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

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

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

Study Overview

• Status: Recruiting
• Conditions: B Cell Lymphoma
• Intervention / Treatment: Drug: Nivolumab Injection [Opdivo]

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 Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ron Ram, Prof; Phone Number: 7830 972-3-6947830; Email: ronr@tlvmc.gov.il

Study Locations

• Israel
  • Tel-Aviv, Israel, 6423906
    • Recruiting
    • Tel-Aviv Sourasky Medicak center / BMT Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Tel-Aviv Sourasky Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2022
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): October 1, 2024

Study Registration Dates

• First Submitted: April 13, 2022
• First Submitted That Met QC Criteria: May 17, 2022
• First Posted (Actual): May 23, 2022

Study Record Updates

• Last Update Posted (Actual): May 26, 2022
• Last Update Submitted That Met QC Criteria: May 22, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 0804-21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No