Phase II trial of nemorubicin hydrocloride (nemorubicin) in combination with cisplatin (cDDP) in patients (pts) with hepatocellular carcinoma (HCC): First step results.
Izzo F., Catino AM., Vogl TJ., Middleton M., Valle JW., Fiore F., Gadaleta CD., Pirotta RM., Martignoni M., Laffranchi B.
4593 Background: Nemorubicin is a novel DNA-intercalator, mainly metabolized in liver by CYP3A4 enzyme and showing synergic antitumor activity with cDDP. The objective of this study was to evaluate the efficacy and adverse effects of nemorubicin administered by intra-hepatic artery in combination with cDDP to unresectable HCC pts. METHODS: The study was in two HCC pt populations: intermediate risk (IRP) (CLIP 0-1, bilirubin < 1.5 x upper normal limit, no portal vein thrombosis [PVT]) and advanced risk (ARP) (CLIP 2, bilirubin < 2.5 mg/dL, PVT admitted). Treatment was repeated every 4-6 weeks for a maximum of six courses, if no toxicity and disease progression occurred. A single-arm, Simon's minimax two-stage design was adopted to evaluate the primary endpoint of tumour response (WHO criteria). In the first step >5/18 responses (IRP) and >2/10 responses (ARP) are needed to proceed with the second step. RESULTS: Twenty-three IRP pts (13 evaluable) and 13 ARP pts (10 evaluable) were enrolled. The median number of treatments was 3 (range 1-6) in IRP (dose 600 mcg/m(2) nemorubicin and 60 mg/m(2) cDDP) and 4 (range 1-4) in ARP (dose 400 mcg/m(2) nemorubicin and 60 mg/m(2) cDDP). In IRP, so far 1 pt (8%) achieved complete response, 3 pts (23%) had partial response (PR), 5 pts (38%) had minor response (MR)/disease stabilization (SD) >3 months. In ARP, 2 pts (20%) had PR, satisfying the first step efficacy criteria. Also, 2 ARP pts (20%) had MR/SD. Overall, the main grade 3 and 4 hematological toxicities were thrombocytopenia (47%), leukopenia (42%), anemia (12%) and neutropenia (6%). Grade 3 and 4 biochemical alterations were aspartate aminotranferase (29%) alanine transferase (24%) and bilirubin increase (12%). The most frequent adverse events were fatigue (35%), vomiting (29%), diarrhoea (24%) and nausea (18%). CONCLUSIONS: Hepatic arterial infusion of nemorubicin with cisplatin showed promising activity in the first step of the study and it was a well tolerated regimen. These encouraging results warrant further development in HCC pts. No significant financial relationships to disclose.