Key clinical studies of defibrotide for treatment or prophylaxis of VOD/SOS
| Phase . | Condition . | Design . | Key end points . | Other results . | Conclusions . |
|---|---|---|---|---|---|
| Phase 1 (N = 19)107 | VOD/SOS with MOD/MOF post-HSCT | CUP DF 5-60 mg/kg/d (dose escalation until response/toxicity) | CR: 42%; minimal toxicity at doses tested | Day +100 survival: 32% | CR rate, day +100 survival, and absence of significant DF-associated toxicity was encouraging and warranted further evaluation |
| Phase 2 (N = 149)108 | VOD/SOS with MOD/MOF post-HSCT | Randomized, dose-finding, ≥14 d Arm A, DF 25 mg/kg/dl Arm B, DF 40 mg/kg/d | Day +100 CR: arm A, 49%; arm B, 43% | Day +100 survival: arm A, 44%; arm B, 39% | DF appears effective in treating VOD/SOS with MOD/MOF post-HSCT with low rates of TRAE |
| Overall TRAE incidence: 8% (greater at 40 vs 25 mg/kg/d) | 25 mg/kg/d selected as phase 3 dose | ||||
| Phase 3 historically controlled (N = 134); DF, 102; controls, 3270 | VOD/SOS with advanced MOD/MOF post-HSCT | Nonrandomized comparison of DF 6.25 mg/kg IV every 6 h (25 mg/kg/d) for ≥21 d vs controls | Day +100 CR: DF, 24%; controls, 9% (P = .0131) | Day +100 survival: DF, 38%; controls, 25% (P = .0341, propensity adjusted) | DF improves survival and CR by day +100 in patients with VOD/SOS and MOD/MOF post-HSCT; DF is generally well tolerated |
| Hemorrhagic AE: DF, 65%; controls, 69% | |||||
| Phase 3 T-IND (N = 867 interim); post-HSCT, 766 (10 not treated); post-CT, 101110,111 | VOD/SOS with and without MOD/MOF | Open-label T-IND DF 6.25 mg/kg IV every 6 h (25 mg/kg per day) for ≥21 d | Day +100 survival in post-HSCT patients: 51.2% | Day +100 survival in post-CT patients: 68.3% | Survival rate with DF is approximately 50% in diverse post-HSCT population |
| Phase 3 pediatric prophylaxis (N = 356); DF, 180; controls, 176112 | Pediatric patients (aged <18 y) receiving HSCT | Open-label, randomized, controlled trial of DF 6.25 mg/kg IV every 6 h (25 mg/kg/d) for prophylaxis of VOD/SOS | VOD/SOS incidence: DF, 12% controls, 20% (–7.7% risk difference) | Incidence of AEs, serious AEs, and AEs leading to discontinuation were similar between groups | DF may be effective for preventing VOD/SOS |
| Phase . | Condition . | Design . | Key end points . | Other results . | Conclusions . |
|---|---|---|---|---|---|
| Phase 1 (N = 19)107 | VOD/SOS with MOD/MOF post-HSCT | CUP DF 5-60 mg/kg/d (dose escalation until response/toxicity) | CR: 42%; minimal toxicity at doses tested | Day +100 survival: 32% | CR rate, day +100 survival, and absence of significant DF-associated toxicity was encouraging and warranted further evaluation |
| Phase 2 (N = 149)108 | VOD/SOS with MOD/MOF post-HSCT | Randomized, dose-finding, ≥14 d Arm A, DF 25 mg/kg/dl Arm B, DF 40 mg/kg/d | Day +100 CR: arm A, 49%; arm B, 43% | Day +100 survival: arm A, 44%; arm B, 39% | DF appears effective in treating VOD/SOS with MOD/MOF post-HSCT with low rates of TRAE |
| Overall TRAE incidence: 8% (greater at 40 vs 25 mg/kg/d) | 25 mg/kg/d selected as phase 3 dose | ||||
| Phase 3 historically controlled (N = 134); DF, 102; controls, 3270 | VOD/SOS with advanced MOD/MOF post-HSCT | Nonrandomized comparison of DF 6.25 mg/kg IV every 6 h (25 mg/kg/d) for ≥21 d vs controls | Day +100 CR: DF, 24%; controls, 9% (P = .0131) | Day +100 survival: DF, 38%; controls, 25% (P = .0341, propensity adjusted) | DF improves survival and CR by day +100 in patients with VOD/SOS and MOD/MOF post-HSCT; DF is generally well tolerated |
| Hemorrhagic AE: DF, 65%; controls, 69% | |||||
| Phase 3 T-IND (N = 867 interim); post-HSCT, 766 (10 not treated); post-CT, 101110,111 | VOD/SOS with and without MOD/MOF | Open-label T-IND DF 6.25 mg/kg IV every 6 h (25 mg/kg per day) for ≥21 d | Day +100 survival in post-HSCT patients: 51.2% | Day +100 survival in post-CT patients: 68.3% | Survival rate with DF is approximately 50% in diverse post-HSCT population |
| Phase 3 pediatric prophylaxis (N = 356); DF, 180; controls, 176112 | Pediatric patients (aged <18 y) receiving HSCT | Open-label, randomized, controlled trial of DF 6.25 mg/kg IV every 6 h (25 mg/kg/d) for prophylaxis of VOD/SOS | VOD/SOS incidence: DF, 12% controls, 20% (–7.7% risk difference) | Incidence of AEs, serious AEs, and AEs leading to discontinuation were similar between groups | DF may be effective for preventing VOD/SOS |
CT, chemotherapy; CUP, compassionate use program; DF, defibrotide.
Adapted from Richardson et al102 with permission.