Doxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC. Phase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3?trial, evaluating five-dose levels from 10 to 40?mg/m(2) with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30?mg/m(2) of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints. In phase I, haematological and respiratory limited toxicities were reported at 35 and 40?mg/m(2), giving MTD at 30?mg/m(2). Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30?mg/m(2) DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95%?CI 8.2 to 34.1) in DT group and 15 months (95%?CI 8.0 to 18.8) in BSC group (p<0.05). The authors concluded that DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen.
Trial registration number: EUDRACT 2006-004088-77; Results.
Authors: Merle P, Camus P, Abergel A, Pageaux GP, Masliah C, Bronowicki JP, Zarski JP, Pelletier G, Bouattour M, Farloux L, Dorval E, Verset G, Si-Ahmed SN, Doffoel M, Couzigou P, Taieb J, Vasseur B, Attali P. ; Full Source: ESMO Open. 2017 Oct 23;2(4): e000238. doi: 10.1136/esmoopen-2017-000238. eCollection 2017.