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

Официальное название

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

Обзор

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.

Вмешательства

• Препарат Prednisone + Jakavi(ruxolitinib)
  The experimental group will receive ruxolitinib 10 mg orally twice daily (BID) and prednisone (or equivalent) at a dosage of 1 mg/kg/day. Subjects are orally administered with an investigational medicinal product (IMP) according to their designated treatment group for 48 weeks, and the investigator may adjust the dosage of IMPs based on symptoms of the target disease. (However, after the 48-week mark, participants in the ruxolitinib treatment group may continue to receive ruxolitinib for an add
• Препарат Prednisone
  The control group will receive prednisone (or equivalent) at a dosage of 1 mg/kg/day. Subjects are orally administered with an investigational medicinal product (IMP) according to their designated treatment group for 48 weeks, and the investigator may adjust the dosage of IMPs based on symptoms of the target disease.

Первичные конечные точки

• Overall Response Rate(ORR) [Срок оценки: on 48 week]

Вторичные конечные точки (9)

• Ratio of subjects who are found steroid-refractory or steroid-dependent [Срок оценки: on Weeks 1, 4, 24, 36 and 48]
• Overall Response Rate (ORR) based on the NIH Consensus Criteria on Weeks 24 and 36 [Срок оценки: on Weeks 24 and 36]
• Failure-free Survival (FFS) [Срок оценки: for 48 weeks]
• Duration of Response (DOR) [Срок оценки: for 48 weeks]
• Ratio of subjects whose daily dosage of systemic corticosteroid is reduced as much as at least 50% [Срок оценки: compared to the baseline on Week 48]
• Ratio of subjects whose daily dosage of systemic corticosteroid is reduced [Срок оценки: compared to the baseline on Week 48]
• Time up to the point of stopping systemic immunosuppressant administration (concomitant medicines other than IMPs) [Срок оценки: for 48 weeks]
• Change in FACT-BMT((Functional Assessment of Cancer Therapy - Bone Marrow Transplantation) score [Срок оценки: compared to the baseline on Week 24, 36 and 48]
• Change in EQ-5D-5L(European Quality of Life 5 Dimension) score [Срок оценки: compared to the baseline on Week 24, 36 and 48]

Критерии участия

\[Inclusion Data\]

• Adult men and women aged 19 or older based on the date of signing on the informed consent form
• 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
• Those who have no history of systemic treatment for chronic graft-versus-host disease and now need systemic corticosteroid treatment
• Those whose ECOG (Eastern Cooperative Oncology Group) performance status is 0 to 2.
• 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
• Those who voluntarily agree on participation in this clinical trial

\[Exclusion Data\]

• 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
• 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)
• 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)
• Those to whom the treatment for chronic graft-versus-host disease cannot begin as prednisone ≥ 0.5 mg/kg/day
• Those whose same-type stem cell transplantation (alloSCT) has been confirmed as engraft-failed within 6 months before the screening visit
• 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.)
• 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.)
• 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)
• Those allergic or sensitive to additives of IMPs and concomitant medicines (systemic corticosteroid) or similar compounds
• Patients with genetic problems such as galactose intolerance, lapp lactase deficiency, glucose - galactose malabsorption, etc.
• Those who are administrated with more than 200 mg of Fluconazole per day
• 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.)
• Pregnant or breast-feeding women
• 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)
• 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.)
• Those whose participation in this clinical trial is viewed as inappropriate in the investigator's opinion.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

South Korea · 1 центр

• The Catholic University of Korea, Seoul St. Mary's Hospital — Seoul

Публикации

• DeFilipp Z, Couriel DR, Lazaryan A, Bhatt VR, Buxbaum NP, Alousi AM, Olivieri A, Pulanic D, Halter JP, Henderson LA, Zeiser R, Gooley TA, MacDonald KPA, Wolff D, Schultz KR, Paczesny S, Inamoto Y, Cutler CS, Kitko CL, Pidala JA, Lee SJ, Socie G, Sarantopoulos S, Pavletic SZ, Martin PJ, Blazar BR, Greinix HT. National Institutes of Health Consensus Development Project on Criteria for Clinical Trial PMID 34147469
• Martin PJ, Lee SJ, Przepiorka D, Horowitz MM, Koreth J, Vogelsang GB, Walker I, Carpenter PA, Griffith LM, Akpek G, Mohty M, Wolff D, Pavletic SZ, Cutler CS. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report. Biol Blood Marrow Transplant. 2015 Aug;21(8):1343-59. d PMID 25985921
• Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, Tabrizi R, Magro L, Vanhove B, Blancho G, Moreau P, Gaugler B, Chevallier P, Mohty M. Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017 Nov 16;130(20):2186-2195. doi: 10.1182/blood-2017-05-786137. Epub 2017 Sep 1. PMID 28864814
• Rongvaux-Gaida D, Dupuis M, Poupon J, Djebrani-Oussedik N, Lemonnier C, Rieger F. High Response Rate and Corticosteroid Sparing with Arsenic Trioxide-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Transplant Cell Ther. 2022 Oct;28(10):679.e1-679.e11. doi: 10.1016/j.jtct.2022.07.004. Epub 2022 Jul 10. PMID 35830931
• Lazaryan A, Lee S, Arora M, Kim J, Betts BC, Khimani F, Nishihori T, Bejanyan N, Liu H, Kharfan-Dabaja MA, Locke FL, Gonzalez R, Jain MD, Davila ML, Perez LE, Mishra A, Perez Perez A, Balke K, Ayala E, Ochoa L, Castaneda Puglianini O, Faramand R, Alsina M, Elmariah H, Nieder ML, Fernandez H, Anasetti C, Pidala JA. A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chro PMID 34649279
• 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
• Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, Shaughnessy PJ, DeVetten MP, Jagasia M, Fay JW, van Besien K, Gupta V, Kitko C, Johnston LJ, Maziarz RT, Arora M, Jacobson PA, Weisdorf D. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009 May 21;113(21):5074-82. doi: 10.1182/blood-2009-02-202937. Epub 2009 Mar 6 PMID 19270260
• Hamilton BK. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):648-654. doi: 10.1182/hematology.2021000301. PMID 34889364

Идентификаторы

NCT: NCT06756061 · CINC424DKR01T

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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