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

NCT ID: NCT05385263

Last Updated: 2022-05-26

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-11
• Study Completion Date: 2024-10-31

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.

Conditions

B Cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Nivolumab Injection [Opdivo]

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tel-Aviv Sourasky Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ron Ram, Prof.

Role: PRINCIPAL_INVESTIGATOR

Sourasky Medical Center

Locations

Tel-Aviv Sourasky Medicak center / BMT Unit

Tel Aviv, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Ron Ram, Prof

Role: CONTACT

ronr@tlvmc.gov.il

972-3-6947830 ext. 7830

Facility Contacts

Ron Ram, MD

Role: primary

ronr@tlvmc.gov.il

+972-3-6974138

References

Ram R, Amit O, Perry C, Herishanu Y, Avivi I, Sarid N, Apel A, Preis M, Aviv A, Shapira S, Shragai T, Joffe E, Shargian L, Herzog-Tsarfati K, Eylati N, Acria L, Fridberg G, Gold R, Glait-Santar C, Kay S, Gal-Rabinovich K, Rosenberg D, Setter-Marco N, Beyar-Katz O. Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion-A Phase 2, Prospective Interventional Study. Transplant Cell Ther. 2024 Dec;30(12):1178-1188. doi: 10.1016/j.jtct.2024.09.024. Epub 2024 Oct 11.

Reference Type: DERIVED

PMID: 39396632 (View on PubMed)

Other Identifiers

0804-21

Identifier Type: -

Identifier Source: org_study_id