Purpose
Nemorubicin hydrochloride (below referred to as nemorubicin) is a third generation doxorubicin (DX) derivative, which was selected for clinical trials in hepatocellular carcinoma (HCC) based on: - the new mechanism of action, which turned out to be different from that of anthracyclines, since it acts primarily through topoisomerase I and is effective regardless the phase of the cell cycle; - the overcoming of anticancer drug-resistance and the activity in cells with up-regulation of the nucleotide excision repair (NER) pathway, which is involved in the repair of lesions caused by several anticancer drugs including platinum derivatives; - the reduced cardiotoxicity observed in experimental models; - its metabolic pathway, CYP450-mediated, which leads to the formation of active metabolites in the liver. The antitumor activity in hepatic lesions observed in the initial clinical studies, with nemorubicin administered by intravenous route to patients (pts) with solid tumors (Vasey, Cancer Research 1995; de Takats, Proc ECCO 9, 1997), suggested the investigation of the compound via loco-regional treatment in HCC. In particular, the loco-regional administration was employed in the attempt to maximize antitumor activity, while limiting systemic toxicity.
Material and methods
Loco-regional administration of nemorubicin via intrahepatic artery (IHA) has been tested in two Phase I and one Phase II clinical studies. In the Phase I setting, two administration modalities were evaluated: - through the common hepatic artery in saline as 30 min. infusion every 4 weeks (q4w) (European trial in pts with unresectable HCC, or metastatic colorectal cancer, or cholangiocarcinoma); - through superselective IHA in iodinated oil as 5-10 min. infusion q6-8w (Chinese trial in pts with AJCC stage II or stage III unresectable HCC). The Phase II trial was conducted in China in pts with AJCC stage II-IIIA unresectable HCC. According to the Chinese common practice, nemorubicin was administered via superselective IHA in iodinated oil at 600 mcg/m² q6w.
Results
Overall, 46 pts were treated with nemorubicin in the Phase I setting (22 pts in the European trial and 24 pts in the Chinese trial). Nemorubicin showed a manageable safety profile with both administration modalities, up to a dose of 600 mcg/m² every 4-6 weeks. In these two Phase I studies, the DLT was found to be CTCAE Grade 3-4 elevations in transaminases, rapidly reversible and clinically asymptomatic; the maximum tolerated dose (MTD) was reached at 800 mcg/m² and the recommended Phase II dose was 600 mcg/m². In both trials, the most frequent toxicities were nausea/vomiting, asthenia (mostly mild/moderate), and reversible transaminase elevations. In the European trial, only Grade 1-2 hematological toxicity occurred without evidence of cumulative toxicity. In the Chinese trial only in three cases the hematological toxicity had maximum severity Grade 3, was of short duration and with full recovery within 7-11 days.The Phase II data (on 32 treated pts) confirmed the good safety profile of nemorubicin, with most Grade 1-2 reversible events and no cumulative liver toxicity. Nausea and vomiting were mainly of severity Grade 1-2, characterized by an early onset followed by a sometimes spontaneous recovery in 1-3 days. As for hematology, Grade 1-2 leukopenia/neutropenia occurred in a few pts and no trend to cumulative toxicity was reported on platelets (maximum Grade 3 thrombocytopenia in 9.4% of pt, all with Grade 2 at study entry). Transient non-cumulative transaminases elevations were reported, reaching maximum Grade 3 in about 41% (SGOT) and 19% (SGPT) of pts.Overall, 57 pt with unresectable HCC were evaluable for efficacy: nemorubicin demonstrated a response rate (CR, PR) of 19.3% (11/57; 95% c.i. 10-31.9%). Notably, objective responses were even observed at doses as low as 200 mcg/m², ie at a dose equivalent to 1/3 of the Phase II dose and almost devoid of toxicity. In addition, disease stabilizations lasting > 3 months (median duration 4.5 months, range 3-12.5 months) were reported in 17/57 (29.8%) pts, most of whom with advanced stage of disease at study entry (AJCC stage III, IIIA, IVA). The compound is currently in Phase I-II clinical evaluation for the treatment of HCC via IHA in saline as a single agent and in combination.
Conclusion
The evidence of efficacy in HCC acquired in the clinical trials conducted in Europe and in China, together with the better tolerability of nemorubicin by IHA route versus intravenous route, have supported further investigations in HCC by loco-regional administration. In addition, the wide therapeutic window and large safety margin observed with the IHA administration, suggested the possibility to improve the therapeutic potential of nemorubicin through combination with other anticancer agents.