Tislelizumab Plus Zeprumetostat for Relapsed or Refractory NK/T-Cell Lymphoma (EpiRev-NKT)

A Multicenter, Open-Label, Seamless Phase Ib/II Study Evaluating the Safety and Efficacy of Tislelizumab in Combination With Zeprumetostat (SHR2554) in Patients With 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Extranodal NK/T-cell Lymphoma; NK/T-cell Lymphoma; Relapsed or Refractory NK/T-Cell Lymphoma
• Intervention / Treatment: Drug: Tislelizumab; Drug: Zeprumetostat

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 107
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rong Tao, MD & PhD; Phone Number: 660103 008621-64175590; Email: hkutao@hotmail.com
• Study Contact Backup: Name: Chuanxu Liu, MD & PhD; Phone Number: 660103 008621-64175590; Email: liuchaunxu@shca.or.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200043
      • Fudan University Shanghai Cancer Center
      • Contact: Chuanxu Liu, MD & PhD; Phone Number: 660103 008621-64175590; Email: liuchaunxu@shca.or.cn
      • Contact: Rong Tao, MD & PhD; Phone Number: 660103 008621-64175590; Email: rtao@shca.or.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ib Dose Level A; Tislelizumab 200 mg IV every 3 weeks plus zeprumetostat 300 mg orally twice daily.	Drug: Tislelizumab; Tislelizumab 200 mg administered intravenously on day 1 of each 21-day cycle.; Drug: Zeprumetostat; Zeprumetostat (SHR2554), an oral EZH2 inhibitor, administered twice daily. In phase Ib, dose levels are 300 mg BID and 350 mg BID. In phase II, zeprumetostat is administered at the recommended phase II dose selected from phase Ib.
Experimental: Phase Ib Dose Level B; Tislelizumab 200 mg IV every 3 weeks plus zeprumetostat 350 mg orally twice daily.	Drug: Tislelizumab; Tislelizumab 200 mg administered intravenously on day 1 of each 21-day cycle.; Drug: Zeprumetostat; Zeprumetostat (SHR2554), an oral EZH2 inhibitor, administered twice daily. In phase Ib, dose levels are 300 mg BID and 350 mg BID. In phase II, zeprumetostat is administered at the recommended phase II dose selected from phase Ib.
Experimental: Phase II Cohort-R (Prior PD-1 Exposed/Refractory); Tislelizumab 200 mg IV every 3 weeks plus zeprumetostat at the RP2D in patients previously exposed or refractory to PD-1 inhibitor therapy.	Drug: Tislelizumab; Tislelizumab 200 mg administered intravenously on day 1 of each 21-day cycle.; Drug: Zeprumetostat; Zeprumetostat (SHR2554), an oral EZH2 inhibitor, administered twice daily. In phase Ib, dose levels are 300 mg BID and 350 mg BID. In phase II, zeprumetostat is administered at the recommended phase II dose selected from phase Ib.
Experimental: Phase II Cohort-N (PD-1 Inhibitor-Naive); Tislelizumab 200 mg IV every 3 weeks plus zeprumetostat at the RP2D in patients without prior PD-1 inhibitor therapy.	Drug: Tislelizumab; Tislelizumab 200 mg administered intravenously on day 1 of each 21-day cycle.; Drug: Zeprumetostat; Zeprumetostat (SHR2554), an oral EZH2 inhibitor, administered twice daily. In phase Ib, dose levels are 300 mg BID and 350 mg BID. In phase II, zeprumetostat is administered at the recommended phase II dose selected from phase Ib.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase II Dose (RP2D) of zeprumetostat in combination with tislelizumab	Determination of the recommended phase II dose based on dose-limiting toxicities during the first 21 days and objective response rate at week 12.	During phase Ib, up to 12 weeks
Objective Response Rate (ORR) at Week 12	Objective response rate assessed by independent blinded imaging review according to Lugano 2014 criteria during phase II.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate (CRR)	Proportion of participants whose best overall response is complete response (CR) at week 12, as assessed according to Lugano 2014 criteria.	12 weeks
Duration of Response (DOR)	Duration of response is defined as the time from first documented complete response (CR) or partial response (PR) to disease progression, relapse, or death, according to Lugano 2014 criteria.	From first documented CR or PR until first documented disease progression, relapse, or death, up to 36 months
Progression-Free Survival (PFS)	Progression-free survival is defined as the time from study enrollment/first dose to the first documentation of progressive disease or death from any cause, whichever occurs first.	From first dose until first documented disease progression or death from any cause, up to 36 months
Overall Survival (OS)	Overall survival is defined as the time from study enrollment/first dose to death from any cause.	From first dose until death from any cause, up to 36 months
Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), and Immune-Related Adverse Events (irAEs)	Safety will be assessed by the incidence, type, severity, timing, seriousness, attribution, actions taken, and outcomes of adverse events, serious adverse events, and immune-related adverse events.	From signing of informed consent through 28 days after the last dose of study treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) in Predefined Biomarker Subgroups	Objective response rate at week 12, assessed according to Lugano 2014 criteria, in predefined biomarker subgroups including PD-L1, EZH2/H3K27me3, EBV-DNA, ctDNA clearance, and other prospectively defined biomarker categories.	12 weeks

Collaborators and Investigators

• Sponsor: Rong Tao
• Collaborators: Fudan University
• Investigators: Study Chair: Rong Tao, MD & PhD, Shanghai Cancer center; Principal Investigator: Chuanxu Liu, MD & PhD, Shanghai Cancer center

Publications and helpful links

General Publications

• Tao 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.
• Song 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.
• Song 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.
• Huang 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.

Study record dates

Study Major Dates

• Study Start (Estimated): March 23, 2026
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: March 20, 2026
• First Submitted That Met QC Criteria: March 27, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: PD-1 inhibitor; Tislelizumab; EZH2 inhibitor; NKTCL; Zeprumetostat
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, T-Cell; Pathological Conditions, Signs and Symptoms; Recurrence; Lymphoma, Extranodal NK-T-Cell; tislelizumab
• Other Study ID Numbers: SHCA-NKT-2601

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: 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.

Drug and device information, study documents

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