Cancer
Conditions
Brief summary
This is a Phase Ib, open-label, multiple-center, multiple-dose study designed to evaluate the pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies (including hepatocellular carcinoma and lymphoma) that are refractory to standard therapy or for whom no standard therapy exists.
Interventions
DRUGVismodegib
oral repeating dose of 150 mg once daily
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Histologically or cytologically confirmed advanced solid malignancy (including hepatocellular carcinoma and lymphoma) that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective * Eastern Cooperative Oncology Group (ECOG) performance status \</= 2 (Karnofsky \>/=60%) * Acceptable bone marrow functions * Normal or varying degrees of renal or hepatic impairment according to NCI Organ Dysfunction Working Group criteria. * Organ function should be stable for at least 2 weeks before Day 1. In addition, there should be no evidence of acute exacerbation of hepatic/renal disease. * Patients with gliomas or known brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment. Patients with known brain metastases must be at least 4 weeks out from any radiation before starting the protocol (Day 1). * Documented negative serum pregnancy test for women of childbearing potential * For women of childbearing potential, agreement to the use of two acceptable methods of contraception during the study and for 7 months after discontinuation of vismodegib * For men with female partners of childbearing potential, agreement to use a latex, non-latex, or any other male condom and to advise their female partners to use an additional acceptable method of birth control during the study and for 2 months after discontinuation of study drug * Agreement not to donate blood/blood products during the study and for 7 months after discontinuing study drug * For men with normal renal and hepatic function, agreement to provide semen during the vismodegib treatment period for study assessment (optional), but otherwise NOT to donate semen during the vismodegib treatment period and for 2 months after discontinuation of study drug
Exclusion criteria
* Pregnancy or lactation * Chemotherapy, biologic therapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier * Investigational agents within 28 days prior to study entry (Day 1) * Use of Pgp inhibitors within 7 days of Day 1 * Use of gastric pH altering drugs except antacids within 7 days of Day 1 * Major surgery within 14 days prior to treatment (Day 1). Patients with recent major surgery must have recovered from that surgery. Patients who are expected to have any major surgery during the study treatment period should not be enrolled. * Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. History of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of vismodegib or that might affect interpretation of the results from this study or renders the patient at high risk from treatment complications. * Severely impaired renal function (Cohort 2 only) should not have active hemolysis, and should not be on hemodialysis or peritoneal dialysis during the screening and study treatment period (Days 1-9).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Day 1,2,4 and 0, 0.5, 1, 2, 4, 8 and 24 hours post dose on Day 8 | 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 |
| The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib | Day 1, 2, 4 and 0, 0.5, 1, 2, 4, 8 and 24 hours postdose on Day 8 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr) | 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. |
| Time to Maximum Plasma Concentration (Tmax) of Vismodegib | Up to 8 days | 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. |
| The Percentage of Dose of Vismodegib in 24-hour Total Urine | 24 hr total interval on Day 8 | The percentage of dose vismodegib excreted in urine over a 24-hr total interval was estimated |
| Apparent Clearance (CL/F) of Vismodegib | Up to 8 days | 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. |
| Apparent Non-renal Clearance (CLNR/F) of Vismodegib | Up to 8 days | 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. |
| Minimum Plasma Concentration (Cmin) of Vismodegib | Up to 8 days | 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. |
| Renal Clearance of Vismodegib | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 9 |
| 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. | 8 |
| 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. | 8 |
| 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. | 6 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
| Overall Study | Death | 0 | 1 | 3 | 1 |
| Overall Study | Physician Decision | 6 | 5 | 2 | 3 |
| Overall Study | related to disease progression | 2 | 2 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Control Cohort With Normal Renal and Normal Hepatic Function | Mild Hepatic Impairment and Normal Renal Function (Mild HI) | Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | Severe Hepatic Impairment and Normal Renal Function (Sev HI) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 12.6 | 60.6 years STANDARD_DEVIATION 14.1 | 65.8 years STANDARD_DEVIATION 10.7 | 64.0 years STANDARD_DEVIATION 8.4 | 63.4 years STANDARD_DEVIATION 11.4 |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 6 Participants | 5 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 9 | 7 / 8 | 8 / 8 | 6 / 6 |
| serious Total, serious adverse events | 3 / 9 | 4 / 8 | 6 / 8 | 3 / 6 |
Outcome results
Primary
Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib
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
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Cohort With Normal Renal and Normal Hepatic Function | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Cmax | 23.6 micromolar | Standard Deviation 9.39 |
| Control Cohort With Normal Renal and Normal Hepatic Function | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Css | 21.6 micromolar | Standard Deviation 9.17 |
| Mild Hepatic Impairment and Normal Renal Function (Mild HI) | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Css | 26.9 micromolar | Standard Deviation 12.4 |
| Mild Hepatic Impairment and Normal Renal Function (Mild HI) | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Cmax | 30.7 micromolar | Standard Deviation 13.1 |
| Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Cmax | 30.5 micromolar | Standard Deviation 11.6 |
| Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Css | 27.2 micromolar | Standard Deviation 10.5 |
| Severe Hepatic Impairment and Normal Renal Function (Sev HI) | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Cmax | 20.5 micromolar | Standard Deviation 9.53 |
| Severe Hepatic Impairment and Normal Renal Function (Sev HI) | Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib | Css | 19.1 micromolar | Standard Deviation 9.11 |
Comparison: Cmax Mild HI vs. Normal: Based on pooled variance estimates90% CI: [0.95, 1.78]
Comparison: Cmax Moderate HI vs. Normal: Based on pooled variance estimates90% CI: [0.92, 1.83]
Comparison: Cmax Severe HI vs. Normal: Based on pooled variance estimates90% CI: [0.55, 1.37]
Comparison: Css Mild HI vs. Normal: Based on pooled variance estimates90% CI: [0.9, 1.71]
Comparison: Css Moderate HI vs. Normal: Based on pooled variance estimates90% CI: [0.89, 1.8]
Comparison: Css Severe HI vs. Normal: Based on pooled variance estimates90% CI: [0.55, 1.41]
Primary
The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib
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).
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Cohort With Normal Renal and Normal Hepatic Function | 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 |
| Mild Hepatic Impairment and Normal Renal Function (Mild HI) | The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib | 639 Micromolar*hour | Standard Deviation 304 |
| Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib | 667 Micromolar*hour | Standard Deviation 274 |
| Severe Hepatic Impairment and Normal Renal Function (Sev HI) | The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib | 437 Micromolar*hour | Standard Deviation 197 |
Comparison: AUC0-24hr Mild HI vs. Normal: Based on pooled variance estimates90% CI: [0.89, 1.73]
Comparison: AUC0-24hr Moderate HI vs. Normal: Based on pooled variance estimates90% CI: [0.91, 1.89]
Comparison: AUC0-24hr Severe HI vs. Normal: Based on pooled variance estimates90% CI: [0.53, 1.39]
Secondary
Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr)
The amount of total vismodegib excreted in urine over a 24-hr total interval (Ae0-24hr) was estimated.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Cohort With Normal Renal and Normal Hepatic Function | Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr) | 1.19 milligrams/24 hour | Standard Deviation 0.869 |
| Mild Hepatic Impairment and Normal Renal Function (Mild HI) | Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr) | 0.425 milligrams/24 hour | Standard Deviation 0.38 |
| Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr) | 0.156 milligrams/24 hour | Standard Deviation 0.0728 |
| Severe Hepatic Impairment and Normal Renal Function (Sev HI) | Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr) | 0.301 milligrams/24 hour | Standard Deviation 0.203 |
Secondary
Apparent Clearance (CL/F) of Vismodegib
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.
Time frame: 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.
Secondary
Apparent Non-renal Clearance (CLNR/F) of Vismodegib
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.
Time frame: 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.
Secondary
Minimum Plasma Concentration (Cmin) of Vismodegib
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.
Time frame: 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.
Secondary
Renal Clearance of Vismodegib
Renal clearance (CLR) is defined as the apparent total clearance of the drug from plasma after oral administration.
Time frame: 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. Participants available at particular time point for assessment were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Cohort With Normal Renal and Normal Hepatic Function | Renal Clearance of Vismodegib | 6.76 Liter/hour | Standard Deviation 5.73 |
| Mild Hepatic Impairment and Normal Renal Function (Mild HI) | Renal Clearance of Vismodegib | 1.97 Liter/hour | Standard Deviation 2.24 |
| Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | Renal Clearance of Vismodegib | 0.618 Liter/hour | Standard Deviation 0.31 |
| Severe Hepatic Impairment and Normal Renal Function (Sev HI) | Renal Clearance of Vismodegib | 2.06 Liter/hour | Standard Deviation 1.53 |
Secondary
The Percentage of Dose of Vismodegib in 24-hour Total Urine
The percentage of dose vismodegib excreted in urine over a 24-hr total interval was estimated
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Cohort With Normal Renal and Normal Hepatic Function | The Percentage of Dose of Vismodegib in 24-hour Total Urine | 0.792 % Dose Excreted in 24 hr | Standard Deviation 0.579 |
| Mild Hepatic Impairment and Normal Renal Function (Mild HI) | The Percentage of Dose of Vismodegib in 24-hour Total Urine | 0.283 % Dose Excreted in 24 hr | Standard Deviation 0.253 |
| Moderate Hepatic Impairment and Normal Renal Function (Mod HI) | The Percentage of Dose of Vismodegib in 24-hour Total Urine | 0.104 % Dose Excreted in 24 hr | Standard Deviation 0.0485 |
| Severe Hepatic Impairment and Normal Renal Function (Sev HI) | The Percentage of Dose of Vismodegib in 24-hour Total Urine | 0.201 % Dose Excreted in 24 hr | Standard Deviation 0.135 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Vismodegib
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.
Time frame: 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.