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2572 Background: Nemorubicin is a novel DNA-intercalator with: in vivo synergistic antitumor activity with cDDP; a metabolic pathway mediated by CYP3A4 enzyme leading to formation of effective metabolites at liver level. In this phase I trial nemorubicin + cDDP are administered by intrahepatic artery every four weeks to pts with unresectable HCC to determine MTD, safety, PK profiles, CYP3A4 activity, antitumor activity. METHODS: the study was in two HCC pts populations: intermediate risk (IRP) (CLIP 0-1, bilirubin <1.5 x upper normal limit, no portal vein thrombosis [PVT]); advanced risk (ARP) (CLIP 2, bilirubin <2.5 mg/dL, PVT admitted). In each population, 3-6 pts cohorts were allotted to progressively higher dose levels (DL) based on the number of dose-limiting toxicities (DLTs) in the first cycle. RESULTS: IRP: 25 pts treated and four DL explored (range 200-600 mcg/m(2) nemorubicin + 40-60 mg/m(2) cDDP). DLTs were thrombocytopenia and fatigue; 600 mcg/m(2) nemorubicin + 60 mg/m(2) cDDP was identified as recommended phase II dose (RP2D). Across DL, 5/16 currently evaluable pts had partial response and 7/16 pts had stable disease >3 months. ARP: 8 pts treated and two DL fully explored (200-400 mcg/m(2) nemorubicin + 60 mg/m(2) cDDP). One DLT (hyperbilirubinemia) occurred at DL 600 mcg/m(2) nemorubicin + 60 mg/m(2) cDDP, currently under evaluation. Stable disease >3 months was observed in 2/3 evaluable pts. Overall, the most frequent drug-related adverse events were fatigue (37%), nausea/vomiting (21%), abdominal pain, diarrhoea, constipation (11%). Uncomplicated hematologic toxicity occurred after repeated cycles at 600 mcg/m(2) nemorubicin + 60 mg/m(2) cDDP. Neither cumulative liver toxicity nor renal toxicity occurred at any DL. Nemorubicin plasma levels were near to the detection limit (0.1 ng/mL). Overall AUC increased with nemorubicin dose, with no compound accumulation. CYP3A4 analyses are ongoing for IRP/ARP. CONCLUSIONS: 600 mcg/m(2) nemorubicin + 60 mg/m(2) cDDP is the RP2D for IRP. PK profiles of nemorubicin and cDDP are comparable with those obtained with the compounds administered as single agents. Partial responses and stable diseases >3 months are reported across DL. No significant financial relationships to disclose.


Journal article


J Clin Oncol

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