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

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)

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.

Inclusion Criteria:

1. Voluntarily provides written informed consent (ICF) and agrees to comply with study procedures.

2. Histopathologically confirmed ENKTL per the 2022 WHO Classification of Lymphoid Neoplasms, with no prior systemic anti-lymphoma therapy.

3. 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.

4. Age ≥18 years at ICF signing.

5. Estimated life expectancy ≥12 weeks.

6. ECOG performance status 0-2.

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

7. 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).

8. Left Ventricular Ejection Fraction (LVEF) ≥50% by MUGA or echocardiogram.

9. 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.

10. 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:

1. Aggressive NK-cell leukemia or ENKTL in leukemic phase.

2. Concurrent hemophagocytic syndrome.

3. Lymphoma involvement of central nervous system (CNS) or meninges.

4. History of other malignancies within 5 years (except cured localized tumors: e.g., basal/squamous cell skin cancer, in situ prostate/cervical/breast cancer).

5. 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.

6. Active viral infections (e.g., herpes zoster) or bacterial infections requiring IV/oral antimicrobials within 30 days (including pneumonia).

7. Active autoimmune diseases requiring systemic therapy within 2 years (allowed if inactive for 2 years; hormone replacement therapy for hypothyroidism/diabetes is allowed).

8. Uncontrolled cardiac disease: NYHA Class >2 heart failure, unstable angina, myocardial infarction within 1 year, clinically significant arrhythmias requiring treatment.

9. Prior interstitial lung disease (except radiation-induced asymptomatic disease).

10. Unresolved Grade >1 AEs (except alopecia) from prior therapies.

11. Hypersensitivity to golidocitinib, pegaspargase, anti-PD-1 mAb, or excipients; history of Grade ≥3 hypersensitivity to mAbs or uncontrolled allergic asthma.

12. Refractory nausea/vomiting, chronic gastrointestinal disease, dysphagia, or prior bowel resection affecting drug absorption.

13. Pregnant or lactating women; unwilling to use contraception.

14. Psychiatric illness or inability to provide informed consent.

15. Investigator-determined unsuitability for study participation.