Extranodal NK/T-cell Lymphoma, NK/T-cell Lymphoma, Relapsed or Refractory NK/T-Cell Lymphoma
Conditions
Keywords
Tislelizumab, Zeprumetostat, EZH2 inhibitor, PD-1 inhibitor, NKTCL
Brief summary
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.
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.
Interventions
DRUGTislelizumab
Tislelizumab 200 mg administered intravenously on day 1 of each 21-day cycle.
DRUGZeprumetostat
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.
Sponsors
Rong Tao
Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
In phase Ib, participants are assigned to 1 of 2 parallel dose levels of zeprumetostat in combination with fixed-dose tislelizumab. In phase II, participants are enrolled into 2 parallel cohorts based on prior exposure to PD-1 inhibitors.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose (RP2D) of zeprumetostat in combination with tislelizumab | During phase Ib, up to 12 weeks | Determination of the recommended phase II dose based on dose-limiting toxicities during the first 21 days and objective response rate at week 12. |
| Objective Response Rate (ORR) at Week 12 | Week 12 | Objective response rate assessed by independent blinded imaging review according to Lugano 2014 criteria during phase II. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CRR) | 12 weeks | Proportion of participants whose best overall response is complete response (CR) at week 12, as assessed according to Lugano 2014 criteria. |
| Duration of Response (DOR) | From first documented CR or PR until first documented disease progression, relapse, or death, up to 36 months | 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. |
| Progression-Free Survival (PFS) | From first dose until first documented disease progression or death from any cause, up to 36 months | 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. |
| Overall Survival (OS) | From first dose until death from any cause, up to 36 months | Overall survival is defined as the time from study enrollment/first dose to death from any cause. |
| Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), and Immune-Related Adverse Events (irAEs) | From signing of informed consent through 28 days after the last dose of study treatment | 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. |
Countries
China
Contacts
CONTACTRong Tao, MD & PhD
CONTACTChuanxu Liu, MD & PhD
STUDY_CHAIRRong Tao, MD & PhD
Shanghai Cancer Center
PRINCIPAL_INVESTIGATORChuanxu Liu, MD & PhD
Shanghai Cancer Center
Outcome results
None listed