First-Line Jaktinib for Acute Graft-Versus-Host Disease (aGVHD)

This study is a single-center, single-arm, prospective interventional trial utilizing a 3+3 dose escalation design to evaluate the safety and efficacy of first-line gecacitinib (also known as jaktinib) in combination with glucocorticoids for the treatment of grades II-IV acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

A total of 35 patients will be enrolled across both the dose exploration phase (using the 3+3 design to determine the Recommended Phase 2 Dose [RP2D]) and the efficacy evaluation phase (where additional patients are treated at the RP2D to further assess efficacy and safety).

The primary objectives include:

• Determining the RP2D of gecacitinib (also known as jaktinib) in combination with glucocorticoids.
• Assessing the safety profile (e.g., incidence and severity of adverse events).
• Evaluating efficacy (e.g., overall response rate at Day 28). Secondary endpoints may include duration of response, survival outcomes, and biomarker analyses.

This design is appropriate for early-phase trials seeking to establish dosing and preliminary activity of a novel combination therapy in a high-risk population.

Inclusion criteria

• Voluntarily provide signed informed consent and be ≥18 years of age at the time of consent.
• Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using bone marrow, peripheral blood stem cells, or umbilical cord blood.
• Have received systemic glucocorticoid therapy for no more than 2 days prior to enrollment.
• Demonstrate clear myeloid and platelet engraftment: absolute neutrophil count (ANC) > 1.0 × 10⁹/L and platelet count > 50 × 10⁹/L (permitted use of growth factors or transfusion support).
• Clinical diagnosis of grade II-IV acute GVHD (aGVHD) per the MAGIC (Mount Sinai Acute GVHD International Consortium) criteria (Appendix 1).
• ECOG performance status of 0-2.
• Life expectancy > 4 weeks.
• Able to swallow tablets.
• Willing and able to comply with study procedures and follow-up.

Exclusion criteria

• History of ≥2 allo-HSCT procedures.
• Development of aGVHD following unplanned donor lymphocyte infusion (DLI) for relapse of underlying malignancy. Note: Planned DLI as part of the transplant protocol is permitted.
• Concurrent treatment with another JAK inhibitor. Note: Patients who previously discontinued JAK inhibitors due to toxicity (not refractory aGVHD) are eligible.
• Active bleeding.
• Diagnosed or suspected chronic GVHD.
• Uncontrolled active infection, defined as sepsis-induced hemodynamic instability or progressive symptoms/signs/imaging findings attributable to infection. Asymptomatic or persistent fever alone is not exclusionary.
• unresolved toxicity or complications from allo-HSCT (excluding aGVHD).
• Clinically significant abnormalities that may compromise safety, including: a) Uncontrolled diabetes (fasting glucose >13.9 mmol/L); b) Hypertension unresponsive to ≥2 agents (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg); c) Peripheral neuropathy ≥Grade 2 (per NCI CTCAE v5.0).
• Within 6 months prior to screening: NYHA Class III/IV heart failure, unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism.
• Arrhythmia requiring treatment or QTcB interval >480 ms at screening.
• Severe renal impairment (serum creatinine >1.5 × ULN) at screening.
• Pre-transplant history of gastrointestinal ulcers, gastrectomy, or intestinal resection that may impair drug absorption.
• Major surgery within 4 weeks prior to screening without full recovery.
• Cholestatic disorders or hepatic sinusoidal obstruction syndrome (SOS/VOD) at screening (defined as persistent hyperbilirubinemia and organ dysfunction unrelated to GVHD).
• Active uncontrolled viral infections at screening: HBV: HBsAg⁺ with detectable HBV-DNA, or detectable HBV-DNA regardless of HBsAg status; HCV: Anti-HCV antibody⁺ with detectable HCV-RNA.
• History of active tuberculosis within 6 months prior to screening.
• Epilepsy or current use of psychotropic/sedative medications.
• Pregnancy, lactation, or intention to conceive; male patients unwilling to use condoms during treatment and for 2 days after the last dose.
• Other active malignancies (excluding the transplanted hematologic malignancy) within 5 years.
• Current use of anticoagulants or antiplatelet agents (except low molecular weight heparin).
• Any condition that, in the investigator's judgment, may compromise patient safety or protocol compliance.
• Known hypersensitivity to jaktinib, its analogs, or excipients.
• Participation in another interventional clinical trial within 4 weeks prior to screening.
• Investigator determination of unsuitability for the study.