Clinical trial NCT05385263: Addition of Nivolumab to Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive DLBCL at Lymphodepletion
Official title: Addition of Nivolumab to Standard of Care With Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive DLBCL at Lymphodepletion
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: B Cell Lymphoma
Lead sponsor: Tel-Aviv Sourasky Medical Center
Sponsor class: OTHER_GOV
First posted: 2022-05-23
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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).
Primary purpose: TREATMENT

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

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.

Eligibility criteria: Inclusion Criteria:

1. Participant must be at least 18 years of age inclusive, at the time of signing the informed consent.
2. DLBCL treated with CAR-T targeting CD19 (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel)
3. PD/SD by PET-CT on the day of lymphodepletion
4. Capable of giving signed informed consent
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
6. No active CRS or ICANS at time of nivolumab administration

Exclusion Criteria:

1. Hypersensitivity to checkpoints inhibitors
2. CRS grade 3 and above or ICANS any grade on days 0-5 following CAR-T
3. AST (Aspartate transaminase) or ALT (Alanine transaminase) over 3 times the upper limit of normal (ULN) or total bilirubin over 3 times ULN
4. Serum creatinine over 1.5 times ULN or over 1.5 times baseline
5. History of or active autoimmune disease
6. Uncontrolled seizure activity and/or clinically evident progressive encephalopathy
7. Active diarrhea (more than 4 bowel movements per day)
8. Clinically significant uncontrolled illness
9. Active infection requiring antibiotics
10. Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
11. Other active malignancy
12. Females only: Pregnant or breastfeeding

Primary outcomes:
measure: Overall response at 1 months after CAR-T infusion
timeFrame: One month post CAR-T infusion
Secondary outcomes:
measure: Overall survival at 1 year after CAR-T infusion and nivolumab
timeFrame: One year post CAR-T infusion
measure: Duration of response
timeFrame: One year post CAR-T infusion
measure: Cytokine release syndrome
timeFrame: One year post CAR-T infusion
measure: Neurotoxicity
timeFrame: One year post CAR-T infusion
measure: Hemophagocytic lymphohistiocytosis (HLH)
timeFrame: One year post CAR-T infusion
Other outcomes:
Locations:
city: Tel-Aviv
country: Israel
facility: Tel-Aviv Sourasky Medicak center / BMT Unit
Study officials:
affiliation: Sourasky Medical Center
name: Ron Ram, Prof.
role: PRINCIPAL_INVESTIGATOR
References: