Safety and Efficacy of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

A Phase III Randomized Open-label Multi-center Study of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

Assess the efficacy and safety of ruxolitinib compared to Best Available Therapy (BAT) in patients with corticosteroid-refractory acute graft vs. host disease (aGvHD) after allogeneic stem cell transplantation.

This randomized, phase III, open-label study investigated the efficacy and safety of ruxolitinib vs. BAT added to the patient's immunosuppressive regimen in adults and adolescents (≥ 12 years old) with grade II-IV Steroid-refractory Acute Graft vs. Host Disease (SR-aGvHD). During the screening period, patients were monitored for a diagnosis of SR-aGvHD, which was defined as patients who had high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with CNI, who either:

1. Progressed based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR

2. Failed to achieve at a minimum a partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR

3. Failed corticosteroid taper defined as fulfilling either one of the following criteria:

   • Requirement for an increase in the corticosteroid dose to methylprednisolone ≥ 2 mg/kg/day (or equivalent prednisone dose ≥ 2.5 mg/kg/day) OR
   • Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days.

Patients meeting eligibility criteria were randomized 1:1 to receive either ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs III vs IV).

Study treatment began on Day 1 (no later than 72 hours after randomization) followed by regular visits for assessments of efficacy and safety. Study treatment was administered until the patient met any of the criteria for discontinuation of study treatment or, in responders (i.e. patients achieving PR or CR) until the dosing schedule for ruxolitinib or BAT was completed.

All responders were to be tapered off during the treatment period by, first tapering from corticosteroids, followed by CNI and ruxolitinib. A slow tapering extending beyond 24 weeks was permitted for ruxolitinib at Investigator's discretion rather than an abrupt cessation, as the latter could result in an aGvHD flare.

During the Treatment Period, patients randomized to BAT could have crossed over to ruxolitinib between Day 28 and Week 24 if they:

• Failed to meet the primary endpoint response definition (CR or PR) at Day 28 OR
• Lost the response thereafter and met criteria for progression, mixed response, or no response, necessitating new additional systemic immunosuppressive treatment for aGvHD.

AND

- Did not have signs/symptoms of chronic Graft vs. Host Disease (cGvHD) (overlap syndrome, progressive, or de novo cGvHD)

Patients who crossed over to ruxolitinib were followed until completion of treatment with ruxolitinib and received the same treatment and tapering schedule as patients randomized to ruxolitinib treatment.

The End of Treatment (EOT) visit occurred when the patient completed the study treatment period or earlier if the patient met any of the criteria for discontinuation of study treatment.

Patient's treatment period was up to 6 months (Week 24). However, ruxolitinib taper could be delayed up to 2 years from randomization due to an aGvHD flare or other safety concerns.

Inclusion Criteria:

• Have undergone Allogeneic Stem Cell Transplanttaion (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

• Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.

• Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:

  • Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
  • Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,OR
  • Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:

• Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day) , OR

• Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days.

Exclusion Criteria:

• Has received more than one systemic treatment for steroid refractory aGvHD.
• 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.
• Evidence of uncontrolled viral infection including Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Human Herpes Virus-6 (HHV-6), Hepatitis Virus (HBV), or Hepatitis C Virus (HCV) based on assessment by the treating physician.
• Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.