Phase 1
Completed N=46
Study of the Pharmacokinetics and Safety of Carfilzomib in Patients With Advanced Malignancies and Hepatic Impairment
Source: ClinicalTrials.gov NCT01949545 ↗Enrolled (actual)
46
Serious AEs
54.4%
Results posted
Oct 2016
Primary outcomePrimary: Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² — 378; 546; 477 ng*hr/mL — p=0.02232
Summary
The purpose of this study is to compare the safety and efficacy of carfilzomib, including measuring the amount of the study drug in the blood at certain times following dosing. This study is being done in people with varying degrees of liver function to see if they respond differently to the study drug.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² |
378; 546; 477 | 0.02232 sig |
| PRIMARY Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² |
348; 529; 500 | 0.02137 sig |
| SECONDARY Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² |
932; 1290; 1020 | — |
| SECONDARY Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² |
0.292; 0.458; 0.483 | — |
| SECONDARY Clearance of Carfilzomib 27 mg/m² |
157; 86.4; 103 | — |
| SECONDARY Terminal Half-life of Carfilzomib 27 mg/m² |
0.469; 0.541; 0.511 | — |
| SECONDARY Mean Residence Time (MRT) of Carfilzomib 27 mg/m² |
0.108; 0.167; 0.235 | — |
| SECONDARY Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m² |
16.9; 14.4; 24.2 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² |
765; 1107; 927 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² |
609; 1108; 929 | — |
| SECONDARY Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² |
1697; 2733; 2119 | — |
| SECONDARY Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² |
0.300; 0.408; 0.400 | — |
| SECONDARY Terminal Half-life of Carfilzomib 56 mg/m² |
0.508; 0.621; 0.740 | — |
| SECONDARY Clearance of Carfilzomib 56 mg/m² |
181; 92.0; 121 | — |
| SECONDARY Mean Residence Time (MRT) of Carfilzomib 56 mg/m² |
0.0834; 0.161; 0.164 | — |
| SECONDARY Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² |
15.0; 14.8; 19.8 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 |
463; 417; 385; 837; 752; 786 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 |
400; 432; 437; 834; 770; 843 | — |
| SECONDARY Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 |
189; 198; 201; 381; 345; 513 | — |
| SECONDARY Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 |
0.867; 0.792; 0.750; 0.842; 0.992; 0.750 | — |
| SECONDARY Terminal Half-life for Metabolite PR-389/M14 |
1.42; 1.20; 1.26; 1.32; 1.30; 1.07 | — |
| SECONDARY Mean Residence Time (MRT) for Metabolite PR-389/M14 |
2.42; 2.13; 2.14; 2.25; 2.27; 1.78 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 |
50.1; 56.7; 85.5; 106; 119; 173 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 |
56.6; 60.8; 92.9; 116; 132; 186 | — |
| SECONDARY Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 |
27.8; 33.9; 46.3; 59.4; 66.0; 103 | — |
| SECONDARY Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 |
0.750; 0.767; 0.650; 0.717; 0.800; 0.750 | — |
| SECONDARY Terminal Half-life for Metabolite PR-413/M15 |
1.34; 1.25; 1.23; 1.18; 1.24; 1.07 | — |
| SECONDARY Mean Residence Time (MRT) for Metabolite PR-413/M15 |
2.13; 2.02; 2.04; 1.96; 2.09; 1.83 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 |
125; 136; 228; 278; 311; 463 | — |
| SECONDARY Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 |
127; 138; 235; 281; 314; 465 | — |
| SECONDARY Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 |
145; 160; 257; 314; 349; 546 | — |
| SECONDARY Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 |
0.500; 0.600; 0.700; 0.483; 0.592; 0.583 | — |
| SECONDARY Terminal Half-life for Metabolite PR-519/M16 |
0.786; 0.728; 0.673; 0.748; 0.680; 0.601 | — |
| SECONDARY Mean Residence Time (MRT) for Metabolite PR-519/M16 |
1.01; 0.961; 0.994; 0.994; 1.00; 0.909 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) |
10; 17; 14; 4; 7; 12 | — |
Eligibility Criteria
Key Inclusion Criteria
- Relapsed or progressive advanced malignancies (solid tumors or hematologic malignancies)
- At least ≥ 2 prior treatment regimens for the underlying malignancy
- Confirmed advanced solid tumor or hematologic malignancy
- Measurable or evaluable disease
- Clinical diagnosis of chronic hepatic impairment that is stable with no acute worsening of liver failure within one month prior to enrollment. Hepatic impairment will be assessed as per National Cancer Institute Organ Dysfunction Working Group Criteria (NCI-ODWG) schema and will fall into one of the following three categories:
- Cohort 2 (mild): Bilirubin > 1-1.5 × upper limit of the normal range (ULN) or aspartate aminotransferase (AST) > ULN, but bilirubin ≤ ULN
- Cohort 3 (moderate): ≥ 1.6-3 × ULN; any AST
- Cohort 4 (severe): Bilirubin > 3 × ULN; any AST
Exception to Inclusion Criterion #5 for Subjects with Normal Hepatic Function:
All subjects enrolled with normal hepatic function (N=10) must meet all inclusion criteria as outlined with the exception of Inclusion Criterion
#5, which should be substituted with the following criterion to be enrolled into the study:
- Cohort 1 (normal hepatic function): Bilirubin ≤ ULN; AST ≤ ULN
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
- Left ventricular ejection fraction (LVEF) ≥ 40%
- Adequate renal function (calculated creatinine clearance ≥ 30 mL/min)
- Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within the protocol-specified period prior to enrollment
Key Exclusion Criteria
- Subjects with symptomatic brain metastasis or central nervous system (CNS) disease
- Significant neurotoxicity (Grade 2 with pain or higher) at the time of enrolment
- Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests [bilirubin, AST] will be allowed)
Data sourced from ClinicalTrials.gov (NCT01949545). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.