A phase I/II study to assess the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) infusion of MB07133 in subjects with unresectable hepatocellular carcinoma (HCC). Free

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MB07133 is a novel cytarabine (araC) monophosphate prodrug that targets production of the active form of araC, araC triphosphate (araCTP), to the liver. In this ongoing study, the primary objectives are to determine the maximum tolerated dose, toxicity profile (NCI-CTC 2.0),PK and antitumor activity of MB07133 in patients (pts) with unresectable HCC. MB07133 is administered as a continuous IV infusion at escalating doses (300, 600, 1200, 1800, & 2400 mg/m²/d) with 3-6 pts/cohort during the first 7 days of a 28-day cycle until disease progression or unacceptable toxicity occurs.

Twenty-eight pts with Child-Pugh Class A liver function have been enrolled. The median age is 57 (20-75) yrs, and the pts are primarily male (96%), Asian (86%), hepatitis B (HBV) positive (82%), cirrhotic (68%) and 36% have extra-hepatic disease. Sixty-eight % of pts had been previously treated by surgery and/or other nonsurgical therapy. Pts had a mean CLIP score of 1.7 and a mean baseline tumor burden of 16.4 cm.

A total of 90 cycles have been administered (mean 3.4 cycles/pt; range 1-20 cycles). Ten pts (39%) received > 3 cycles of treatment, and 3 pts received > 12 cycles. To date, a total of 6 cycle 1 treatment-related dose limiting-toxicities (DLTs) has been reported, of which 4 (67%) were mild to moderate in severity (grade 2-3 neutropenia, hypoalbuminemia, increased alkaline phos. or ascites). There was one grade 4 toxicity (increased bilirubin). Nineteen % of pts discontinued the study due to AEs. No infectious adverse events (AEs) were associated with neutropenia. All drug-related hematological and hepatic AEs were mild to moderate in severity and completely reversible. No evidence of HBV reactivation was observed. Eight pts experienced 13 serious adverse events (SAEs) with one being drug-related (jaundice); the remaining 12 (92%) SAEs were unrelated or unlikely related to study drug.

MB07133 and araC both exhibited predictable dose-linear plasma PK. AraC concentrations in the plasma were low (< 1% of MB07133 levels), which is consistent with previous animal studies, demonstrating that MB07133 targets araCTP production in the liver. MB07133 and araC plasma PK were comparable in cirrhotic and non-cirrhotic pts.

Tumor measurements at baseline, after cycle 1, and every 2 cycles thereafter were assessed retrospectively by an independent radiologist. Seven pts (27%) had intra-hepatic tumor shrinkage (0.4-35%), and median survival of 65 weeks (with 4 of the 7 currently alive). The median overall survival was 43 weeks. Three pts received > 12 cycles of treatment with one pt at 20 cycles.

Conclusions:To date,MB07133 has been well tolerated at doses up to 2400 mg/m²/d in pts with unresectable HCC. The intra-hepatic tumor response observed in this study, although preliminary, warrants further investigation in Phase 2.