Phaes Ⅱ Study of Golidocitinib-Pegaspargase-PD-1 Antibody First-Line for Advanced ENKTL

Official title

A Single-Arm, Open-Label Phase II Clinical Study to Evaluate the Safety and Efficacy of Golidocitinib in Combination With Pegaspargase and Anti-Programmed Death-1 (PD-1) Monoclonal Antibody as First-Line Therapy for Advanced Extranodal Natural Killer/T-Cell Lymphoma (ENKTL)

Overview

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma with poor prognosis in advanced stages, with a 5-year overall survival (OS) rate of less than 30% despite asparaginase-based regimens. Preclinical and clinical evidence suggests that PD-L1 is highly expressed in ENKTL, and PD-1 inhibitors show promising activity, while JAK1 inhibitors (e.g., golidocitinib) can reverse PD-1/PD-L1 inhibitor resistance and enhance anti-tumor immunity. This phase II study aims to evaluate the safety, tolerability, and anti-tumor activity of golidocitinib combined with pegaspargase and anti-PD-1 mAb as first-line therapy for advanced treatment-naive ENKTL, providing a novel therapeutic option for this patient population.

Interventions

• Drug Golidocitinib + Pegaspargase + Anti-PD-1 mAb
  * Golidocitinib: 150 mg orally, once daily, continuous administration. * Pegaspargase: 2000-2500 IU/m² intravenously, once every 3 weeks (Day 1 of each cycle). * Anti-PD-1 mAb: Administered per product labeling, once every 3 weeks (Day 1 of each cycle). * Treatment Cycle: 3 weeks per cycle; combined treatment for up to 6 cycles. Patients achieving response may receive maintenance therapy with golidocitinib and/or anti-PD-1 mAb for up to 24 months.

Primary outcome measures

• Complete Response Rate (CRR) [Time frame: At the end of 6 cycles of combined treatment (each cycle is 21 days, total 18 weeks from the first dose of treatment).]

Secondary outcome measures (5)

• Overall Response Rate (ORR) [Time frame: At the end of 6 cycles of combined treatment (each cycle is 21 days, total 18 weeks from the first dose of treatment).]
• Duration of Response (DoR) [Time frame: From the first date of confirmed complete response (CR) or partial response (PR) to the date of first documented disease progression or recurrence, assessed up to 24 months from study enrollment.]
• Progression-Free Survival (PFS) [Time frame: From the date of study enrollment to the date of first documented progressive disease (PD) or death from any cause (whichever occurs first), assessed up to 24 months from study enrollment.]
• Overall Survival (OS) [Time frame: From the date of study enrollment to the date of death from any cause, assessed up to 24 months from study enrollment.]
• Incidence of AEs/SAEs/irAEs [Time frame: Throughout treatment and 28-day safety follow-up]

Eligibility criteria

Inclusion criteria

• Voluntarily provides written informed consent (ICF) and agrees to comply with study procedures.
• Histopathologically confirmed ENKTL per the 2022 WHO Classification of Lymphoid Neoplasms, with no prior systemic anti-lymphoma therapy.
• At least one measurable or evaluable lesion per 2014 Lugano Classification:

Measurable lesion: Lymph node ≥1.5 cm (long axis) × ≥1.0 cm (short axis); extranodal lesion ≥1.0 cm (long axis); if the only measurable lesion was previously irradiated, radiological progression after radiotherapy is required.

Evaluable lesion: FDG-PET uptake higher than liver in lymph nodes or extranodal sites, consistent with lymphoma.

• Age ≥18 years at ICF signing.
• Estimated life expectancy ≥12 weeks.
• ECOG performance status 0-2.

Adequate organ and bone marrow function (without supportive care within 14 days):

• Hematology: Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L (≥0.5×10⁹/L with bone marrow involvement); Platelet (PLT) ≥100×10⁹/L (≥50×10⁹/L with bone marrow involvement); Hemoglobin (HGB) ≥8.0 g/dL.

Liver function: Total Bilirubin (TBIL) ≤1.5×ULN (≤3.0×ULN for Gilbert syndrome or liver involvement); Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×ULN (≤5.0×ULN for liver involvement).

Renal function: Serum Creatinine (Cr) ≤1.5×ULN or Creatinine Clearance Rate (Ccr) ≥50 mL/min (Cockcroft-Gault method).

Coagulation: International Normalized Ratio (INR) ≤1.5×ULN; Prothrombin Time (PT)/Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN (unless on anticoagulants with stable levels).

Thyroid function: Thyroid Stimulating Hormone (TSH), Free Thyroxine (FT4), Free Triiodothyronine (FT3) within ±10% of normal range (non-autoimmune TSH abnormalities allowed).

• Left Ventricular Ejection Fraction (LVEF) ≥50% by MUGA or echocardiogram.
• Resolution of acute toxicities from prior therapies to ≤Grade 1 (CTCAE v5.0) or baseline; irreversible Grade 2 toxicities (e.g., neuropathy, alopecia) are allowed if not worsening.
• Women of Childbearing Potential (WOCBP) must have negative serum pregnancy test within 7 days of first dose; WOCBP and male partners must use effective contraception from ICF signing to 6 months after last study drug dose.

Exclusion criteria

• Aggressive NK-cell leukemia or ENKTL in leukemic phase.
• Concurrent hemophagocytic syndrome.
• Lymphoma involvement of central nervous system (CNS) or meninges.
• History of other malignancies within 5 years (except cured localized tumors: e.g., basal/squamous cell skin cancer, in situ prostate/cervical/breast cancer).
• Prior therapy:

Allogeneic hematopoietic stem cell transplantation (HSCT) within 5 years (allowed if >5 years with no graft-versus-host disease).

Autologous HSCT within 3 months. Prior JAK/STAT3 inhibitors. Concurrent use of strong CYP3A inducers/inhibitors (unable to discontinue 1 week before first dose).

Concurrent vitamin K antagonists, antiplatelet agents, or anticoagulants (unable to discontinue 1 week before first dose).

Systemic glucocorticoids or immunosuppressants within 14 days (local/ocular/inhaled/nasal glucocorticoids or short-term ≤7 days for prophylaxis allowed).

Cytotoxic chemotherapy within 21 days. Systemic anti-tumor therapy (including mAbs, immunotherapy) within 4 weeks. Major surgery within 6 weeks or radiotherapy within 90 days. Toxin/isotope-antibody conjugates within 10 weeks. Investigational drugs within 30 days.

Active infections:

Active/latent tuberculosis (PPD positive with induration >10 mm or radiological evidence).

HIV infection. Active chronic hepatitis B (HBsAg positive with HBV DNA >2500 copies/mL or 500 IU/mL) or hepatitis C (HCV RNA positive). HBV carriers with controlled HBV DNA and cured HCV are allowed; HBsAg-positive patients require monthly HBV DNA monitoring and prophylactic entecavir until 12 months after anti-tumor therapy.

• Active viral infections (e.g., herpes zoster) or bacterial infections requiring IV/oral antimicrobials within 30 days (including pneumonia).
• Active autoimmune diseases requiring systemic therapy within 2 years (allowed if inactive for 2 years; hormone replacement therapy for hypothyroidism/diabetes is allowed).
• Uncontrolled cardiac disease: NYHA Class >2 heart failure, unstable angina, myocardial infarction within 1 year, clinically significant arrhythmias requiring treatment.
• Prior interstitial lung disease (except radiation-induced asymptomatic disease).
• Unresolved Grade >1 AEs (except alopecia) from prior therapies.
• Hypersensitivity to golidocitinib, pegaspargase, anti-PD-1 mAb, or excipients; history of Grade ≥3 hypersensitivity to mAbs or uncontrolled allergic asthma.
• Refractory nausea/vomiting, chronic gastrointestinal disease, dysphagia, or prior bowel resection affecting drug absorption.
• Pregnant or lactating women; unwilling to use contraception.
• Psychiatric illness or inability to provide informed consent.
• Investigator-determined unsuitability for study participation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07457177 · TREC2025-KY247

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗