Efficacy and Safety of Gecacitinib Hydrochloride in Prophylaxis Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Myelofibrosis

Official title

Efficacy and Safety of Gecacitinib Hydrochloride Combined With Rabbit Anti-Human Thymocyte Immunoglobulin (ATG) in Prophylaxis Acute Graft-Versus-Host Disease (aGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) in Patients With Myelofibrosis (MF)

Overview

Gecacitinib hydrochloride is a novel JAK/ACVR1 inhibitor approved for intermediate- and high-risk myelofibrosis (MF). Clinical and real-world data demonstrate significant efficacy in spleen reduction, symptom relief, and anemia improvement, with favorable safety and tolerability. Preclinical studies confirm that this agent can mitigate GVHD and suppress inflammation. MF patients undergoing allo-HSCT are at risk of delayed engraftment and aGVHD. Based on the immunomodulatory effects of JAK inhibitors, gecacitinib is expected to have potential for aGVHD prophylaxis. This study aims to evaluate the efficacy and safety of geltrectinib hydrochloride combined with ATG for preventing aGVHD in MF patients after allo-HSCT.

Interventions

• Drug Gecacitinib
  (i) Rabbit anti-human thymocyte immunoglobulin (ATG): administered on Days -4 to -2.(ii) Cyclosporine A: initiated on Day -9 through Day +180, tapered gradually after Day +90.(iii) Mycophenolate mofetil (MMF): administered at 0.5 g twice daily (bid) from Day -9 to Day +30.(iv) Geltrectinib hydrochloride: administered between Day +6 and Day +28 post-engraftment at a dose of 50 mg twice daily (bid).

Primary outcome measures

• Incidence of grade 3-4 aGVHD [Time frame: 14 weeks.]

Secondary outcome measures (1)

• Incidence of poor graft function [Time frame: 14 weeks]

Eligibility criteria

Inclusion criteria

• Voluntarily sign the informed consent form (ICF), and be aged ≥ 18 years at the time of signing.
• Diagnosis of primary myelofibrosis (PMF) according to the 2016 WHO criteria (DIPSS intermediate-2/high risk, MPISS70 high/very high risk, or RR6 high risk), or post-ET/PV secondary myelofibrosis (MYSEC intermediate-2/high risk), with intention to undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• Recipient with myelofibrosis scheduled to receive myeloablative conditioning allo-HSCT from a matched unrelated donor, matched sibling donor, or haploidentical donor.
• Karnofsky Performance Scale score ≥ 60.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-2.
• Male participants must agree to abstinence or use barrier contraception throughout the study.
• Female participants of childbearing potential must have a negative pregnancy test and agree to use two effective methods of contraception throughout the study.
• Ability to swallow tablets.
• Ability to comply with study and follow-up procedures.

Exclusion criteria

• Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy.
• Hepatic insufficiency defined as bilirubin ≥ 2 × upper limit of normal (ULN), except for patients with a history of Gilbert Syndrome.
• Renal impairment defined as serum creatinine > 2 mg/dL.
• Cardiac dysfunction defined as left ventricular ejection fraction (LVEF) ≤ 45%.
• Pulmonary dysfunction defined as forced expiratory volume in the first second (FEV1) or diffusing capacity for carbon monoxide (DLCO) (corrected for hemoglobin) ≤ 50% of predicted value.
• Chronic or active infection requiring systemic therapy during the peri-transplant and post-transplant period.
• Diagnosis of another active malignancy within the past 12 months, except for adequately treated non-melanoma skin cancer, adequately treated melanoma of grade 2 or below, or cervical intraepithelial neoplasia. Active malignancy is defined as malignancy undergoing active treatment.
• Any significant clinical or laboratory abnormality that may compromise safety evaluation, such as:

• Uncontrolled diabetes mellitus (fasting blood glucose > 13.9 mmol/L);
• Hypertension uncontrolled by two or more antihypertensive agents (systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 100 mmHg);
• Peripheral neuropathy of grade ≥ 2 per NCI-CTCAE v5.0.
• Pre-transplant diagnosis of gastrointestinal impairment or disease that may affect drug absorption, including ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or history of gastrectomy or intestinal resection.
• Cholestatic disease or sinusoidal obstruction syndrome / hepatic veno-occlusive disease at screening (defined as persistent bilirubin abnormality and progressive organ dysfunction not due to graft-versus-host disease).
• Active and uncontrolled viral infection at screening, including CMV, EBV, HIV (positive anti-HIV antibody), HBV (positive HBsAg or positive HBV-DNA), HCV (positive anti-HCV antibody or positive HCV-RNA).
• Active tuberculosis within 6 months prior to screening.
• History of epilepsy or use of psychotropic or sedative medications at screening.
• Female patients who are pregnant, breastfeeding, or planning pregnancy, or who cannot use effective contraception throughout the study; male patients who do not use condoms during dosing and for 2 days (approximately 5 half-lives) after the last dose.
• History of malignancy other than the transplanted tumor within the previous 5 years.
• Use of anticoagulant or antiplatelet agents (except low-molecular-weight heparin).
• Presence of other severe diseases that, in the investigator's opinion, may affect patient safety or compliance.
• Suspected hypersensitivity to geltrectinib hydrochloride, its analogs, or any of its excipients.
• Participation in another clinical trial of an investigational drug or medical device within 4 weeks prior to screening.
• Any other condition that, in the investigator's judgment, renders the patient ineligible 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

Center list to be confirmed — check the primary protocol.

Publications

• Saad A, de Lima M, Anand S, Bhatt VR, Bookout R, Chen G, Couriel D, Di Stasi A, El-Jawahri A, Giralt S, Gutman J, Ho V, Horwitz M, Hsu J, Juckett M, Kharfan-Dabaja MA, Loren A, Meade J, Mielcarek M, Moreira J, Nakamura R, Nieto Y, Roddy J, Satyanarayana G, Schroeder M, Tan CR, Tzachanis D, Burn J, Pluchino L. Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in PMID 32519831
• Zhang Y, Zhou H, Zhuang J, et al. A randomized, double-blind, phase 3 study of jaktinib versus hydroxyurea (HU) in patients (pts) with intermediate-2 or high-risk myelofibrosis (MF). Journal of Clinical Oncology 41, no. 16_suppl (2023): 7015-7015.
• De Togni E, Cole O, Abboud R. Janus kinase inhibition in the treatment and prevention of graft-versus-host disease. Front Immunol. 2024 Feb 6;15:1304065. doi: 10.3389/fimmu.2024.1304065. eCollection 2024. PMID 38380328

Identifiers

NCT: NCT07440654 · NFEC-2026-043 · GCA-aGVHD-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗