Tislelizumab Plus Zeprumetostat for Relapsed or Refractory NK/T-Cell Lymphoma

This is a multicenter, open-label, phase Ib/II study evaluating tislelizumab in combination with zeprumetostat (SHR2554) in patients with relapsed or refractory NK/T-cell lymphoma after at least one prior asparaginase-based chemotherapy-containing regimen, with or without radiotherapy. In phase Ib, two fixed dose levels of zeprumetostat in combination with tislelizumab will be evaluated to determine the recommended phase II dose (RP2D). In phase II, patients will be enrolled into 2 predefined cohorts according to prior exposure to PD-1 inhibitors to further evaluate efficacy and safety. The primary phase II endpoint is objective response rate at week 12 assessed by independent blinded imaging review according to Lugano 2014 criteria.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Age 18 years or older.
* Pathologically confirmed NK/T-cell lymphoma.
* Relapsed or refractory disease after at least 1 prior asparaginase-based chemotherapy-containing regimen, with or without radiotherapy.
* At least 1 measurable or evaluable lesion according to Lugano 2014 criteria.
* ECOG performance status 0 to 2.
* Life expectancy greater than 12 weeks.
* Adequate hematologic, hepatic, renal, coagulation, and cardiac function.
* Recovery from prior anti-cancer treatment-related toxicities to CTCAE grade 1 or baseline, except for specified stable irreversible toxicities allowed by the investigator.
* Negative pregnancy test for women of childbearing potential.
* Willingness to use effective contraception.
* Written informed consent.

Exclusion Criteria:

* Prior treatment with any EZH1/2 or EZH2 inhibitor.
* Allogeneic hematopoietic stem cell transplantation within 5 years before study treatment.
* Autologous hematopoietic stem cell transplantation within 3 months before study treatment.
* Requirement for high-dose systemic corticosteroids or other immunosuppressive therapy within 14 days before study treatment, except permitted local/inhaled or short-course use.
* Cytotoxic chemotherapy not discontinued within 14 days before study treatment.
* Systemic anti-cancer therapy or investigational therapy within 4 weeks before study treatment.
* Major surgery within 4 weeks or radiotherapy within 90 days before study treatment.
* Active infection, including active/latent tuberculosis, HIV infection, active hepatitis B or C with detectable viral nucleic acid, or other clinically significant active viral infection.
* Uncontrolled cardiovascular disease.
* Persistent unresolved toxicities greater than CTCAE grade 1 from prior therapy, except alopecia.
* Gastrointestinal disorders or prior intestinal surgery that may impair oral drug absorption.
* Pregnancy or breastfeeding.
* Psychiatric illness or inability to provide informed consent.
* Any other condition that, in the investigator's judgment, makes the patient unsuitable for the study.

• RESULTSong Y, Liu Y, Li ZM, Li L, Su H, Jin Z, Zuo X, Wu J, Zhou H, Li K, He C, Zhou J, Qi J, Hao S, Cai Z, Li Y, Wang W, Zhang X, Zou J, Zhu J. SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial. Lancet Haematol. 2022 Jul;9(7):e493-e503. doi: 10.1016/S2352-3026(22)00134-X. PMID 35772429
• RESULTSong Y, Jin Z, Li ZM, Liu Y, Li L, He C, Su H, Zhou H, Li K, Hao S, Zuo X, Wu J, Li D, Wu M, Sun X, Qi J, Cai Z, Li Z, Li Y, Huang Y, Shen J, Xiao Z, Zhu J. Enhancer of Zeste Homolog 2 Inhibitor SHR2554 in Relapsed or Refractory Peripheral T-cell Lymphoma: Data from the First-in-Human Phase I Study. Clin Cancer Res. 2024 Apr 1;30(7):1248-1255. doi: 10.1158/1078-0432.CCR-23-2582. PMID 38190117
• RESULTHuang H, Tao R, Hao S, Yang Y, Cen H, Zhou H, Guo Y, Zou L, Cao J, Huang Y, Jin J, Zhang L, Yang H, Xing X, Zhang H, Liu Y, Ding K, Qi Q, Zhu X, Zhu D, Wang S, Fang T, Dai H, Shi Q, Yang J. Sugemalimab Monotherapy for Patients With Relapsed or Refractory Extranodal Natural Killer/T-Cell Lymphoma (GEMSTONE-201): Results From a Single-Arm, Multicenter, Phase II Study. J Clin Oncol. 2023 Jun 1;41(16):3032-3041. doi: 10.1200/JCO.22.02367. Epub 2023 Mar 30. PMID 36996373
• RESULTTao R, Fan L, Song Y, Hu Y, Zhang W, Wang Y, Xu W, Li J. Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4). Signal Transduct Target Ther. 2021 Oct 27;6(1):365. doi: 10.1038/s41392-021-00768-0. PMID 34702811