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To characterize the pharmacokinetics and safety of alpelisib in subjects with hepatic impairment compared to matched healthy control subjects.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Moderate hepatic impairment group | Experimental | Subjects with moderate hepatic impairment with Child-Pugh score 7 - 9 |
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| Severe hepatic impairment group | Experimental | Subjects with severe hepatic impairment with Child-Pugh score 10 - 15 |
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| Matching healthy control group | Experimental | Subjects with apparent normal liver function matched to the hepatic impairment subjects by sex, race, age, and weight. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Alpelisib | Drug | Subjects will receive a single dose of 300 mg alpelisib. |
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| Measure | Description | Time Frame |
|---|---|---|
| Plasma pharmacokinetic (PK) parameter Cmax | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the maximum plasma concentration (PK parameter Cmax). Cmax directly determined from the plasma concentration-time profile. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| PK parameter AUClast | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUClast (area under the concentration-time curve from time zero to the last measurable concentration sampling time). AUC determined from the plasma concentration-time profile using non-compartmental analysis. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| PK parameter AUCinf | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUCinf (area under the concentration-time curve from time zero to infinity ). AUC determined from the plasma concentration-time profile using non-compartmental analysis. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| PK parameter AUC0-t | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUC0-t (the partial area under the concentration-time curve from time zero to t hours post dose). AUC determined from the plasma concentration-time profile using non-compartmental analysis. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
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Inclusion Criteria:
-Other then hepatic impairment, subjects should be in good health as determined by past medical history, physical examination, vital signs, electrocardiogram (except for additional inclusion criteria for hepatic impaired subjects). -Subjects must weigh at least 50 kg and no more than 120 kg and have a body mass index in the range 18.0-36.0 kg/m2.
Additional criteria for hepatic impaired subjects: -Subjects must have a score clinically determined and calculated as per the Child-Pugh classification and consistent with the degree of hepatic impairment in which study is currently enrolling. -Stable Child-Pugh status within 28 days prior to dosing.
Exclusion Criteria: All subjects:
History of acute pancreatitis within 1 year of study entry.
Additional criteria for subjects with normal liver function:
-Use of any prescription or non-prescription medication. -Positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
Additional criteria for hepatic impaired subjects: -Use of any prescription or non-prescription medication, that has the potential to interact with alpelisb. Concomitant medications without potential to interact with alpelisib must be stable in dose. -Encephalopathy grade 3 or worse. -Total bilirubin > 6 mg/dl. Screening or baseline ECG: QTcF>480msec for both genders
Other protocol-defined inclusion/exclusion criteria may apply.
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| DaVita Clinical Research-Denver | Lakewood | Colorado | 80228 | United States | ||
| University of Miami / Clinical Research Services, Inc. |
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| Label | URL |
|---|---|
| Results for CBYL719A2105 can be found on the Novartis Clinical Trial Results Website | View source |
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| ID | Term |
|---|---|
| C585539 | Alpelisib |
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| PK parameter tmax | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter tmax (time to reach maximum plasma concentration), directly determined from the plasma concentration-time profile. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| PK parameter Cl/F | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter Cl/F (apparent oral total drug total plasma clearance calculated from steady-state exposure data ). Cl/F determined from the plasma concentration-time profile using non-compartmental analysis. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| PK parameter Vz/F | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter Vz/F (the apparent volume of distribution during terminal phase). Vz/F determined from the plasma concentration-time profile using non-compartmental analysis. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| PK parameter T1/2 | Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter T1/2 (elimination half-life associated with the terminal slope (lambda-z) of a semi logarithmic concentration-time curve). T1/2 determined from the plasma concentration-time profile using non-compartmental analysis. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| Relationship between PK parameters Cmax, AUClast, AUCinf and hepatic function parameters | Determination of the relationship between the primary PK parameters Cmax, AUClast, AUCinf and baseline hepatic function parameters total bilirubin, INR and serum albumin. | predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose |
| Adverse events severity and frequency | Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the frequency and severity of adverse events based on the CTCAE criteria. | Baseline Day 1 to 30 days post-dose |
| Change from baseline in laboratory parameters | Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the change from baseline in hematological and biochemical laboratory parameters. | Baseline Day 1 to 30 days post-dose |
| Change from baseline in ECG parameters | Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the change from baseline in ECG parameters. | Baseline Day 1 to 30 days post-dose |
| Miami |
| Florida |
| 33136 |
| United States |
| Orlando Clinical Research Center | Orlando | Florida | 32809 | United States |
| DaVita Clinical Research | Minneapolis | Minnesota | 55404 | United States |