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.

This is a multicenter, open-label, phase Ib/II clinical trial in relapsed or refractory NK/T-cell lymphoma.

In phase Ib, patients with relapsed or refractory NK/T-cell lymphoma after at least 1 prior asparaginase-based chemotherapy-containing regimen will receive tislelizumab 200 mg intravenously every 3 weeks in combination with zeprumetostat at 1 of 2 dose levels: 300 mg orally twice daily or 350 mg orally twice daily. The dose-limiting toxicity observation window is 21 days. If neither dose level is excessively toxic, enrollment will continue until 12 evaluable patients are included in each arm. Dose selection for phase II will be based on dose-limiting toxicity and objective response rate at week 12 assessed by independent blinded imaging review according to Lugano 2014 criteria. If efficacy is similar, the lower dose level will be preferred.

In phase II, patients will receive zeprumetostat at the RP2D plus tislelizumab 200 mg intravenously every 3 weeks. Patients will be enrolled into 2 predefined cohorts according to prior exposure to PD-1 inhibitors: Cohort-R (prior PD-1 exposed/refractory) and Cohort-N (PD-1 inhibitor-naive). Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, death, or study termination.

The primary phase II endpoint is objective response rate at week 12 assessed by independent blinded imaging review according to Lugano 2014 criteria. Secondary endpoints include complete response rate, duration of response, progression-free survival, overall survival, and safety. Exploratory endpoints include the association of ctDNA and EBV-DNA dynamics, PD-L1, EZH2/H3K27me3, and tumor microenvironment biomarkers with clinical outcome.

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.

IPD sharing is currently undecided. The study team will determine whether de-identified participant-level data can be shared after study completion in accordance with institutional policy, participant consent, and applicable regulations.