Comparing the Therapeutic Effects of Using Ruxolitinib and Steroids Concurrently to Steroids Alone as Initial Treatment In Patients Diagnosed With Chronic Graft-versus-host Disease at a Grade of Moderate or Higher Severity

A Nation-wide, Multi-center, Prospective, Randomized, Parallel-group, Open-label, Investigator Initiated Pilot Study to Evaluate Efficacy and Safety of Systemic Corticosteroid Plus Ruxolitinib as First-line Therapy in Patients With New-onset Moderate to Severe Chronic Graft-versus-host Disease

Chronic graft-versus-host disease (cGVHD) is a complication that occurs in 30-40% of recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is a major cause of late non-relapse mortality. In cases where the initial treatment response is inadequate, irreversible tissue damage often persists, making it a fatal complication that significantly reduces quality of life even for long-term survivors.

Therefore, the success of first-line treatment is crucial, but to date, there are no approved drugs specifically for the first-line treatment of chronic graft-versus-host disease. Besides corticosteroids, which have been used palliatively for over 50 years, there are no proven effective treatments available.

Against this background, this study was designed to explore the potential of new treatments as first-line therapy for chronic graft-versus-host disease, where effective treatment options are currently lacking.

Initially, the objective response rate will be analyzed at the 48-week mark based on the NIH Consensus Criteria (Lee 2015). Additionally, the study will evaluate the proportion of patients with steroid-resistant or steroid-dependent conditions, the objective response rate(ORR), failure-free survival(FFS), duration of response(DOR), and the proportion of patients who have reduced corticosteroids. Furthermore, the differences in treatment effects between the two groups of patients will be analyzed based on safety endpoints, including adverse events, laboratory tests, physical examinations, and vital signs.

[Inclusion Data]

1. Adult men and women aged 19 or older based on the date of signing on the informed consent form

2. On the screening visit, those who are diagnosed of a moderate to severe chronic graft-versus-host disease according to 2014 NIH consensus criteria

   -Moderate: At least one of the following conditions: >1 point for at least three organs >2 points for at least one organ except the lungs >1 point for the lungs

   -Severe: At least one of the following conditions: >3 points for at least one organ

   • At least 2 points for the lungs

3. Those who have no history of systemic treatment for chronic graft-versus-host disease and now need systemic corticosteroid treatment

4. Those whose ECOG (Eastern Cooperative Oncology Group) performance status is 0 to 2.

5. Regardless of the donor (matched sibling-family donor, matched unrelated donor, or partially matched family donor), those who have successfully taken same-type stem cell transplantation (alloSCT) from the marrow, peripheral blood stem cell, or cord blood

6. Those who voluntarily agree on participation in this clinical trial

[Exclusion Data]

1. Those who meet the following criteria in laboratory tests during the screening and randomization visits

   • Those whose platelet count is less than or equal to 25,000/mm3 without blood transfusion
   • Those whose absolute neutrophil count is less than or equal to 1,000/mm3
   • Those whose total bilirubin > 3 x ULN for any reason other than chronic graft-versus-host disease

2. Those with gastrointestinal troubles that hinder the intake and absorption of IMPs and concomitant medicines (systemic corticosteroid) (e.g.: signs such as ulcerative disease, unregulated nausea, vomiting, diarrhea, malabsorption, etc. or small intestine removal)

3. Those with a history of graft-versus-host disease treatment

   • Corticosteroid administration is permitted for chronic graft-versus-host disease treatment within 72 hours before the randomization visit
   • Except those who had therapeutic or preventive use of systemic corticosteroids and/or systemic immunosuppressants (CNI, MMF) for acute graft-versus-host disease (In case of prednisone administration for maintenance, only 0.5 mg/kg/day or less is permitted)

4. Those to whom the treatment for chronic graft-versus-host disease cannot begin as prednisone ≥ 0.5 mg/kg/day

5. Those whose same-type stem cell transplantation (alloSCT) has been confirmed as engraft-failed within 6 months before the screening visit

6. Those with an experience of ruxolitinib administration for acute graft-versus-host disease treatment (however, the patient may participate on the assumption that the response to the acute graft-versus-host disease treatment reaches the level of complete or partial response and that there is no ruxolitinib administration history within 4 weeks before the randomization visit. In addition, if ruxolitinib administration was for another disease, the patient may participate unless there is no history of ruxolitinib administration within 4 weeks before the randomization visit.)

7. Those who suffer chronic graft-versus-host disease after an unscheduled donor lymphocyte infusion for proactive treatment to prevent the recurrence of a malignant tumor (Participation is allowed if the scheduled lymphocyte infusion is performed as part of the transplantation procedure, not for the prevention of the recurrence of a malignant tumor.)

8. Those found to have the following history in the screening visit:

   • Relapsed primary malignancy
   • Those found to involve an unregulated sinusoidal obstruction syndrome
   • Those with a history of progressive multifocal leukoencephalopathy (PML)
   • Nephropathy whose creatinine clearance rate is lower than 30 mL/min (Cockroft Gault equation)
   • Infections that are clinically active and uncontrolled, requiring treatment, including significant bacteria, fungi, viruses, or parasitic infections. (However, if there are no signs of progression at the time of screening due to appropriate treatment, the infection is considered controlled. The progression of infection is defined by hemodynamic instability due to sepsis, new symptoms caused by the infection, worsening physical signs, or radiological findings. A persistent fever without other signs or symptoms is not interpreted as progressive infection.)
   • Active tuberculosis
   • HIV-infected individual
   • Active infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) that the investigator views as significant
   • Cardiovascular disease that the investigator considers as clinically significant (acute cardiac infarction (within 6 months before randomization), NYHA class III or IV congestive heart failure, unstable angina (within 6 months before randomization), clinically significant symptomatic cardiac arrhythmia (e.g.: continued ventricular tachycardia, clinically significant level 2 or 3 AV blockage with no pacemaker used), unregulated hypertension)

9. Those allergic or sensitive to additives of IMPs and concomitant medicines (systemic corticosteroid) or similar compounds

10. Patients with genetic problems such as galactose intolerance, lapp lactase deficiency, glucose - galactose malabsorption, etc.

11. Those who are administrated with more than 200 mg of Fluconazole per day

12. Those being treated with systemic medicines that may hinder blood coagulation or platelet functions such as aspirin, heparin, and warfarin (However, those whose aspirin administration does not exceed 150 mg/day may participate.)

13. Pregnant or breast-feeding women

14. Those who do not agree on utilizing proper methods of contraception(e.g. a copper intrauterine device (copper loop), an intrauterine device containing hormones, condoms, a vasectomy, tubal surgery, a spermicide, a vagina-inserted contraceptive, a subdermal implant, an injectable contraceptive, a female condom, oral contraceptive, etc.) during the period of this clinical trial(the period of IP administration and at least 30 days after IP administration ends)

15. Those who have participated in another clinical trial within 30 days before the screening visit and have a history of IMP administration/medical equipment application (However, if the investigator views such a previous trial as not affecting this clinical trial's efficacy and safety assessment such as observational study or retrospective study, the subject may participate.)

16. Those whose participation in this clinical trial is viewed as inappropriate in the investigator's opinion.