2070 Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (>2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours. [Table: see text]
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