Belumosudil mesilate for Chronic graft-versus-host disease | Steroid-refractory overlap syndrome (osGVHD)

Inclusion criteria

• {"criterion_text":"- Male and female patients aged ≥18 years\n- Participant is willing and able to give informed consent for participation in the study\n- Patient body weight ≥40kg.\n- 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.\n- Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines.\n- SR-osGVHD diagnosis: Patients with clinically diagnosed moderate to severe osGVHD according to NIH Consensus Criteria\n- 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 osGVHD defined per 2014 NIH consensus criteria (Martin 2015) irrespective of the concomitant use of a CNI, 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)\n- Evident myeloid and platelet engraftment: absolute neutrophil count (ANC)>1x109/L and platelet count >20x109/L\n- 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.\n- Able to swallow tablets\n- Eastern Co-operative Oncology Group (ECOG) performance status 0, 1, or 2"}

Exclusion criteria

• {"criterion_text":"- Patient has received more than one systemic treatment for cGVHD other than corticosteroids + calcineurin inhibitors (CNI) (prophylaxis or treatment).\n- 10.\tHepatic impairment with Child-Pugh B or C liver cirrhosis. AST or ALT 5x upper limit of normal (ULN) or higher or bilirubin 1.5x ULN or higher even if liver impairment is likely due to GVHD\n- Impairment of gastrointestinal (GI) function (unrelated to GVHD) or GI disease (unrelated to GVHD) that may significantly alter the absorption of oral belumosudil (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).\n- Any corticosteroid therapy for indications other than cGVHD at doses >1 mg/kg/day methylprednisolone or equivalent within 7 days before Cycle 1 Day 1.\n- 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.\n- Known allergies, hypersensitivity, or intolerance of belumosudil or any of its excipients or similar compounds.\n- 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 1 week after the last belumosudil\n- Pregnancy and lactation\n- Failed prior allogeneic hematopoietic stem cell transplantation (alloSCT) within the past 6 months.\n- Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of 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.\n- Evidence of active viral infection (confirmed by peripheral blood viral load) including CMV, EBV, HBV, or HCV. Patients with pre-transplant positive serology results indicative of high risk for viral reactivation must have negative viral load results within 28 days prior toCycle 1 Day 1. Patients whose immune status is unknown or uncertain (e.g. serologies not obtained prior to transplant) must have viral load results confirming no evidence of active viral infection within 28 days prior toCycle 1 day 1.\n- Presence of relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.\n- 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\n- SR-osGVHD 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.\n- 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.\n- 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)."}

Primary endpoints

• {"endpoint_text":"- Assessment by ORR at the week 25 (Cycle 7 Day 1) visit. The ORR is defined as the proportion of patients demonstrating a CR or PR without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response will be relative to the organ score at the time of baseline assessment. Missing values will be counted as non-responders","definition_or_measurement_approach":"Overall Response Rate (ORR) assessed at week 25 (Cycle 7 Day 1); defined as proportion of patients achieving CR or PR without requirement of additional systemic therapies; scoring relative to organ score at baseline; missing values counted as non-responders."}

Secondary endpoints

• {"endpoint_text":"- FFS is defined as time from start of treatment to the earliest recurrence of underlying disease, start of a new systemic treatment for osGVHD, or death, or the date the patient is last seen alive without event (censored observation)","definition_or_measurement_approach":"Failure-free survival (FFS): time from treatment start to earliest recurrence, start of new systemic treatment for osGVHD, or death; censored at last seen alive without event."}
• {"endpoint_text":"- To evaluate change in the mLSS (Symptom control). Response defined as a ≥7-point reduction from baseline in total symptom score (evaluation at week 25).","definition_or_measurement_approach":"Change in modified Lee Symptom Scale (mLSS); response = ≥7-point reduction from baseline at week 25."}
• {"endpoint_text":"- 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":"Overall survival (OS): time from treatment start to death from any cause; censored at last seen alive."}
• {"endpoint_text":"- BOR - Proportion of patients who achieved OR (CR+PR) at any time point (up to Cycle 7 day 1 or the start of additional systemic therapy for osGVHD)","definition_or_measurement_approach":"Best overall response (BOR): proportion achieving CR or PR at any time up to Cycle 7 Day 1 or before start of additional systemic therapy."}
• {"endpoint_text":"- DOR is assessed for responders only. DOR is defined as the time from first response until osGVHD progression, death, or the date of change/addition of systemic therapies for osGVHD, or the date the patient is last seen alive without event (censored observation)","definition_or_measurement_approach":"Duration of response (DOR): time from first response to progression, death, change/addition of systemic therapy, or censored at last seen alive without event; assessed for responders only."}
• {"endpoint_text":"- 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":"Non-relapse mortality (NRM): time from treatment start to death not preceded by disease relapse; relapse considered competing event."}
• {"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 organ score at baseline."}
• {"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 completely tapered off steroids by week 25."}
• {"endpoint_text":"- 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":"Malignancy relapse/recurrence (MR): time from treatment start to hematologic malignancy relapse; NRM considered competing event; calculated for patients with underlying hematologic malignancy."}
• {"endpoint_text":"- 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 to response: time from treatment start to first documentation of PR or CR; death without prior response is competing event."}
• {"endpoint_text":"- 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 7.6.16.","definition_or_measurement_approach":"Immunophenotyping of specified immune cell subsets and immune metabolism during treatment (methods per protocol section 7.6.16); site-limited (Freiburg)."}
• {"endpoint_text":"- Change in FACT-BMT from baseline to each visit where measured.","definition_or_measurement_approach":"Change in FACT-BMT quality-of-life score from baseline to each assessment visit."}
• {"endpoint_text":"- The AE and SAE reporting and documentation period begins with the ICF signature and ends 30 days after last treatment with belumosudil, further information see section 10.","definition_or_measurement_approach":"AE/SAE reporting window: from ICF signature until 30 days after last belumosudil dose; details in protocol section 10."}
• {"endpoint_text":"- The incidence of AEs defined by preferred term (PT) according to MedDRA will be calculated and analysed.","definition_or_measurement_approach":"Incidence of AEs tabulated and analyzed by MedDRA preferred term (PT)."}

Germany

Earliest CTIS Part Ii Submission Date

20-11-2025

Latest Decision Or Authorization Date

05-12-2025

Processing Time Days

15

Number Of Sites

1

Number Of Participants

24

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":"Sanofi Aventis GmbH","duties_or_roles":"Source of monetary support","organisation_type":""}