Extracorporal Photopheresis With UVADEX Plus Standard Steroid Treatment for High Risk Acute Graft-versus-host Disease

This study is a single arm phase 2 study for adult patients who have acute GVHD Grade II-IV according to Glucksberg and Ann Arbor score 2 or 3 after first allogeneic stem cell transplantation. The staging according to Glucksberg is based on clinical parameters while Ann Arbor scoring is based on the MAGIC biomarkers. Patients will receive standard acute GVHD treatment consisting of 2mg/kg methylprednisolone plus extracorporeal photopheresis (ECP) with Uvadex. Day 0 of the study will be the first day of ECP, which will be performed 3x weekly for the first 2 weeks, 2x weekly for the next two weeks and thereafter once weekly until day 56. A taper schema for methylprednisolone is proposed but not obligatory. Patients will be followed until one year after start of ECP.

The study plans to enroll 72 patients in order to be able to detect a 15% difference in rate of complete responses on day 28, assuming a type I error rate of 0.05. Patients treated on this study will have three possible comparators:

• Cohort of patients with high risk aGvHD who received standard treatment and whose data were prospectively reported to MAGIC during the last 2 years preceding the trial
• Cohort of patients with high risk aGvHD who received standard treatment and whose data are reported to MAGIC during the trial period
• Cohort of patients with high risk aGvHD treated within the ongoing prospective MAGIC USA phase 2 Trial

Treatment:

Prior to an ECP treatment each patient will be assessed by a physician to verify that the patient is acceptable for ECP treatment. This assessment will include vital signs (diastolic and systolic blood pressures, pulse, temperature) which will be taken prior to and at the end of each ECP treatment. Blood cell counts will be analyzed prior to each treatment. If a patient's WBC count is below 1 X 109/L or platelet count is below 20 X 109/L ECP should be postponed until rise in WBC or platelet counts. Platelet transfusions and use of cytokines is permitted. Whenever possible, peripheral venous access is preferable to central venous catheters. In patients with platelet counts below 40 X 109/L acid citrate dextrose (ACD) instead of heparin should be used for ECP. When severe acute infections occur during study ECP should be discontinued until the infection has been controlled under appropriate therapy

Topical therapy for acute GvHD of the skin and non-absorbable steroids for GI GvHD are allowed. Ancillary/supportive care measures for acute GvHD such as the use of anti-motility agents for diarrhea, including octreotide, is allowed at the discretion of the treating physician. Use of ursodiol to prevent/reduce gall bladder sludging, or prevent hepatic transplant complications is also allowed according to institutional guidelines.

In addition to prescribed study drug plus corticosteroids, all patients should receive the following:

• Transfusion support per institutional practice
• Anti-infective prophylaxis against herpes virus is required but otherwise institutional practice can be followed for the medication to be used and the dosing
• Anti-infective prophylaxis against Pneumocystis jiroveci, bacterial and fungal infections according to standard institutional guidelines.
• Anti-infective prophylaxis against fungi (aspergillosis) is required but otherwise institutional practice can be followed
• Pre-emptive monitoring and treatment for CMV and EBV infections are required but otherwise institutional practice can be followed.

Efficacy and stopping rules:

Efficacy of the treatment plan will be assessed by the proportion of patients with complete response at day 28. The treatment plan will be considered efficacious if it produces a day 28 CR rate of ≥ 52%, representing an improvement over the day 28 CR rate of approximately 15% achieved with the standard of care. Stopping boundaries for efficacy are presented in Table 5, in terms of the number of observed positive responses out of the total number observed. Our expectation is represented by a prior distribution for a positive response that has a mean of 0.37, or 37%. Characterizing our expectation as a distribution of values, rather than a fixed value, naturally accounts for uncertainty in the response. The prior is based on observed data treating similar patients with the standard of care. More specifically, let θS be the day 28 CR rate of patients treated with the standard of care. Likewise, let θE be the day 28 CR of patients treated with ECP and high dose systemic corticosteroid. Assume that θS ~ beta (37, 63) and θE ~ beta (0.74, 1.26) so that each prior has a mean of 0.37. Let the improvement of the experimental treatment over the standard, δ, be 0.1. The study will be stopped when P (θS + δ >θE |observed data)>0.90.

The boundaries provide guidelines for determining when treatment with ECP and high dose systemic corticosteroid is inferior to what would be expected if patients were treated with the standard of care. We will initiate these guidelines with the 10th outcome, and enroll a maximum of 72 patients.

Further stopping rules:

For the individual patient:

Any of the following criteria will lead to study discontinuation:

• Inter-current illness that prevents further administration of treatment
• Unacceptable adverse event(s)
• Patient voluntarily withdraws from treatment OR
• General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator or Sponsor

The reason for ending protocol therapy and the date the patient was removed from treatment will be documented in the study record. All patients who discontinue treatment should comply with protocol specific follow-up procedures as outlined in Section 13.13. The only exception to this requirement is when a patient withdraws consent for all study procedures.

Patients may withdraw from the study treatment at their request at any time. If they withdraw, they will be asked to perform a study termination visit and be documented in eCRF as "early termination". The reasons should be documented in the eCRF.

For the entire study cohort:

The whole study can be discontinued by the Coordinating Investigator in case of excessive toxicity.

For safety reasons, a study termination visit should be performed and the included patients should be further followed-up until disease progression or death from any cause (relapse or other reason).

Once we have enrolled 10 patients, and for additional patients thereafter, we will assess the cumulative number of patients with overall response and NRM and stop the trial if the observed number responses or NRM equals or exceeds the thresholds specified in section 19.