Belumosudil With Ruxolitnib as Second Line Therapy for Chronic Graft Versus Host Disease (cGvHD) After Steroid Failure

A Phase 2 Study of Belumosudil Combined With Ruxolitinib as Second Line Therapy to Treat Chronic Graft Versus Host Disease (cGvHD) After Steroid Failure (BELRUX)

Chronic graft-versus-host disease (cGvHD) is a serious condition that can happen after a stem cell or bone marrow transplant. The donor's immune cells attack the patient's body, causing inflammation, pain, and damage to organs like the skin, liver, or lungs. For patients with moderate to severe cGvHD who don't improve with or can't tolerate standard front line therapy with steroids, there's a significant unmet need. Steroid-refractory cGvHD is hard to treat, with limited effective options, often leading to ongoing symptoms and reduced quality of life.

This Phase II study tests a new treatment combining two oral drugs, ruxolitinib and belumosudil, for these patients. Both drugs have helped cGvHD individually, but this trial explores if they work better together. For the first 28 days (Cycle 1), patients take ruxolitinib (10 mg twice daily). From Cycle 2, they add belumosudil (200 mg once or twice daily, depending on other medications) for 48 weeks (12 cycles) unless their condition worsens or side effects become intolerable. Follow-up visits occur 30 days and 6 months after treatment ends to check health status.

The study is non-randomized (all get the same treatment) and open-label (patients and doctors know the drugs used). It aims to see if this combination better controls cGvHD in patients where steroids failed. This could offer hope for better symptom management and improved quality of life for those with limited treatment options.

Inclusion Criteria:

• 18 years of age or older at the time of enrollment.

• Has previously been diagnosed with moderate to severe cGvHD OR mild cGvHD with high-risk features (defined as platelet counts < 100 x 109/L at screening).

• Capable of providing informed consent.

• Meets the criteria of steroid-refractory cGvHD after first line therapy at the time of enrollment, as follows:

  • Lack of response or disease progression after prednisone ≥1 mg/kg/day for ≥1 week OR
  • Disease persistence without improvement with prednisone >0.5 mg/kg/day or 1 mg/kg/every other day for ≥4 weeks OR
  • Increase in prednisone dose to >0.25 mg/kg/day after 2 unsuccessful attempts to taper the dose.

• Taking a steroid dose at the time of enrollment that is <0.5mg/kg/day of prednisone or equivalent.

• Absolute neutrophil count ≥ 1.5 × 109/L within 2 weeks (14 days) of enrollment.

• Platelet count ≥ 50 × 109/L within 2 weeks of enrollment.

• ALT and AST ≤ 5 × ULN (<7.5 x ULN if due to liver GvHD) within 2 weeks of enrollment.

• Total bilirubin ≤ 1.5 × ULN within 2 weeks of enrollment.

• Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 using the MDRD-4 variable formula within 2 weeks of enrollment.

• Female patients of childbearing potential will use 2 reliable methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study from the time of study enrollment until 3 months following the discontinuation of all study treatment and agree not to donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this period. Patients of childbearing potential are those who have not been surgically sterilized (i.e. have a documented hysterectomy, or documented bilateral salpingectomy, or documented bilateral oophorectomy) or have not been free from menses for > 2 years. For individuals with permanent infertility due to an alternate medical cause other than the above (e.g. Mullerian agenesis, androgen insensitivity, gonadal dysgenesis) investigator discretion should be applied to determining study entry eligibility. Male patients will use an adequate method of contraception for the course of the study from the time of enrollment to 3 months after discontinuation of all study treatment. These participants must refrain from donating or cryopreserving sperm, be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception (a male condom and an additional highly effective contraceptive method as described in section 4.2.3) when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.

• Patients showing overlap syndrome with components of aGvHD at the time of enrollment are eligible to participate unless the acute component of their overlap syndrome is Grade 3 or 4.

• Must be able and willing to comply with study procedures.

Exclusion Criteria:

• Have never been treated with systemic steroids as first line therapy for cGvHD.

• Receiving >0.5 mg/kg/day of prednisone or equivalent corticosteroids at the time of enrollment.

• Has had prior treatment with a JAK inhibitor or ROCK2 inhibitor within 8 weeks of enrollment. Participants who received a JAK inhibitor for aGvHD are eligible only if they achieved CR or PR prior to screening.

• Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been initiated and, at the time of screening, no signs of infection are present.

• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment, or is at risk for HBV reactivation (i.e., positive HBsAg) within 4 weeks of enrollment. Participants with negative HBsAg and positive total HBc antibody may be included if HBV DNA is undetectable at the time of screening. Participants who are positive for HCV antibody are eligible only if PCR is negative for HCV RNA. Participants whose immune status is unknown or uncertain must have results confirming immune status before enrollment. Prior serology results within 2 years are acceptable for determining eligibility.

• Known active infection or history of human immunodeficiency virus (HIV).

• Evidence of relapsed primary hematologic disease, or receipt of treatment for relapse after the allo-HCT was performed. Patients treated with Donor Lymphocyte Infusion (DLI) who have developed GvHD will not be excluded if the primary hematological disease has resolved.

• Maintenance therapy for the primary hematologic disease started within 4 weeks before initiation of study treatment (Cycle 1 Day 1) or plans to start maintenance therapy after Day 1.

• Participants on mechanical ventilation,requiring oxygen support or with a FEV1 < 30%.

• History or current diagnosis of cardiac disease indicating significant risk of safety for participation in the study, such as uncontrolled or significant cardiac disease, including any of the following:

  1. Recent myocardial infarction (within 6 months of enrollment)
  2. New York Heart Association Class III or IV congestive heart failure
  3. Unstable angina (within 6 months of enrollment)
  4. Clinically significant (symptomatic) cardiac arrhythmias (e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker).

• Uncontrolled hypertension, defined as blood pressure that remains above 130/80 mmHg in spite of concurrent use of three antihypertensive agents of different classes.

• Patients with known active CNS disease (malignant involvement of CNS).

• Patients with active acute GvHD grade III-IV.

• History or other evidence of severe illness or any other conditions that would make the patient, in the opinion of the treating Investigator, unsuitable for the study (such as malabsorption syndromes, poorly controlled psychiatric disease or coronary artery disease).

• Known hypersensitivity to belumosudil, ruxolitinib or any of their excipients

• Patients unable to swallow oral medications

• Female participants who are pregnant or breastfeeding