxicity, Neurotoxicity Syndromes, Cytokine Release Syndrome

Intervention / Treatment
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* Drug: Anakinra
* Drug: Axicabtagene Ciloleucel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma 1. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy however steroids only require a 7-day washout. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc). Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia) Age 18 or older Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ANC ≥1000/uL Platelet count ≥75,000/uL Absolute lymphocyte count ≥100/uL Adequate renal, hepatic, pulmonary and cardiac function defined as: Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min Serum ALT/AST ≤2.5 ULN Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome. Cardiac ejection fraction ≥ 50%, no clinically significant pericardial effusion, and no clinically significant ECG findings No clinically significant pleural effusion Baseline oxygen saturation >92% on room air Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential) Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years History of Richter's transformation of CLL Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion History of allogeneic stem cell transplantation Prior CD19 targeted therapy with the exception of subjects who received axicabtagene ciloleucel in this study and are eligible for re-treatment Prior chimeric antigen receptor therapy or other genetically modified T cell therapy History of severe, immediate hypersensitivity reaction attributed to aminoglycosides Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. History of HIV infection or acute or chronic active hepatitis B or C infection. Subjects 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. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement Subjects 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 Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome) Primary immunodeficiency 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 History of severe immediate hypersensitivity reaction to any of the agents used in this study Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential Subjects of both genders who are not willing to practice birth control from the time of consent through 6 months after the completion of axicabtagene ciloleucel In the investigators 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 History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years

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: Anakinra and Axicabtagene Ciloleucel<br>Patients who meet eligibility criteria for the study will subsequently be enrolled for treatment. Screening Enrollment/Leukapheresis period Bridging therapy (if applicable) Lymphodepleting chemotherapy period Investigational Product (IP) treatment period Anakinra Axicabtagene Ciloleucel Post treatment assessment period Long term follow-up period | Drug: Anakinra<br>* Subcutaneous, dosage per protocol. Day 0 through Day 6.<br>* Other names: Kineret®;Drug: Axicabtagene Ciloleucel<br>* Once, intravenous infusion, dosage per protocol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of neurotoxicity as per CTCAE v4.03 criteria | The incidence of grade 2+ neurotoxicity will be assessed in comparison to a historical rate of 45% via a two-sized exact binomial test with significant level of 0.05. | 30 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The incidence of objective response and exact 2-sided 95% confidence intervals will be generated | 24 Months | 
| Duration of Response | Cumulative incidence of relapse. | first objective response to disease progression death regardless of cause up 100 Months | 
| Progression-free Survival | Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for progression-free survival time | infusion date to the date of disease progression or death from any cause up 100 Months | 
| Overall Survival | Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS. | time from axicabtagene ciloleucel infusion to the date of death or analysis data cutoff date will be censored at last contact date up to 100 months. | 
| Number of Participants with Adverse Events CTCAE version 4.03 Grade 3 or higher | Subject incidence rates of adverse events including all, serious, fatal, CTCAE version 4.03 Grade 3 or higher and treatment related AEs reported throughout the conduct of the study will be tabulated by preferred term and system organ class | 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Relapsed Non Hodgkin Lymphoma, Neurotoxicity, Neurotoxicity Syndromes, Cytokine Release Syndrome