Investigator Initiated Study to Assess the Safety of Combination of CLS-015 With Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive Large B Cell Lymphoma at Lymphodepletion.

Official title

CLS-015-TAMSC-LBCL-PR An Exploratory, Investigator Initiated Study to Assess the Safety of Combination of CLS-015 (DFF) With Anti-CD-19 CAR-T Cells in Patients With Stable/ Progressive Large B Cell Lymphoma at Lymphodepletion.

Overview

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

• Drug rhDNase I
  CLS-015 IV infusions after CAR-T infusion done on Days 0,3,6,10 and 15 after CAR-T infusion

Primary outcome measures

• 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. [Time frame: Through study completion, an average of 2 years.]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

Israel · 1 center

• Sourasky Medical Center — Tel Aviv

Publications

• Nie M, Yang L, Bi X, Wang Y, Sun P, Yang H, Liu P, Li Z, Xia Y, Jiang W. Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling. Clin Cancer Res. 2019 Mar 15;25(6):1867-1879. doi: 10.1158/1078-0432.CCR-18-1226. Epub 2018 Nov 16. PMID 30446590
• Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wojcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, Garcia MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Pha PMID 33449799
• Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA, Kato K, Sumbul A, Farsaci B, Ansell SM. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate PMID 29584546
• Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson TM, Garcia J, Kostic A, Mallaney M, Ogasawara K, Newhall K, Kim Y, Li D, Siddiqi T. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020 Sep 1 PMID 32888407

Identifiers

NCT: NCT07361224 · 0126-25

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗