Acute Graft Versus Host Disease
Conditions
Keywords
acute graft-versus-host disease, Jaktinib, hematopoietic stem cell transplantation, gecacitinib
Brief summary
This study aims to evaluate the optimal dose (Recommended Phase 2 Dose, RP2D), preliminary safety, and efficacy of gecacitinib (also known as jaktinib) in combination with glucocorticoids as first-line therapy for patients with grade II-IV acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Detailed description
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: 1. Determining the RP2D of gecacitinib (also known as jaktinib) in combination with glucocorticoids. 2. Assessing the safety profile (e.g., incidence and severity of adverse events). 3. 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.
Interventions
DRUGGecacitinib (also known as Jaktinib) combined glucocorticoids
This clinical trial employs a standard 3+3 design to establish the Recommended Phase 2 Dose (RP2D) of gecacitinib (also known as jaktinib) combined with methylprednisolone. The dose escalation begins at 50 mg QD. Based on the safety observed in the initial cohort of three subjects, the dose will either be escalated to 50 mg BID or the cohort will be expanded. The subsequent escalation level is to 150 mg QD. Throughout this phase, the methylprednisolone dose is adjusted per the investigator's assessment. After determining the RP2D, the study advances to an efficacy evaluation stage, where approximately 25 additional subjects are enrolled to receive the combination at the RP2D for a minimum of 28 days. The primary objective of the initial phase is to assess safety and tolerability, while the secondary goal of the expansion is to gather preliminary efficacy data on the combination regimen.
Sponsors
First Affiliated Hospital of Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntarily provide signed informed consent and be ≥18 years of age at the time of consent. 2. Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using bone marrow, peripheral blood stem cells, or umbilical cord blood. 3. Have received systemic glucocorticoid therapy for no more than 2 days prior to enrollment. 4. 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). 5. Clinical diagnosis of grade II-IV acute GVHD (aGVHD) per the MAGIC (Mount Sinai Acute GVHD International Consortium) criteria (Appendix 1). 6. ECOG performance status of 0-2. 7. Life expectancy \> 4 weeks. 8. Able to swallow tablets. 9. Willing and able to comply with study procedures and follow-up.
Exclusion criteria
1. History of ≥2 allo-HSCT procedures. 2. 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. 3. Concurrent treatment with another JAK inhibitor. Note: Patients who previously discontinued JAK inhibitors due to toxicity (not refractory aGVHD) are eligible. 4. Active bleeding. 5. Diagnosed or suspected chronic GVHD. 6. 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. 7. unresolved toxicity or complications from allo-HSCT (excluding aGVHD). 8. 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). 9. Within 6 months prior to screening: NYHA Class III/IV heart failure, unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism. 10. Arrhythmia requiring treatment or QTcB interval \>480 ms at screening. 11. Severe renal impairment (serum creatinine \>1.5 × ULN) at screening. 12. Pre-transplant history of gastrointestinal ulcers, gastrectomy, or intestinal resection that may impair drug absorption. 13. Major surgery within 4 weeks prior to screening without full recovery. 14. Cholestatic disorders or hepatic sinusoidal obstruction syndrome (SOS/VOD) at screening (defined as persistent hyperbilirubinemia and organ dysfunction unrelated to GVHD). 15. 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. 16. History of active tuberculosis within 6 months prior to screening. 17. Epilepsy or current use of psychotropic/sedative medications. 18. Pregnancy, lactation, or intention to conceive; male patients unwilling to use condoms during treatment and for 2 days after the last dose. 19. Other active malignancies (excluding the transplanted hematologic malignancy) within 5 years. 20. Current use of anticoagulants or antiplatelet agents (except low molecular weight heparin). 21. Any condition that, in the investigator's judgment, may compromise patient safety or protocol compliance. 22. Known hypersensitivity to jaktinib, its analogs, or excipients. 23. Participation in another interventional clinical trial within 4 weeks prior to screening. 24. Investigator determination of unsuitability for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Reactions by Dosage Group in Patients with Grade II-IV Acute GVHD Treated with First-Line Gecacitinib (also known as Jaktinib) and corticosteroids | 28 days | The primary outcome of this study was the incidence of adverse reactions, stratified by Gecacitinib (also known as Jaktinib) dosage group, in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) receiving first-line treatment with Gecacitinib (also known as Jaktinib) in combination with corticosteroids. |
| The Day 28 Overall Response Rate (ORR) in patients with grade II-IV acute graft-versus-host disease (GVHD) treated with Ggecacitinib (also known as Jaktinib) in combination with corticosteroids as first-line therapy. | 28 days | The Day 28 Overall Response Rate (ORR) in patients with grade II-IV acute graft-versus-host disease (GVHD) treated with Gecacitinib (also known as Jaktinib) in combination with corticosteroids as first-line therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | 1 year | Defined as the time from the first achievement of response to disease progression of aGVHD, initiation of alternative systemic therapy, or death from any cause. |
| 180-day cumulative non-relapse mortality (NRM) | 180 days | Defined as the proportion of subjects who die from causes other than progression or relapse of the underlying hematologic malignancy within 180 days from treatment initiation. |
| Change in levels of serum biomarkers | Days 7, 14, and 28 | Change in levels of serum biomarkers from baseline to Days 7, 14, and 28 following treatment with Jaktinib in combination with corticosteroids. |
| To determine the Recommended Phase 2 Dose (RP2D) of Jaktinib for the efficacy evaluation phase. | 28 days | To determine the Recommended Phase 2 Dose (RP2D) of Jaktinib for the efficacy evaluation phase. |
| 1-year cumulative incidence of moderate-to-severe chronic graft-versus-host disease (cGVHD). | 1 year | 1-year cumulative incidence of moderate-to-severe chronic graft-versus-host disease (cGVHD). |
| Immune reconstitution at Weeks 4, 12, and 24 post-transplantation | Weeks 4, 12, and 24 post-transplantation | Immune reconstitution at Weeks 4, 12, and 24 post-transplantation, as assessed by lymphocyte subset counts (CD3⁺ T cells, CD19⁺ B cells, CD56⁺ NK cells). |
| 1-year GVHD-free, relapse-free survival (GRFS) | 1 year | Defined as the proportion of subjects who are alive and free from relapse of the underlying malignancy and without active chronic GVHD requiring systemic immunosuppressive therapy at 1 year after treatment initiation. |
| Overall Response Rate (ORR) at Weeks 1, 2, 6, 8, 12, and 24 following treatment with Jaktinib in combination with corticosteroids. | Weeks 1, 2, 6, 8, 12, and 24 | Overall Response Rate (ORR) at Weeks 1, 2, 6, 8, 12, and 24 following treatment with Jaktinib in combination with corticosteroids. |
Countries
China
Contacts
Primary ContactYIBO Wu, MD
Backup ContactYi Luo
Outcome results
None listed