Addition of Nivolumab to Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive DLBCL at Lymphodepletion

Study Overview
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Brief Summary
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Progression of DLBCL is the major obstacle for the success of chimeric antigen receptor-T cell (CAR-T) with approximately 60% of the patients relapsing in the first year, and 40% within 3 months, after infusion. While patient with DLBCL in Partial Response/Complete Response at lymphodepletion have a 1-year Progression Free Survival (PFS) of 60-80%, those with Stable Disease/Progressive Disease at time of lymphodepletion have a dismal PFS of 20-30%. Trials showed that better expansion of CAR-T cells, even in patients with a progressive disease, may overcome this grave prognosis and may result in better PFS

Detailed Description
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Factors that may introduce resistance to CAR-T. in addition to the bulk of disease, include also expression of check point molecules that eventually interfere with the CAR-T action. The investigator, have recently shown (EBMT 2022, # LWP-03) a real-life data, that day +7 CAR-T concentration in patients with stable or progressive disease (SD/PD) at lymphodepletion segregates patients to those with high CAR-T blood concentrations that achieve a high CR/PR rate after CAR-T infusion ,those with 20-100 CAR-T cells/microL that achieve a lower CR/PR rate after CAR-T infusion, and those with <20 cells/microL that achieve the lowest CR/PR rate after infusion. Thus, the extent of CAR-T cell expansion on day 7 after treatment is a prognostic marker predicting response to treatment in this patient group. Considering all these - patients with SD/PD at time of lymphodepletion, and specifically those with lower CAR-T blood concentrations on day +7 are at a very high risk for early disease progression after CAR-T infusion and, as such, there is an urgent unmet medical need to improve their outcomes. Addition of anti PD-1 to patients with low expansion of CAR-T cells may overcome the inhibitory effect of PD-1 expression and may result in a better function of the CAR-T and eventually tumor suppression. Nivolumab is a human monoclonal antibody targeting (programmed death-1 ) PD-1, a negative regulatory molecule expressed by activated T and B lymphocytes. Anti PD-1 treatment has been administered as a single dose or repeated administration in different time points during CAR-T cell therapy. These studies showed that this treatment is safe, well tolerated and does not result in increased CAR-T associated toxicities, mainly cytokine release syndrome(CRS) and immune effector cell associated neurotoxicity(ICANS). The optimal time window to administer these agents for achieving safety and efficacy is not determined.

Official Title
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Addition of Nivolumab to Standard of Care With Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive DLBCL at Lymphodepletion

Conditions
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B Cell Lymphoma

Intervention / Treatment
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* Drug: Nivolumab Injection [Opdivo]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be at least 18 years of age inclusive, at the time of signing the informed consent. DLBCL treated with CAR-T targeting CD19 (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) PD/SD by PET-CT on the day of lymphodepletion Capable of giving signed informed consent Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 No active CRS or ICANS at time of nivolumab administration Exclusion Criteria: Hypersensitivity to checkpoints inhibitors CRS grade 3 and above or ICANS any grade on days 0-5 following CAR-T AST (Aspartate transaminase) or ALT (Alanine transaminase) over 3 times the upper limit of normal (ULN) or total bilirubin over 3 times ULN Serum creatinine over 1.5 times ULN or over 1.5 times baseline History of or active autoimmune disease Uncontrolled seizure activity and/or clinically evident progressive encephalopathy Active diarrhea (more than 4 bowel movements per day) Clinically significant uncontrolled illness Active infection requiring antibiotics Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection Other active malignancy Females only: Pregnant or breastfeeding

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
Interventional Model Description: All patients enrolled to this study with DLBCL in SD/PD at time of lymphodepletion will be given nivolumab ( 3mg/kg IV) on day +5 Patients with CAR-T expansion<100 cells/microL on day +7 will be given 1 additional dose of nivolumab (3mg/kg IV) on day +19 (two weeks after first dose of nivolumab).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIVOLUMAB<br>All patients enrolled will be given nivolumab ( 3mg/kg IV) on day +5 Patients with CAR-T expansion<100 cells/microL on day +7 will be given 1 additional dose of nivolumab (3mg/kg IV) on day +19 (two weeks after first dose of nivolumab). | Drug: Nivolumab Injection [Opdivo]<br>* Nivolumab ( 3mg/kg IV) on day +5. If CAR-T expansion<100 cells/microL on day +7 one additional dose of nivolumab (3mg/kg IV) will be given on day +19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response at 1 months after CAR-T infusion | Complete or partial remission rate assessed by PET-CT (Positron Emission Tomography ) at 1 month after combination therapy with nivolumab and CAR-T. | One month post CAR-T infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at 1 year after CAR-T infusion and nivolumab | To assess survival of patients at 1 year after infusion of CAR-T and addition of nivolumab. | One year post CAR-T infusion | 
| Duration of response | Assess duration of disease response after CAR-T infusion | One year post CAR-T infusion | 
| Cytokine release syndrome | Assesment of cytokine release syndrome according to the American Society for Transplantation and Cellular Therapy (ASTCT) grading system (grade 0-4, 4 being the worse) (TCT. 2019 Apr; 25(4);625-638) | One year post CAR-T infusion | 
| Neurotoxicity | Assesment of neurotoxicity according to the American Society for Transplantation and Cellular Therapy (ASTCT) grading system (grade 0-4, 4 being the worse) (TCT. 2019 Apr; 25(4);625-638) | One year post CAR-T infusion | 
| Hemophagocytic lymphohistiocytosis (HLH) | Assesment of HLH according to the Common Terminology Criteria for Adverse Events CTCAE (version 5.0) (grade 3-5, 5 being the worse) | One year post CAR-T infusion |