The benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas was studied in international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021). This study was registered with ClinicalTrials.gov, number NCT01440088. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (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).

TH-302 strongly inhibited the growth of both SCCVII and HT29 cells under hypoxia. The IC50 under hypoxia [IC50 (0.1% O2)] was 31.2±8.1 µM for SCCVII and 79.4±28.6 µM for HT29 cells, respectively. The IC50 under aerobic conditions [IC50 (21% O2)] was estimated to be >200 µM for both cell lines. These results suggest that TH-302 is significantly activated under hypoxic microenvironment to release the Br-IPM effecter moiety, thereby inhibiting cell growth.