Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial

BACKGROUND: Withaferin-A (WA), an active principle obtained from a traditional Indian herb known as Ashwagandha or the Indian ginseng, has been shown to prevent and cure urethane-induced lung tumors in mice, and also inhibit the growth of transplanted sarcoma in mice. OBJECTIVES: In this study, we evaluated the safety and pharmacokinetics of WA in patients with advanced stage high-grade osteosarcoma. METHODS: A phase I dose escalation study was planned using the classical 3 + 3 design (C33D). Dose escalation cohorts comprised of 72, 108, 144 and 216 mg of WA administered in two to four divided doses per day. Three patients were enrolled in each cohort and the last patient was observed for at least 30 days for any dose-limiting toxicity before progressing to a higher cohort. Pharmacokinetic studies were performed using high performance liquid chromatography (HPLC) technique with sensitivity up to 50 ng/ml. Safety evaluation including clinical examination, detailed history of adverse events, Liver Function Tests , Renal Function Tests and complete blood counts were performed at each visit. WA was administered daily till progression. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used for grading adverse events. RESULTS: The formulation used was generally well tolerated. Eleven adverse events of grade 1 or grade 2 severity were observed. No grade 3 or grade 4 adverse events were observed. Elevation of liver enzymes (5/11) and skin rash (2/11) was the most common adverse events. Other adverse effects include fatigue, fever, edema, and diarrhea (one each). None of the patients had detectable levels of WA in circulation. CONCLUSION: The formulation was well tolerated. However, WA appears to have low oral bioavailability. Further studies with improved formulations are warranted.