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

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.