Oncology
Conditions
Brief summary
The primary objective of this study is to evaluate the pharmacokinetics of entospletinib (ENTO) and/or its metabolites (if applicable) in participants with impaired hepatic function (stratified by smoking status, as appropriate) relative to matched, healthy controls.
Interventions
DRUGEntospletinib
Entospletinib 100 mg tablet administered orally
Sponsors
Gilead Sciences
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
Key Inclusion Criteria: * Calculated body mass index from 18 to 40 kg/m\^2 * Not pregnant * Normal electrocardiogram * Participants with impaired liver function must be sufficiently healthy based upon medical history and physical examination, vital signs, and screening laboratory evaluations. Key
Exclusion criteria
* Participation in another clinical study (current or within last 30 days) * HIV, hepatitis B virus, or active hepatitis C virus infection Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose on Day 5 | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). |
| Pharmacokinetic (PK) Parameter: Cmax of ENTO | 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose on Day 5 | Cmax is defined as the maximum concentration of drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | Baseline up to Day 9 plus 30 days | TEAEs are defined as events that meet one of the following criteria: * Any adverse events (AEs) with onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or * Any AEs leading to premature discontinuation of study drug. |
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Baseline up to Day 9 plus 30 days | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each subject. |
Countries
Germany, New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States, New Zealand, and Germany. The first participant was screened on 16 November 2015. The last study visit occurred on 25 October 2017.
Pre-assignment details
102 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Severe Hepatic Impairment Participants with severe hepatic impairment received entospletinib (ENTO) 100 mg tablet twice daily on Days 1-4, and 1 morning dose only on Day 5. | 7 |
| Moderate Hepatic Impairment Participants with moderate hepatic impairment received ENTO 100 mg tablet twice daily on Days 1-4, and 1 morning dose only on Day 5. | 18 |
| Mild Hepatic Impairment Participants with mild hepatic impairment received ENTO 100 mg tablet twice daily on Days 1-4, and 1 morning dose only on Day 5. | 10 |
| Healthy Control Participants with normal hepatic function received ENTO 100 mg tablet twice daily on Days 1-4, and 1 morning dose only on Day 5. | 20 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Enrolled, But Not Treated | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Severe Hepatic Impairment | Moderate Hepatic Impairment | Mild Hepatic Impairment | Healthy Control | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 10.6 | 59 years STANDARD_DEVIATION 8.5 | 58 years STANDARD_DEVIATION 11.4 | 56 years STANDARD_DEVIATION 9.3 | 57 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 3 Participants | 9 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 13 Participants | 7 Participants | 11 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 17 Participants | 9 Participants | 17 Participants | 50 Participants |
| Region of Enrollment Germany | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Region of Enrollment New Zealand | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 5 Participants | 17 Participants | 8 Participants | 19 Participants | 49 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 14 Participants | 5 Participants | 15 Participants | 40 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 | 0 / 7 | 0 / 18 | 0 / 10 | 0 / 20 |
| other Total, other adverse events | 1 / 7 | 4 / 18 | 3 / 10 | 6 / 20 |
| serious Total, serious adverse events | 0 / 7 | 0 / 18 | 0 / 10 | 0 / 20 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUCtau of ENTO
AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Time frame: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose on Day 5
Population: Participants in the PK Analysis Set (all enrolled participants who received at least one dose of ENTO and had at least one evaluable PK concentration data value reported by the PK lab) with available data were analyzed. Healthy control participants may participate in more than one cohorts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Moderate Hepatic Impairment Smoking | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 1788.9 h*ng/mL | Standard Deviation 771.3 |
| Cohort 1: Moderate Hepatic Impairment Non-smoking | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 7490.0 h*ng/mL | Standard Deviation 3805.03 |
| Cohort 1: Healthy Control Matched to Smoking | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 4081.5 h*ng/mL | Standard Deviation 2464.77 |
| Cohort 1: Healthy Control Matched to Non-smoking | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 3318.0 h*ng/mL | Standard Deviation 1788.9 |
| Cohort 2: Severe Hepatic Impairment | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 7036.0 h*ng/mL | Standard Deviation 2814.95 |
| Cohort 2: Healthy Control | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 3402.7 h*ng/mL | Standard Deviation 1771.79 |
| Cohort 3: Mild Hepatic Impairment | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 4071.9 h*ng/mL | Standard Deviation 913.47 |
| Cohort 3: Healthy Control | Pharmacokinetic (PK) Parameter: AUCtau of ENTO | 4123.0 h*ng/mL | Standard Deviation 1874.33 |
90% CI: [24.59, 77.62]
90% CI: [141.85, 384.79]
90% CI: [139.74, 343.84]
90% CI: [77.2, 152.48]
Primary
Pharmacokinetic (PK) Parameter: Cmax of ENTO
Cmax is defined as the maximum concentration of drug.
Time frame: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose on Day 5
Population: Participants in the PK Analysis Set with available data were analyzed. Healthy control participants may participate in more than one cohorts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Moderate Hepatic Impairment Smoking | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 313.1 ng/mL | Standard Deviation 122.39 |
| Cohort 1: Moderate Hepatic Impairment Non-smoking | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 1007.3 ng/mL | Standard Deviation 480.63 |
| Cohort 1: Healthy Control Matched to Smoking | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 582.3 ng/mL | Standard Deviation 326.04 |
| Cohort 1: Healthy Control Matched to Non-smoking | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 497.4 ng/mL | Standard Deviation 292.67 |
| Cohort 2: Severe Hepatic Impairment | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 837.7 ng/mL | Standard Deviation 326.52 |
| Cohort 2: Healthy Control | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 521.1 ng/mL | Standard Deviation 280.65 |
| Cohort 3: Mild Hepatic Impairment | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 569.8 ng/mL | Standard Deviation 166.56 |
| Cohort 3: Healthy Control | Pharmacokinetic (PK) Parameter: Cmax of ENTO | 590.5 ng/mL | Standard Deviation 326.08 |
90% CI: [34.7, 89.42]
90% CI: [132.49, 339.03]
90% CI: [108.17, 271.37]
90% CI: [72.71, 158.51]
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
TEAEs are defined as events that meet one of the following criteria: * Any adverse events (AEs) with onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or * Any AEs leading to premature discontinuation of study drug.
Time frame: Baseline up to Day 9 plus 30 days
Population: Safety Analysis Set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Moderate Hepatic Impairment Smoking | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 14.3 percentage of participants |
| Cohort 1: Moderate Hepatic Impairment Non-smoking | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 22.3 percentage of participants |
| Cohort 1: Healthy Control Matched to Smoking | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 30.0 percentage of participants |
| Cohort 1: Healthy Control Matched to Non-smoking | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 30.0 percentage of participants |
Secondary
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each subject.
Time frame: Baseline up to Day 9 plus 30 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Moderate Hepatic Impairment Smoking | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | 100.0 percentage of participants |
| Cohort 1: Moderate Hepatic Impairment Non-smoking | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | 88.9 percentage of participants |
| Cohort 1: Healthy Control Matched to Smoking | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | 60.0 percentage of participants |
| Cohort 1: Healthy Control Matched to Non-smoking | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | 50.0 percentage of participants |