Acute Graft vs Host Disease
Conditions
Brief summary
Graft-versus-host disease (GVHD) is a common severe complication and a primary cause of mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT).Previous studies have demonstrated that the JAK/STAT signaling pathway exerts anti-GVHD effects by reducing the expression of pro-inflammatory cytokines, thereby inhibiting T-cell signaling transduction. Jaktinib is a broad-spectrum kinase inhibitor that targets non-receptor tyrosine Janus-associated kinases (JAK1, JAK2, JAK3, and TYK2), as well as FLT3 (FMS-like tyrosine kinase 3) and c-Kit. Preclinical studies indicated that Jaktinib significantly prolonged survival, mitigated weight loss, and improved clinical symptoms of GVHD in a dose-dependent manner in murine models.Based on this rationale, this prospective, single-arm, multicenter, exploratory clinical study was designed to evaluate the safety and efficacy of Jaktinib in the treatment of Grade II-IV steroid-refractory acute graft-versus-host disease (aGVHD).
Interventions
DRUGJaktinib
Beginning on Day 1, participants will receive jaktinib orally at the recommended phase 2 dose (RP2D) , until the earliest occurrence of clinically meaningful aGVHD progression (defined as disease progression necessitating the initiation of new systemic therapy for aGVHD), hematologic disease relapse, unacceptable AE, withdrawal of consent by the participant, investigator's decision to discontinue, or study completion, whichever occurs first.
Sponsors
Nanfang Hospital, Southern Medical University
Suzhou Zelgen Biopharmaceuticals Co.,Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary written informed consent; aged 18 to 70 years, inclusive; male or female. 2. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) with documented myeloid engraftment. 3. Patients with grade II-IV steroid-refractory acute graft-versus-host disease (aGvHD). 4. Karnofsky Performance Status (KPS) score ≥ 60, with an expected survival of greater than 6 months. 5. Absence of uncontrolled infection or severe hepatic, renal, pulmonary, or cardiac disease. 6. Male participants must agree to practice abstinence or use contraception; female participants must have a negative pregnancy test and agree to use dual methods of contraception. 7. Able to swallow tablets. 8. Able to comply with study and follow-up procedures.
Exclusion criteria
1. Has received more than one systemic treatment for aGvHD other than corticosteroids +/- CNI (prophylaxis or treatment). 2. Has previously received chimeric antigen receptor (CAR) T-cell therapy. 3. Has previously received JAK inhibitor therapy after allogeneic hematopoietic stem cell transplantation (allo-HSCT). 4. Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features. 5. Failed prior alloHSCT within the past 6 months. 6. Presence of severe respiratory disease, severe renal impairment, clinically significant or uncontrolled cardiac disease, unresolved cholestasis, and hepatic disease (not attributable to aGvHD). 7. Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present.Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. 8. Evidence of active viral infection (confirmed by peripheral blood viral load) including CMV, EBV, HHV-6, HBV, or HCV. Patients with pre-transplant positive serology results indicative of high risk for viral reactivation must have negative viral load results within 28 days prior to enrollment. Patients whose immune status is unknown or uncertain (e.g. serologies not obtained prior to transplant) must have viral load results confirming no evidence of active viral infection within 28 days prior to enrollment. 9. Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse. 10. Has participated in any other clinical trials within 28 days before first administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | Day 28 | The proportion of patients who had a complete response or partial response as compared with baseline organ staging without the use of additional systemic therapy for acute GVHD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Durable overall response (DOR) at Day 56 | Day 56 | The proportion of patients who had response at day 28 that was maintained at day 56. |
| Best Overall Response (BOR) | Day 56 | The proportion of patients who achieved a complete response or partial response at any time point up to and including Day 56 and before the start of additional systemic therapy for aGVHD. |
| Overall response rate (ORR) | Day 56 | The proportion of patients who had a complete response or partial response as compared with baseline organ staging without the use of additional systemic therapy for acute GVHD. |
| Overall Survival (OS) | 1 year | The time from the date of enrollment to the date of death due to any cause. |
| Failure-Free Survival (FFS) | 1 year | The time from the date of enrollment to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment. |
| Relapse-Free Survival (RFS) | 1 year | The interval from enrollment to the date of death from any cause in the absence of hematologic disease relapse or progression. |
| Disease Relapse Rate | 1 year | Cumulative incidence of hematological malignancy relapse or progression. |
| Event-Free Survival (EFS) | 1 year | Time from the date of enrollment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause. |
| Incidence of Chronic Graft-Versus-Host Disease (cGVHD) | 1 year | Cumulative incidence of cGVHD post-allogeneic hematopoietic stem cell transplantation. cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe. |
| Safety and Tolerability (TEAEs) | Treatment period to 28 days after the last dose of trial treatment. | Evaluation of the safety and tolerability profiles of jaktinib, including the incidence of treatment-related adverse events (TRAEs). |
Countries
China
Contacts
CONTACTQifa Liu
CONTACTHua Jin
Outcome results
None listed