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

Official title

The Safety and Efficacy of Gecacitinib (Also Known as Jaktinib) Combined Glucocorticoids as First-line Treatment for Grade II-IV Acute Graft-versus-host Disease.

Overview

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

• Drug Gecacitinib (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 ass

Primary outcome measures

• 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 [Time frame: 28 days]
• 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. [Time frame: 28 days]

Secondary outcome measures (8)

• To determine the Recommended Phase 2 Dose (RP2D) of Jaktinib for the efficacy evaluation phase. [Time frame: 28 days]
• Overall Response Rate (ORR) at Weeks 1, 2, 6, 8, 12, and 24 following treatment with Jaktinib in combination with corticosteroids. [Time frame: Weeks 1, 2, 6, 8, 12, and 24]
• Duration of Response (DOR) [Time frame: 1 year]
• 180-day cumulative non-relapse mortality (NRM) [Time frame: 180 days]
• Change in levels of serum biomarkers [Time frame: Days 7, 14, and 28]
• 1-year GVHD-free, relapse-free survival (GRFS) [Time frame: 1 year]
• 1-year cumulative incidence of moderate-to-severe chronic graft-versus-host disease (cGVHD). [Time frame: 1 year]
• Immune reconstitution at Weeks 4, 12, and 24 post-transplantation [Time frame: Weeks 4, 12, and 24 post-transplantation]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital, Zhejiang University School of Medicine. — Hangzhou

Publications

• Moiseev IS, Morozova EV, Bykova TA, Paina OV, Smirnova AG, Dotsenko AA, Borzenkova ES, Galimov AN, Gudognikova YV, Ekushov KA, Kozhokar PV, Osipova AA, Pirogova OV, Rudakova TA, Klimova OU, Tcvetkov NY, Kulagin EA, Surkova EA, Lapin SV, Rodionov GG, Moiseev SI, Serov YA, Zubarovskaya LS, Afanasyev BV. Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in chil PMID 32071418
• Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Hadzic N, Shaw BE, Potter MN; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012 Jul;158(1):30-45. doi: 10.1111/j.1365-2141.2012.09129.x. Epub 20 PMID 22533831
• Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socie G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22. PMID 32320566
• Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. doi: 10.1182/blood.2020004823. PMID 32160294

Identifiers

NCT: NCT07285889 · ZJU-GVHD-JAKTINIB1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗