Abstract CT308: Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic dysfunction
Authors: Abou-Alfa Ghassan K. , Lewis Lionel D. , LoRusso Patricia , Maitland Michael , Cheeti Sravanthi , Colburn Dawn , Williams Sarah , Simmons Brian , Graham Richard A. , Chandra Priya 
Published: August 2015

Abstract
Background: Vismodegib is an inhibitor of the hedgehog signaling pathway approved for treatment of advanced basal cell carcinoma. Pharmacokinetics (PK) and safety of vismodegib in patients (pts) with hepatic dysfunction are unknown.
Methods: Pts with advanced solid malignancies and hepatic impairment (HI) were enrolled into 4 cohorts as defined by NCI Organ Dysfunction Working Group Criteria: normal (bilirubin [bili] &lt; upper limit of normal [ULN]), mild (ULN&lt;bili ≤1.5xULN), moderate (1.5xULN&lt;bili ≤3xULN), and severe (3xULN&lt;bili&lt;10xULN) dysfunction. Pts received 150 mg of oral V/d for 8 days. Predose blood PK samples on Days 1, 3, 5, and 8 were collected; additionally on Day 8, serial blood and urine samples were collected up to 24 hours post-dose. vismodegib therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent. Safety and tolerability were assessed throughout the study and up to 45 days after the last dose of vismodegib.
Results: The average concentration of vismodegib in semen on Day 8 was 1.16 μM, approximately 7% of the average Css observed in plasma from these same male patients of the normal cohort (n = 3) (Table 1). Best response among the 21 patients with HCC was 38% stable disease, 19% disease progression, and 43% not assessed.
Conclusion: HI does not appear to impact vismodegib PK. However, the study is influenced by the high number of patients with HCC with advanced cirrhosis, rendering it difficult to draw any causality relationships between DLT and SAE, and vismodegib. This is confirmed by inability to deduce any correlation between Css values and AST or total bilirubin concentrations. Stable disease is reported in 38% of patients with HCC. Further study of vismodegib in pts with severe HI and HCC should be carefully considered within the context of the DLT and SAE events reported herein.
ParameterNormal (n = 9)Mild (n = 8)Moderate (n = 8)Severe (n = 6)DemographicsMedian Age (years)6764.56865n (%) male8 (88.9%)5 (62.5%)6 (75%)5 (83.3%)n (%) ECOG 0/1/23 (33.3%)/ 6 (66.7%) /02 (25%)/ 4 (50%) / 2 (25%)0/8 (100%) /00/5 (83.3%)/ 1 (16.7%)Cancer diagnosisBasal Cell Carcinoma n (%)1 (11.1%)000Colorectal Cancer n (%)2 (22.2%)001 (16.7%)Hepatocellular Carcinoma (HCC) n (%)5 (55.6%)5 (62.5%)6 (75%)5 (83.3%)Other n (%)1 (11.1%)3 (37.5%)2 (25%)0Safety and tolerabilityMedian Duration of Therapy (days)(range)65 (43 - 225)28.5 (8 - 64)27.5(7 - 56)20(2 - 103)Total cumulative dose (mg) (range)9750 (5400 - 33750)4050 (1200 - 8100)3975 (1050 - 8100)3000 (300 - 15450)DLT Hyperbilirubinemia0012Deaths Due to Progression of Disease0131AE led to Withdrawal of V01 (Intracranial bleed)1 (Hyperbilirubinemia) and 2 (GI bleeds)2 (Hyperbilirubinemia) 1 (Leukocytosis) 1 (Fatigue) 1 (Hyponatremia)PK ParameterNormal (n = 9)Mild (n = 8)Moderate (n = 6)Severe (n = 3)AUC0-24hr (μM*hr) Median/ Geometric Mean Ratio (90% CI)409/Comparator605/1.24(0.9-1.7)562/1.31(0.9-1.9)368/0.86(0.5-1.4)Cmax (μM) Median/ Geometric Mean Ratio (90% CI)18.1/Comparator27.4/1.3(0.95-1.8)26.9/ 1.3(0.9-1.8)17.1/0.87(0.5-1.4)Css (μM) Median/ Geometric Mean Ratio (90% CI)17/Comparator24.3/1.24(0.9-1.7)24.5/1.27(0. 9-1.8)15.7/0.88(0.6-1.4)Median Alpha-1-Acid Glycoprotein (AAG) concentration (μM)18.825.421.514.2
Citation Format: Ghassan K. Abou-Alfa, Lionel D. Lewis, Patricia LoRusso, Michael Maitland, Sravanthi Cheeti, Dawn Colburn, Sarah Williams, Brian Simmons, Richard A. Graham, Priya Chandra. Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic dysfunction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT308. doi:10.1158/1538-7445.AM2015-CT308