Trial Outcomes & Findings for A Study of Vismodegib in Patients With Advanced Solid Malignancies Including Hepatocellular Carcinoma With Varying Degrees of Renal or Hepatic Function (NCT NCT01546519)

Last Updated: 2016-05-23

Results Overview

Maximum observed plasma Concentration (Cmax) \& Concentration at steady-state (Css) following multiple doses of vismodegib (150 mg QD) were analyzed. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated. Blood samples for assessing Cmax and Css for analysis were collected following multiple oral doses of vismodegib at pre-dose and at 0.5, 1, 2, 4, 8 and 24 hours post-dose on Day 8. From the plasma concentration-time curve, the PK parameter Cmax and Css were determined by standard non-compartmental analysis using WinNonlin

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

31 participants

Primary outcome timeframe

Day 1,2,4 and 0, 0.5, 1, 2, 4, 8 and 24 hours post dose on Day 8

Results posted on

2016-05-23

Participant Flow

This was an open-label study with no randomization. Participants were categorized according to their baseline renal and hepatic function, and assigned to one of the five cohorts.

After assessing the additional data since the study initiation and after discussions with regulators, the sponsor concluded that renal impairment does not impact the pharmacokinetics of vismodegib and, therefore, a dedicated renal impairment cohort was eliminated.

Participant milestones

Participant milestones
Measure	Control Cohort With Normal Renal and Normal Hepatic Function Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60 Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60 Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60 Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
Overall Study STARTED	9	8	8	6
Overall Study Safety-Evaluable Participants	9	8	8	6
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	9	8	8	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Control Cohort With Normal Renal and Normal Hepatic Function Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60 Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60 Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60 Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
Overall Study Adverse Event	0	0	1	1
Overall Study Death	0	1	3	1
Overall Study related to disease progression	2	2	2	1
Overall Study Physician Decision	6	5	2	3
Overall Study Withdrawal by Subject	1	0	0	0

Baseline Characteristics

A Study of Vismodegib in Patients With Advanced Solid Malignancies Including Hepatocellular Carcinoma With Varying Degrees of Renal or Hepatic Function

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=9 Participants Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=8 Participants Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=8 Participants Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=6 Participants Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Total n=31 Participants Total of all reporting groups
Age, Continuous	63.3 years STANDARD_DEVIATION 12.6 • n=5 Participants	60.6 years STANDARD_DEVIATION 14.1 • n=7 Participants	65.8 years STANDARD_DEVIATION 10.7 • n=5 Participants	64.0 years STANDARD_DEVIATION 8.4 • n=4 Participants	63.4 years STANDARD_DEVIATION 11.4 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants	5 Participants n=4 Participants	24 Participants n=21 Participants

PRIMARY outcome

Timeframe: Day 1,2,4 and 0, 0.5, 1, 2, 4, 8 and 24 hours post dose on Day 8

Population: Pharmacokinetic (PK) Population: A participant was considered evaluable for the PK analyses if he or she had a full profile of vismodegib samples

Outcome measures

Outcome measures
Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=9 Participants Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=8 Participants Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=6 Participants Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=3 Participants Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib Cmax	23.6 micromolar Standard Deviation 9.39	30.7 micromolar Standard Deviation 13.10	30.5 micromolar Standard Deviation 11.60	20.5 micromolar Standard Deviation 9.53
Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib Css	21.6 micromolar Standard Deviation 9.17	26.9 micromolar Standard Deviation 12.4	27.2 micromolar Standard Deviation 10.5	19.1 micromolar Standard Deviation 9.11

PRIMARY outcome

Timeframe: Day 1, 2, 4 and 0, 0.5, 1, 2, 4, 8 and 24 hours postdose on Day 8

Population: Pharmacokinetic (PK) Population: A participant was considered evaluable for the PK analyses if he or she had a full profile of vismodegib samples

The steady state pharmacokinetic profile following oral administration of multiple doses of vismodegib included determining the area under the curve over the dosing interval (AUC\[0-24 hours\]). The AUC\[0-24 hrs\]) was determined by standard non-compartmental analysis using WinNonlin. Blood samples were collected at pre-dose and at 0.5, 1, 2, 4, 8 and 24 hours post-dose on Day 8 to estimate AUC(0-24 hrs).

Outcome measures

Outcome measures
Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=9 Participants Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=8 Participants Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=6 Participants Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=3 Participants Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib	512 Micromolar*hour Standard Deviation 222	639 Micromolar*hour Standard Deviation 304	667 Micromolar*hour Standard Deviation 274	437 Micromolar*hour Standard Deviation 197

SECONDARY outcome

Timeframe: 24 hr total interval on Day 8

Population: Pharmacokinetic (PK) Population: A participant was considered evaluable for the PK analyses if he or she had a full profile of vismodegib samples. Participants available at particular time point for assessment were included in the analysis.

The percentage of dose vismodegib excreted in urine over a 24-hr total interval was estimated

Outcome measures

Outcome measures
Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=8 Participants Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=7 Participants Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=3 Participants Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=3 Participants Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
The Percentage of Dose of Vismodegib in 24-hour Total Urine	0.792 % Dose Excreted in 24 hr Standard Deviation 0.579	0.283 % Dose Excreted in 24 hr Standard Deviation 0.253	0.104 % Dose Excreted in 24 hr Standard Deviation 0.0485	0.201 % Dose Excreted in 24 hr Standard Deviation 0.135

SECONDARY outcome

Timeframe: 0, 0.5, 1, 2, 4, 8 and 24 hours postdose on Day 8

Renal clearance (CLR) is defined as the apparent total clearance of the drug from plasma after oral administration.

Outcome measures

Outcome measures
Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=8 Participants Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=7 Participants Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=3 Participants Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=3 Participants Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
Renal Clearance of Vismodegib	6.76 Liter/hour Standard Deviation 5.73	1.97 Liter/hour Standard Deviation 2.24	0.618 Liter/hour Standard Deviation 0.31	2.06 Liter/hour Standard Deviation 1.53

SECONDARY outcome

Timeframe: 24 hr total interval on Day 8

The amount of total vismodegib excreted in urine over a 24-hr total interval (Ae0-24hr) was estimated.

Outcome measures

Outcome measures
Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=8 Participants Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=7 Participants Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=3 Participants Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=3 Participants Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr)	1.19 milligrams/24 hour Standard Deviation 0.869	0.425 milligrams/24 hour Standard Deviation 0.380	0.156 milligrams/24 hour Standard Deviation 0.0728	0.301 milligrams/24 hour Standard Deviation 0.203

SECONDARY outcome

Timeframe: Up to 8 days

Population: PK population was the anticipated population for analysis. However, this outcome measure was not analyzed due to the minimal fluctuation of vismodegib concentrations at steady state.

Tmax is the time to reach maximum plasma concentration of vismodegib. This was a pre-specified PK parameter. However, due to minimal fluctuation of Vismodegib concentrations at steady state, this parameter could not be determined.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 8 days

Population: PK population was the anticipated population for analysis. However, this outcome measure was not analyzed due to the minimal fluctuation of vismodegib concentrations at steady state.

Cmin is defined as the minimum observed plasma concentration of Vismodegib. This was a pre-specified PK parameter. However, due to minimal fluctuation of Vismodegib concentrations at steady state, this parameter could not be determined.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 8 days

Population: PK population was the anticipated population for analysis. However, this outcome measure was not analyzed due to the minimal fluctuation of vismodegib concentrations at steady state.

CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in liter/hour (L/hr). This was a pre-specified PK parameter. However, due to minimal fluctuation of vismodegib concentrations at steady state, this parameter could not be determined.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 8 days

Population: PK population was the anticipated population for analysis. However, this outcome measure was not analyzed due to the minimal fluctuation of vismodegib concentrations at steady state.

Apparent Non-Renal Clearance (CLNR) describes the removal of vismodegib by organs other than the kidneys. This was a pre-specified PK parameter. However, due to minimal fluctuation of vismodegib concentrations at steady state, this parameter could not be determined.

Outcome measures

Outcome data not reported

Adverse Events

Control Cohort With Normal Renal and Normal Hepatic Function

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Mild Hepatic Impairment and Normal Renal Function (Mild HI)

Serious events: 4 serious events

Other events: 7 other events

Deaths: 0 deaths

Moderate Hepatic Impairment and Normal Renal Function (Mod HI)

Serious events: 6 serious events

Other events: 8 other events

Deaths: 0 deaths

Severe Hepatic Impairment and Normal Renal Function (Sev HI)

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Roche Trial Information Hotline

F. Hoffmann-La Roche AG

Phone: +41 61 6878333

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights
Publication restrictions are in place

Restriction type: OTHER

Measure	Control Cohort With Normal Renal and Normal Hepatic Function n=9 participants at risk Participants with normal renal and normal hepatic function were included. Normal renal function was defined as Body Surface Area (BSA) - indexed creatinine clearance (CrCl) (mL/min) = / \>= 60 Normal hepatic function was indicated by total bilirubin (TB) \<= upper limit of normal (ULN) range and aspartate transaminase (AST) \<= ULN. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Mild Hepatic Impairment and Normal Renal Function (Mild HI) n=8 participants at risk Participants with mild hepatic impairment and normal renal function were included. Mild Hepatic was defined as = TB\<=ULN, AST\>ULN; OR ULN\<TB\<=1.5× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Moderate Hepatic Impairment and Normal Renal Function (Mod HI) n=8 participants at risk Participants with moderate hepatic impairment and normal renal function were included. Moderate hepatic impairment was defined as 1.5 × ULN\< TB\<3× ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.	Severe Hepatic Impairment and Normal Renal Function (Sev HI) n=6 participants at risk Participants with severe hepatic impairment and normal renal function were included. Severe hepatic impairment is defined as 3×ULN\<TB\<10×ULN, AST any Normal renal function was defined as BSA - indexed CrCl (mL/min) = / \>= 60. Participants were administered 150 mg oral vismodegib once daily for 8 consecutive days (Day 1 to Day 7 doses were taken with or without food; Day 8 dose was administered on an empty stomach) at approximately the same time with about 240 mL of water.
Gastrointestinal disorders Abdominal pain	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	25.0% 2/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	25.0% 2/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Ascites	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Haematemesis	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Nausea	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Oesophageal varices haemorrhage	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Small intestinal obstruction	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	33.3% 2/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Hepatobiliary disorders Cholangitis	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Infections and infestations Pneumococcal sepsis	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	16.7% 1/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Infections and infestations Wound infection	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Mediastinal haemorrhage	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Pleural effusion	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Cardiac disorders Atrial fibrillation	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
General disorders Chills	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
General disorders Drug withdrawal syndrome	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
General disorders Fatigue	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
General disorders Pain	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
General disorders Pyrexia	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	16.7% 1/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	11.1% 1/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour Haemorrhage	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.
Nervous system disorders Haemorrhage Intracranial	0.00% 0/9 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	12.5% 1/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/8 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.	0.00% 0/6 • Up to 60 days AEs and SAEs were collected for all the participants who received at least one dose of study medication.