Addition of Nivolumab to Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive DLBCL at Lymphodepletion
Study Details
Study Description
Brief Summary
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: NIVOLUMAB 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]
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
|
Outcome Measures
Primary Outcome Measures
- Overall response at 1 months after CAR-T infusion [One month post 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.
Secondary Outcome Measures
- Overall survival at 1 year after CAR-T infusion and nivolumab [One year post CAR-T infusion]
To assess survival of patients at 1 year after infusion of CAR-T and addition of nivolumab.
- Duration of response [One year post CAR-T infusion]
Assess duration of disease response after CAR-T infusion
- Cytokine release syndrome [One year post CAR-T infusion]
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)
- Neurotoxicity [One year post CAR-T infusion]
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)
- Hemophagocytic lymphohistiocytosis (HLH) [One year post CAR-T infusion]
Assesment of HLH according to the Common Terminology Criteria for Adverse Events CTCAE (version 5.0) (grade 3-5, 5 being the worse)
Eligibility Criteria
Criteria
Inclusion Criteria:
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Participant must be at least 18 years of age inclusive, at the time of signing the informed consent.
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DLBCL treated with CAR-T targeting CD19 (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel)
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PD/SD by PET-CT on the day of lymphodepletion
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Capable of giving signed informed consent
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Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
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No active CRS or ICANS at time of nivolumab administration
Exclusion Criteria:
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Hypersensitivity to checkpoints inhibitors
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CRS grade 3 and above or ICANS any grade on days 0-5 following CAR-T
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AST (Aspartate transaminase) or ALT (Alanine transaminase) over 3 times the upper limit of normal (ULN) or total bilirubin over 3 times ULN
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Serum creatinine over 1.5 times ULN or over 1.5 times baseline
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History of or active autoimmune disease
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Uncontrolled seizure activity and/or clinically evident progressive encephalopathy
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Active diarrhea (more than 4 bowel movements per day)
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Clinically significant uncontrolled illness
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Active infection requiring antibiotics
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Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
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Other active malignancy
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Females only: Pregnant or breastfeeding
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Tel-Aviv Sourasky Medicak center / BMT Unit | Tel-Aviv | Israel | 6423906 |
Sponsors and Collaborators
- Tel-Aviv Sourasky Medical Center
Investigators
- Principal Investigator: Ron Ram, Prof., Sourasky Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 0804-21