Title: Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial

Tap, WD et al.


What You Need to Know:

For patients with advanced, unresectable, or metastatic soft-tissue sarcomas, adding evofosfamide, a prodrug of bromo-isophosphoramide mustard, to doxorubicin did not improve overall survival compared to treatment with doxorubicin alone.

Trial Design:

  • Open-label, multicenter, phase 3 study evaluated whether adding evofosfamide to doxorubicin was beneficial for the treatment of advanced, unresectable, or metastatic soft-tissue sarcomas
  • 640 patients were randomized (1:1) “to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles)”
  • After six cycles of treatment was complete, patients receiving doxorubicin only were followed up expectantly, while patients receiving combination therapy continued treatment with evofosfamide only until progression of disease was documented
  • Primary endpoint: overall survival; utilized intention-to-treat analysis
  • Safety: analysis included all patients who received study medication

Key Outcomes:

  • 323 patients received doxorubicin monotherapy; 317 patients received combination therapy with doxorubicin + evofosfamide
  • Overall survival outcome was not attained (HR: 1.06; 95% CI: 0.88, 1.29; P=0.527)
  • Median overall survival: 18.4 months (95% CI: 15.6, 22.1) for doxorubicin + evofosfamide patients vs 19.0 months (95% CI: 16.2, 22.4) for doxorubicin only patients
  • Most common adverse events grade 3 or higher experienced by doxorubicin + evofosfamide patients vs doxorubicin patients, respectively: anemia (48% vs 21%), neutropenia (15% vs 30%), febrile neutropenia (18% vs 11%), leukopenia (7% vs 6%), decreased neutrophil count (10% vs 13%), and decreased white blood cell count (13% vs 11%)
  • Patients receiving combination therapy not only experienced more grade 3-4 thrombocytopenia compared to monotherapy patients (14% vs 1%, respectively), but also experienced more grade 3-4 stomatitis as well (8% vs 2%, respectively)
  • Serious adverse events: experienced by 46% of patients in the doxorubicin + evofosfamide group vs 32% of patients in the monotherapy group
  • Five treatment-related deaths occurred in the doxorubicin + evofosfamide group: sepsis (n=2), septic shock (n=1), congestive cardiac failure (n=1), unknown cause (n=1); 1 treatment-related death occurred in the doxorubicin group: lactic acidosis (n=1)