A Phase 3 Randomized, Historically-Controlled Clinical Trial Investigating the Use of Defibrotide in the Treatment of Severe Veno-Occlusive Disease Post-SCT: A Novel Approach to the Validation of a Promising New Drug for the Treatment of a Life Threatening Disease.
Authors: Richardson Paul , Kernan Nancy , Tomblyn Marcie , Martin Paul , Arai Sally , Brochstein Joel , Guinan Eva , Steinbach Gideon , Nemecek Elizabeth , D’Agostino Ralph , Revta Carolyn , Hannah Alison , Iacobelli Massimo , Soiffer Robert 
Published: October 2019

Abstract
Introduction: Veno-occlusive disease (VOD) with multi-organ failure (MOF) has an extremely poor prognosis, with mortality at day (D) +100 after SCT ≥80%. A prior randomized phase 2 study (n=150) comparing 2 doses of defibrotide (DF) demonstrated complete response (CR) in 46% of patients (pts) with severe VOD, and D+100 survivorship of 41%. CR with DF therapy correlated closely with survival, with >90% of pts achieving a CR living to D+100 post SCT, and best dose of DF was 25 mg/kg/day. A large, multi-center, international phase 3 trial is now being conducted, comparing the use of DF (6.25 mg/kg IV q6h) in pts with VOD/MOF post SCT to a rigorous historical control.
Methods: Eligible pts (adult and pediatric) met Baltimore criteria (total bilirubin ≥ 2.0 mg/dL; and ≥ 2 of the following: hepatomegaly, ascites or 5% weight gain) by D +21 and were diagnosed with either severe renal or pulmonary dysfunction by D +28. Exclusion criteria included pre-existing cirrhosis, viral hepatitis, GvHD involving liver or gut, clinically significant bleeding or inability to maintain blood pressure except with multiple pressors. To create the comparator arm, each site performed a retrospective screen of SCT pts: cohorts of 133 pts were sequentially reviewed. All pts who met Baltimore criteria and had MOF were subsequently assessed by 2 independent experts blinded to outcome data (CR, survival and/or autopsy information) to confirm eligibility. Projected sample size (80 in each group) was based on an estimated 20% survivorship to D+100 in the historical control arm compared to 40% in the DF-treated group. Interim analysis (after 40 pts were enrolled) is being performed to confirm treatment difference and sample size.
Results: In the DF-treated group, 52 pts have been enrolled across 36 sites to date. The interim analysis of D+100 survival and CR is in process and final analysis will follow upon study completion. For the historical control database, 4065 charts have been reviewed to date. In the treatment arm, toxicities related to DF have been minimal and generally manageable, although 2 pts with intercurrent severe coagulopathy, sepsis and platelet-refractory progressive VOD/MOF experienced serious hemorrhage (CNS and GI).
Conclusions: This phase 3 study of DF for the treatment of severe VOD post SCT is the first comparative study of its kind in this life-threatening disease. DF has been generally well tolerated and toxicity has been consistent with prior studies, with CR rate and D+100 survival data pending. Results from this novel design should provide validation of DF as therapy for established VOD/MOF in pts with a high risk of mortality and for whom no effective alternative treatment exists.