This open-label, multicenter Ib/II phase clinical trial investigates the safety, tolerability, and preliminary efficacy of tislezumab (anti-PD-1 monoclonal antibody), golidocitinib (JAK1/STAT3 signaling pathway inhibitor), and selinexor (selective inhibitor of nuclear export, XPO1 antagonist) in patients with relapsed/refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) progressing after ≥1 line of L-asparaginase-containing chemotherapy or chemoradiotherapy.
This phase Ib/II open-label, multicenter clinical trial addresses the critical unmet need in relapsed/refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL), an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma subtype characterized by extranodal predominance, angiocentric growth patterns, and geographic prevalence in Asian and Latin American populations. Despite incorporation of L-asparaginase-based regimens into first-line therapy, approximately 30-40% of patients experience primary refractory disease or relapse, with median overall survival (OS) of \<6 months in PD-1 inhibitor-resistant cohorts and limited sustained responses to salvage therapies, highlighting the imperative for novel mechanism-driven combinations. The investigational triplet regimen-comprising tislelizumab (anti-PD-1 monoclonal antibody), golidocitinib (JAK1/STAT3 inhibitor), and selinexor (XPO1 antagonist)-was rationally designed to exploit synergistic mechanisms targeting ENKTL pathogenesis: PD-1 blockade reverses T-cell exhaustion, JAK/STAT3 inhibition disrupts constitutive oncogenic signaling (e.g., STAT3 Y705 phosphorylation), and XPO1 antagonism promotes nuclear retention of tumor suppressors (p53, IkBα) while destabilizing EBV latency proteins. Part 1 (Phase Ib) employs dose escalation across combinatorial cohorts to establish the recommended Phase II dose (RP2D), prioritizing safety and tolerability through rigorous assessment of dose-limiting toxicities (DLTs), while Part 2 (Phase II) evaluates preliminary efficacy in a dedicated anti-PD-1-refractory population, focusing on objective response rate (ORR) by Lugano 2014 criteria as the primary endpoint. The trial specifically targets patients with histologically confirmed ENKTL per WHO classification and radiographically confirmed progression post-L-asparaginase-containing therapy and failed to prior anti-PD-1/PD-L1 therapy, excluding those with prior exposure to JAK or XPO1 inhibitors to isolate the novel therapeutic effect. By integrating PD-1 pathway modulation with simultaneous disruption of STAT3-driven survival signals and viral oncoprotein dependencies, this combination strategy aims to discover the potential therapeutic paradigms for R/R ENKTL, particularly in populations failing contemporary immunochemotherapy approaches.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
68
Tislelizumab will be administered intravenously at a fixed dose of 200 mg every 3 weeks (Q3W).
Golidocitinib: Dose-escalating oral regimens: Dose level A: 150 mg every other day (QOD). Dose level B: 150 mg once daily (QD).
Selinexor: Dose-escalating oral regimens: Dose A: 40 mg once weekly (QW) . Dose B: 60 mg QW for 2 consecutive weeks, followed by 1 week off.
Dept of lymphoma and medical oncology, Shanghai Cancer Center
Shanghai, Shangai, China
RECRUITINGRP2D of golidocitinib in combination with selinexor
Recommended Phase II Dose of golidocitinib in combination with selinexor
Time frame: 4 weeks after the initiation of combination treatment
Satety profile
Safety profile, including: Incidence, severity, and drug-relatedness of adverse events (AEs) and serious adverse events (SAEs) per NCI CTCAE ver 5.0
Time frame: 6 months after the last lose of combination treatment
Overall response rate
Phase II (Dose-Expansion Phase) part 12-week objective response rate (ORR) assessed per Lugano 2014 criteria for lymphoma response evaluation.
Time frame: 12-weeks after the initiation of combination treatment
Complete Response Rate
Phase II (Dose-Expansion Phase) part 12-week complete response rate (CRR) assessed per Lugano 2014 criteria for lymphoma response evaluation.
Time frame: 12-weeks after the initiation of combination treatment
Duration of Response
Duration of Response (DoR) per Lugano 2014 response criteria
Time frame: 12 months after the last patient enrolled
Progression-Free Survival (PFS)
The length of time from the start of treatment until disease progression or death from any cause, whichever occurs first.
Time frame: 12 months after the last patient enrolled
Overall survival(OS)
The length of time from the start of treatment until death from any cause.
Time frame: 12 months after the last patient enrolled
Treatment-Emergent Adverse Events(TEAE)
The incidence of TEAEs (Treatment-Emergent Adverse Events), AEs/SAEs/immune-related adverse events (irAEs), their association with the investigational drug, and their severity as assessed according to CTCAE v5.0.
Time frame: 6 months after the last patient quit the trial treatment
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