RUXOLITINIB for Chronic graft-versus-host disease (steroid-refractory)

Inclusion criteria

• {"criterion_text":"- Male and female patients aged ≥18 years"}
• {"criterion_text":"- Patients have undergone alloSCT from any donor source (matched unrelated donor sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are eligible."}
• {"criterion_text":"- Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines."}
• {"criterion_text":"- SR-cGvHD diagnosis: Patients with clinically diagnosed moderate to severe cGvHD according to NIH Consensus Criteria (Jagasia 2015). Moderate: - at least one organ (not lung) with a score of 2-3 or more organs with score 1 or - lung score 1 Severe: - at least one organ with a score of 3 or - lung score 2"}
• {"criterion_text":"- Patients who have received systemic glucocorticoids for the treatment of chronic graft-versus-host disease for a duration of < 6 months prior to cycle 1 day 1 and have a confirmed diagnosis of steroid refractory cGvHD defined per 2014 NIH consensus criteria (Martin 2015) irrespective of the concomitant use of a calcineurin inhibitor, as follows:  A lack of response or disease progression after administration of minimum prednisone 1 mg/kg/day for ≥1 week (or equivalent) or  Disease persistence without improvement despite continued treatment with prednisone at >0.5 mg/kg/day or 1 mg/kg/every other day for ≥4 weeks (or equivalent) or  Increase to prednisone dose to >0.25 mg/kg/day after two unsuccessful attempts to taper the dose (or equivalent)"}
• {"criterion_text":"- Evident myeloid and platelet engraftment: absolute neutrophil count >1x109/L and platelet count >25x109/L"}
• {"criterion_text":"- Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug."}
• {"criterion_text":"- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2"}

Exclusion criteria

• {"criterion_text":"- Patients that transition from active aGvHD to cGvHD without tapering off corticosteroids ± CNI and any systemic treatment (acute to chronic GvHD overlap syndrome). Patients receiving up to 30 mg by mouth once a day of hydrocortisone (i.e., physiologic replacement dose) of corticosteroids are allowed."}
• {"criterion_text":"- Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)."}
• {"criterion_text":"- Any corticosteroid therapy for indications other than cGvHD at doses >1 mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1."}
• {"criterion_text":"- Prior treatment with ruxolitinib or ECP except if the treatment was for acute GvHD."}
• {"criterion_text":"- Patient is receiving treatment with medications that interfere with coagulation or platelet function including, but not limited to, heparin or warfarin sodium (Coumadin®). Use of low molecular weight heparin is allowed. In patients in whom aspirin is indicated for secondary cardiovascular disease prevention, aspirin daily dose must not exceed 150 mg/day."}
• {"criterion_text":"- Patient is receiving fluconazole at daily doses higher than 200 mg."}
• {"criterion_text":"- Patient is receiving and does not agree to stop herbal preparations/medications. These herbal medications include, but are not limited to, St. John’s Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients must stop using herbal medications at least 7 days prior to first dose of study treatment."}
• {"criterion_text":"- Known allergies, hypersensitivity, or intolerance of ruxolitinib or any of its excipients or similar compounds, methoxypsoralen or psoralen compounds"}
• {"criterion_text":"- Photosensitive disease"}
• {"criterion_text":"- Aphakia"}
• {"criterion_text":"- Failed prior alloSCT within the past 6 months from Cycle 1 Day 1 (relapsed original disease)."}
• {"criterion_text":"- History of tuberculosis infection that developed after alloSCT."}
• {"criterion_text":"- Patients with relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed."}
• {"criterion_text":"- SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Patients who have received a scheduled DLI as part of their transplant procedure (up to day 120) and not for management of malignancy relapse are eligible."}
• {"criterion_text":"- History of progressive multifocal leuko-encephalopathy (PML)."}
• {"criterion_text":"- Active treatment in a clinical study of any investigational agent within 30 days prior to Cycle 1 Day1, or within 5 half-lives of the study treatment, whichever is longer."}
• {"criterion_text":"- Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection 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."}
• {"criterion_text":"- Positive result for HIV at screening."}
• {"criterion_text":"- Inability to tolerate extracorporeal volume loss"}
• {"criterion_text":"- Sexually active men and female patients of child-bearing potential who are not willing to use highly effective methods of contraception during the trial and at least 5 months after the last ECP procedure"}
• {"criterion_text":"- Pregnancy and lactation"}
• {"criterion_text":"- Previous splenectomy"}
• {"criterion_text":"- Evidence of active viral disease including CMV, EBV, HHV-6, HBV, HCV, or BK virus (e.g. CMV pneumonia, not just CMV copy number increase). Patients with pre-transplant positive serology results must have negative viral load results for HBV and HCV within 28 days prior to Cycle 1 Day 1. Patients with unknown viral testing results prior to transplant must have viral load results confirming no evidence of active viral disease within 28 days prior to Cycle 1 Day 1."}
• {"criterion_text":"- Coagulation disorder"}
• {"criterion_text":"- Leucocytes > 25x109/L"}
• {"criterion_text":"- Current Melanoma, basal cell carcinoma or squamous cell carcinoma of the skin requiring treatment"}
• {"criterion_text":"- Mechanical ventilation or patients who have resting O2 saturation <90% by pulse-oximetry."}
• {"criterion_text":"- History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study including any of the following:  recent myocardial infarction (within last 6 months prior to Cycle 1 Day 1)  New York Heart Association Class III or IV congestive heart failure  unstable angina (within last 6 months prior to Cycle 1 Day 1  clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker); ventricular arrhythmias  uncontrolled hypertension"}
• {"criterion_text":"- Patients requiring vasopressors."}
• {"criterion_text":"- Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration and contraindications of study drug/study procedure and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data."}
• {"criterion_text":"- Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (> 176.8μmol/L), renal dialysis requirement, or have estimated creatinine clearance <30 ml/min measured or calculated by Cockroft Gault equation (confirmed within 48 hours prior to study treatment start)."}
• {"criterion_text":"- Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD and ongoing organ dysfunction) OR total bilirubin >2mg/dL not attributable to GvHD."}

Primary endpoints

• {"endpoint_text":"- The Overall Response Rate (ORR) at the week 25 (Cycle 7 Day 1) visit.","definition_or_measurement_approach":"The ORR is defined as the proportion of patients demonstrating a complete response (CR) or partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or nonresponse. Scoring of response will be relative to the organ score at the time of baseline assessment."}

Secondary endpoints

• {"endpoint_text":"- To evaluate failure-free survival (FFS), FFS will be used as the first key secondary; FFS is defined as time from start of treatment to the earliest recurrence of underlying disease, start of a new systemic treatment for cGvHD, or death, or the date the patient is last seen alive without event (censored observation)","definition_or_measurement_approach":"FFS defined as time from start of treatment to earliest recurrence of underlying disease, start of new systemic treatment for cGvHD, or death (censored if last seen alive without event)."}
• {"endpoint_text":"- To evaluate change in the modified Lee Symptom Scale score (Symptom control); Response defined as a ≥7-point reduction from baseline in total symptom score (evaluation at week 25).","definition_or_measurement_approach":"Response defined as a ≥7-point reduction from baseline (Day 1 week 1) in total symptom score; evaluated at week 25."}
• {"endpoint_text":"- To assess Overall Survival (OS); OS is defined as time from start of treatment to the date of death from any cause, or the date the patient is last seen alive (censored observation)","definition_or_measurement_approach":"OS defined as time from start of treatment to date of death from any cause (censored if last seen alive)."}
• {"endpoint_text":"- To assess the best overall response (BOR); Proportion of patients who achieved OR (CR+PR) at any time point (up Cycle 7 day 1 or the start of additional systemic therapy for cGvHD)","definition_or_measurement_approach":"BOR: proportion achieving CR or PR at any time up to Cycle 7 Day 1 or start of additional systemic therapy."}
• {"endpoint_text":"- Response according to organs; Scoring of response will be relative to the organ score at the time of baseline assessment","definition_or_measurement_approach":"Organ-specific response scored relative to baseline organ score."}
• {"endpoint_text":"- To assess the duration of response (DOR), Duration of response (DOR) is assessed for responders only. DOR is defined as the time from first response until cGvHD progression, death, or the date of change/addition of systemic therapies for cGvHD, or the date the patient is last seen alive without event (censored observation)","definition_or_measurement_approach":"DOR defined as time from first response until cGvHD progression, death, change/addition of systemic therapies, or censored at last seen alive without event."}
• {"endpoint_text":"- To assess the non-relapse mortality (NRM); Non-relapse mortality (NRM) is defined as the time from start of treatment to date of death not preceded by underlying disease relapse/recurrence. Underlying disease relapse/ recurrence is considered as a competing event","definition_or_measurement_approach":"NRM defined as time from start of treatment to death not preceded by relapse; relapse considered competing event."}
• {"endpoint_text":"- To assess the proportion of patients with ≥50% reduction in daily steroid dose at week 25","definition_or_measurement_approach":"Proportion of patients achieving ≥50% reduction in daily steroid dose at week 25."}
• {"endpoint_text":"- To assess the proportion of patients who successfully tapered off all steroids at week 25","definition_or_measurement_approach":"Proportion of patients who have tapered off all steroids by week 25."}
• {"endpoint_text":"- To assess the cumulative incidence of Malignancy Relapse/Recurrence (MR); Malignancy Relapse/Recurrence (MR) is defined as the time from start of treatment to hematologic malignancy relapse/recurrence. Calculated for patients with underlying hematologic malignant disease. NRM is considered as a competing event.","definition_or_measurement_approach":"Cumulative incidence of hematologic malignancy relapse/recurrence from treatment start; NRM treated as competing event; calculated for patients with underlying hematologic malignant disease."}
• {"endpoint_text":"- To assess time to treatment response (TTTR), Time to response is defined as time from treatment start to the date of first documentation of PR or CR. Death without prior response will be considered to be a competing event.","definition_or_measurement_approach":"Time from treatment start to first documented PR or CR; death without prior response is competing event."}
• {"endpoint_text":"- To assess changes in immune cell phenotype during treatment (only Freiburg), Changes in immune cell phenotype (T cells (CD3, CD4 and CD8), NK cells (CD56, CD3-, TCR-), NKT cells (CD3+ CD1d Tetramer+), monocytes (CD11bCD14); neutrophils (CD11b, CD15)) B cells (CD21low) and immune metabolism during treatment as described in section 7.6.15.","definition_or_measurement_approach":"Assessment of immune cell phenotypes and biomarkers during treatment (Freiburg only) as described in protocol section 7.6.15 (panels: T cells, NK, NKT, myeloid cell types, B cells, neutrophils and immune metabolism)."}
• {"endpoint_text":"- To evaluate changes in FACTBMT, Change in FACT-BMT from baseline to each visit where measured.","definition_or_measurement_approach":"Change from baseline in FACT-BMT scores at each assessment visit."}

Germany

Earliest CTIS Part Ii Submission Date

24-09-2024

Latest Decision Or Authorization Date

16-01-2026

Processing Time Days

479

Number Of Sites

2

Number Of Participants

24

Austria

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

21-01-2026

Processing Time Days

540

Number Of Sites

1

Number Of Participants

16

Primary sponsor

Full Name

Medical Center - University Of Freiburg

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"","full_name":"Mallinckrodt Pharmaceuticals / Therakos EMEA Ltd.","duties_or_roles":"Source of monetary support","organisation_type":""}