Large B-Cell Lymphoma (LBCL)
Conditions
Keywords
Large B-Cell lymphoma
Brief summary
This is a Phase 1, single-center, open-label study to evaluate the safety of CLS-015 in combination with anti-CD19 CAR-T therapy in patients with large B-cell lymphoma. The goal is to improve clinical response by reversing the negative effects of NETs on immune function and CAR-T cells.
Detailed description
Disease progression in large B-cell lymphoma is a major obstacle to successful CAR-T therapy, with approximately 40% of patients experiencing disease progression within 3 months of CAR-T infusion and 60% of patients experiencing disease progression within the first year. While patients with large B-cell lymphoma in partial response or complete response during lymphodepletion have a progression-free survival (PFS) of 60-80% at 1 year, patients with stable disease (SD) or progressive disease (PD) in the lymphodepletion phase have a poor PFS of 20-30%. Patients with SD/PD in the lymphoid depletion phase, particularly those with low CAR-T concentrations on day +7, are at very high risk of early disease progression after CAR-T infusion, and there is an urgent and unmet medical need to improve their outcomes. Preclinical studies have shown that CLS-015 enhances the performance of CAR T-cell therapy against CD19-expressing malignancies through various mechanisms, including enhancing CAR T-cell activity, preventing T-cell exhaustion, reducing cytokine release syndrome (CRS), and enhancing CAR-T cell penetration into areas with lymphoma cells by enzymatically degrading NETs in tumor tissue and the bloodstream. All patients enrolled in the study with large B-cell lymphoma in SD/PD during lymphodepletion will receive CLS-015 on days 0, 3, 6, 10, and 15 after CAR-T cell infusion, as an intravenous infusion. Patient will be followed for blood test, incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), immune effector cell-associated HLH-like syndrome (IEC-HS), and cytopenias. Follow up in the study will be done daily for 15 days post CAR-T infusion, then twice weekly for 15 more days. More checkups will be done at 2-, 6-, 9- and 12-months post CAR-T infusion.
Interventions
DRUGrhDNase I
CLS-015 IV infusions after CAR-T infusion done on Days 0,3,6,10 and 15 after CAR-T infusion
Sponsors
Tel-Aviv Sourasky Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
CLS-015 (Dornase Alpha; DFF) is a recombinant human DNase I (rhDNase I), designed to degrade NETs both at the tumor tissue and in systemic blood circulation. CLS-015 increases performance of anti-CD19 CAR-T therapy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be at least 18 years of age inclusive, at the time of signing the informed consent. * Large B-Cell lymphoma treated with CAR-T targeting CD19 (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) * Stable Disease or Progressive Disease confirmed by PET-CT on the day of lymphodepletion * Capable of giving signed informed consent * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Exclusion criteria
* Hypersensitivity to CLS-015 * Evidence of any clinically significant condition, disorder, condition, or disease that, in the opinion of the Investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. * Active infection requiring antibiotics * Females only: Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the safety and tolerability of CLS-015 in combination with anti CD19 CAR T therapy in subjects with stable/progressive Large B-Cell lymphoma at lymphodepletion when CLS-015 is given in adjuvant setting. | Through study completion, an average of 2 years. | Safety and tolerability of CLS-015 based on adverse events evaluation and recording will be evaluated from screening to the end of study. |
Countries
Israel
Contacts
CONTACTRon Ram, Prof.
PRINCIPAL_INVESTIGATORRon Ram, Prof.
Sourasky Medical Center
Outcome results
None listed