Cancer
Conditions
Keywords
Esomeprazole, Pharmacogenetics, Pharmacokinetics, Ketoconazole, Pazopanib, Drug Interaction, Safety, Solid Tumors
Brief summary
The purpose of this study is to determine how dosing with ketoconazole (Nizoral) or esomeprazole (Nexium) affects the pharmacokinetics of oral pazopanib. The study will also test for safety of pazopanib when administered with ketoconazole or esomeprazole.
Detailed description
The study is a 2-arm, open-label, repeat-dose, single sequence, crossover, study designed to evaluate the effects of ketoconazole (Arm A) and esomeprazole (Arm B) on the pharmacokinetics (PK) of oral pazopanib in subjects with solid tumor malignancies. This study will compare the PK parameters of oral pazopanib and its metabolite concentrations when given alone and when co-administered with either ketoconazole (Arm A) or esomeprazole (Arm B). Safety assessments (physical examinations, vital signs, 12-lead electrocardiograms, Eastern Cooperative Oncology Group performance status, clinical laboratory assessments, and monitoring of adverse events) will also be evaluated during the study.
Interventions
DRUGpazopanib
Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet derivative growth factor receptor (PDGFR)
Sponsors
GlaxoSmithKline
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
No
Inclusion criteria
* Signed, written informed consent * 18 years of age or legal age of consent if greater than 18 years at the time of signing consent * Histologically confirmed diagnosis of refractory or relapsed advanced solid tumor malignancy after standard therapy OR for which there is no standard therapy OR for which subject opts not to receive standard therapy * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate baseline organ function * Subjects may not have had a transfusion within 7 days of screening assessment. * Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the protocol recommended range. * Male OR * Female of non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: a hysterectomy, a bilateral oophorectomy (ovariectomy), a bilateral tubal ligation, or is post-menopausal OR * Non-pregnant Female of childbearing potential, including any female who has had a negative serum pregnancy test within 14 days prior to the first dose of study treatment, agrees to use acceptable contraceptive methods, used consistently and in accordance with both the product label and the instructions of the study physician. OR * Female, if lactating, agrees to stop nursing prior to first dose until 14 days after last dose of study drug * Able to swallow and retain orally administered medication
Exclusion criteria
* History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 2 months prior to first dose of study drug * Clinically significant GI abnormalities that may increase the risk for GI bleeding including, but not limited to: active peptic ulcer disease, known intraluminal metastatic lesion/s with risk of bleeding inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), or other GI conditions with increased risk of perforation, history of abdominal fistula, GI perforation, or intra abdominal abscess within 28 days prior to beginning study treatment. * Clinically significant GI abnormalities that may affect absorption of investigational product including, but not limited to: malabsorption syndrome, major resection of the stomach or small bowel. * Presence of uncontrolled infection. * Corrected QT interval (QTc) \>480 msec. * History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction,unstable angina,coronary artery bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA). * Poorly controlled hypertension Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. * History of cerebrovascular accident including transient ischemic attack, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible. * Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major). * Evidence of active bleeding or bleeding diathesis. * Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels. * Hemoptysis in excess of 2.5 mL (or one-half teaspoon) within 8 weeks of first dose of study drug. * Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. * Treatment with any of the following anti-cancer therapies: radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of pazopanib. * Any ongoing toxicity from prior anti-cancer therapy that is \> Grade 1 (graded by NCI-CTCAE, version 4.0), at the time of enrollment and/or that is progressing in severity, except alopecia as well as stable (\>4 weeks) ≤Grade 2 neuropathy or rash. -Unable or unwilling to discontinue use of protocol-prohibited medications for at least 14 days or 5 half- lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study. -Use of HRT prior to study enrollment due to the potential for inhibition of cytochrome P450 enzymes that metabolize estrogens and progestins (Arm A female subjects only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. | Blood samples for pharmacokinetic (PK) analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter AUC(0-24) was determined by standard non-compartmental analysis using WinNonlin. Plasma AUC(0-24) is a measure of the amount of drug a participant has been exposed to in 24 hours. |
| Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. | Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. The concentration-time curve is the result of time points of blood sampling and its measured concentration of pazopanib in the plasma. |
| Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. | Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Nominal data collection time points (TPs) were defined in the protocol; however, the actual data collection TP often differed slightly from the nominal TP for various reasons. This leads to medians and ranges that don't coincide with planned nominal data collection TPs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. | Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Nominal data collection time points (TPs) were defined in the protocol; however, the actual data collection TP often differed slightly from the nominal TP for various reasons. This leads to medians and ranges that don't coincide with planned nominal data collection TPs. |
| Plasma Ketoconazole Concentration at the Indicated Time Points | Day 5 of Period 2 (combination therapy). Blood samples were collected within 60 minutes prior to pazopanib administration and 1 and 2 hours after pazopanib administration. | Blood samples for the determination of plasma ketoconazole concentrations were collected before (pre-dose \[within 60 minutes prior to pazopanib administration\]) and after the final pazopanib and ketoconazole dose (fifth dose) during Period 2 at the indicated time points, relative to pazopanib administration (at 1 and 2 hours after pazopanib administration). Blood samples were obtained via peripheral intravenous cannula or central line. Concentrations of ketoconazole were determined in plasma samples using the currently approved analytical methodology. |
| Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained 24 hours after administration of pazopanib. | Pazopanib plasma concentration-time data were analyzed by non-compartmental methods with WinNonlin. Calculations were based on the actual sampling times. From the plasma concentration-time data, the PK parameter C24 was determined. |
| Number of Participants With the Indicated Event of Dose Limiting Toxicity (DLT) | From Baseline (Day 1) to a maximum of 4 weeks after the last dose of study drug was administered (on Study Day 12) | The following were considered DLTs only while participants were receiving pazopanib co-administered with either ketoconazole or esomeprazole: Grade 4 hematologic toxicities, excluding lymphopenia; and Grade 3/4 non-hematologic toxicities, excluding alopecia and nausea/vomiting/diarrhea for which adequate supportive therapy had not been instituted. Toxicities observed once co-administration of pazopanib with ketoconazole or esomeprazole was complete (after Day 5 of Period 2) could also be considered DLTs if judged to be relevant by the investigator and the GlaxoSmithKline Medical Monitor. |
| Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | From Baseline (Day 1) to a maximum of 4 weeks after the last dose of study drug was administered (on Study Day 12) | AEs were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Grades range from 0 (no toxicity) to 4 (life-threatening or disabling). A Grade 3 AE is severe; defined as considerable interference with the participant's daily activities, medical intervention/therapy required, and hospitalization possible. A Grade 4 AE is life-threatening; defined as extreme limitation in activity, significant medical intervention/therapy required, and hospitalization probable. |
| Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. | Blood samples for PK analysis of the metabolites of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter AUC(0-24) was determined by standard non-compartmental analysis using WinNonlin. Plasma AUC(0-24) is a measure of the amount of drug a participant has been exposed to in 24 hours. |
| Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. | Blood samples for PK analysis of the metabolites of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. The concentration-time curve is the result of time points of blood sampling and its measured concentration of pazopanib in the plasma. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib, Followed by Pazopanib + Ketoconazole Pazopanib 400 milligrams (mg) (2x200 mg tablets) once daily (QD), for at least 7 consecutive days in the morning during Period 1, followed by ketoconazole 400 mg (2x200 mg tablets) QD in combination with pazopanib 400 mg (2x200 mg tablets) QD for 5 consecutive days in the morning during Period 2 | 21 |
| Pazopanib, Followed by Pazopanib + Esomeprazole Pazopanib 800 mg (4x200 mg tablets) QD, for at least 7 consecutive days in the morning during Period 1, followed by pazopanib 800 mg (4x200 mg tablets) QD in the morning in combination with esomeprazole 40 mg (1x40 mg capsule) QD in the evening (approximately 3 hours after the evening meal) for 5 consecutive days during Period 2 | 13 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Pazopanib, Followed by Pazopanib + Ketoconazole | Pazopanib, Followed by Pazopanib + Esomeprazole | Total |
|---|---|---|---|
| Age Continuous Years | 60.0 Years STANDARD_DEVIATION 12.27 | 57.9 Years STANDARD_DEVIATION 13.09 | 59.2 Years STANDARD_DEVIATION 12.43 |
| Race/Ethnicity, Customized African American/African Heritage | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 17 participants | 10 participants | 27 participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 10 Participants | 2 Participants | 12 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 | 11 / 21 | 17 / 21 | 2 / 13 | 8 / 13 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. The concentration-time curve is the result of time points of blood sampling and its measured concentration of pazopanib in the plasma.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pazopanib 400 mg QD | Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 40.7 mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 59.2 mcg/mL |
| Pazopanib 800 mg QD | Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 48.9 mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 28.4 mcg/mL |
90% CI: [1.14, 1.86]
90% CI: [0.5, 0.67]
Primary
Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
Blood samples for pharmacokinetic (PK) analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter AUC(0-24) was determined by standard non-compartmental analysis using WinNonlin. Plasma AUC(0-24) is a measure of the amount of drug a participant has been exposed to in 24 hours.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration.
Population: Pharmacokinetic (PK) Population: all participants who underwent plasma PK sampling and had evaluable PK assay results from at least one analyte
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pazopanib 400 mg QD | Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 786 Hour*micrograms/milliliters (hr*mcg/mL) |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 1300 Hour*micrograms/milliliters (hr*mcg/mL) |
| Pazopanib 800 mg QD | Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 848 Hour*micrograms/milliliters (hr*mcg/mL) |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 512 Hour*micrograms/milliliters (hr*mcg/mL) |
90% CI: [1.39, 1.99]
90% CI: [0.52, 0.7]
Primary
Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Nominal data collection time points (TPs) were defined in the protocol; however, the actual data collection TP often differed slightly from the nominal TP for various reasons. This leads to medians and ranges that don't coincide with planned nominal data collection TPs.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration.
Population: PK Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 400 mg QD | Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 3.48 hours (hr) |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 3.48 hours (hr) |
| Pazopanib 800 mg QD | Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 3 hours (hr) |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 3.9 hours (hr) |
90% CI: [-1.06, 0.06]
90% CI: [-0.1, 2.44]
Secondary
Number of Participants With the Indicated Event of Dose Limiting Toxicity (DLT)
The following were considered DLTs only while participants were receiving pazopanib co-administered with either ketoconazole or esomeprazole: Grade 4 hematologic toxicities, excluding lymphopenia; and Grade 3/4 non-hematologic toxicities, excluding alopecia and nausea/vomiting/diarrhea for which adequate supportive therapy had not been instituted. Toxicities observed once co-administration of pazopanib with ketoconazole or esomeprazole was complete (after Day 5 of Period 2) could also be considered DLTs if judged to be relevant by the investigator and the GlaxoSmithKline Medical Monitor.
Time frame: From Baseline (Day 1) to a maximum of 4 weeks after the last dose of study drug was administered (on Study Day 12)
Population: All Treated Population. Per protocol, a DLT could not occur during single-agent pazopanib administration in Period 1; thus, data were only collected and analyzed for those participants receiving pazopanib co-administered with either ketoconazole or esomeprazole in Period 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Number of Participants With the Indicated Event of Dose Limiting Toxicity (DLT) | 2 participants |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Number of Participants With the Indicated Event of Dose Limiting Toxicity (DLT) | 0 participants |
Secondary
Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs)
AEs were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Grades range from 0 (no toxicity) to 4 (life-threatening or disabling). A Grade 3 AE is severe; defined as considerable interference with the participant's daily activities, medical intervention/therapy required, and hospitalization possible. A Grade 4 AE is life-threatening; defined as extreme limitation in activity, significant medical intervention/therapy required, and hospitalization probable.
Time frame: From Baseline (Day 1) to a maximum of 4 weeks after the last dose of study drug was administered (on Study Day 12)
Population: All Treated Population: all participants who were enrolled into the study and received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Lymphopenia | 0 participants |
| Pazopanib 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypokalemia | 0 participants |
| Pazopanib 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypertension | 1 participants |
| Pazopanib 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypophosphatemia | 0 participants |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypertension | 2 participants |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypokalemia | 1 participants |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypophosphatemia | 1 participants |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Lymphopenia | 1 participants |
| Pazopanib 800 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Lymphopenia | 0 participants |
| Pazopanib 800 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypokalemia | 0 participants |
| Pazopanib 800 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypophosphatemia | 0 participants |
| Pazopanib 800 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypertension | 0 participants |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypophosphatemia | 0 participants |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypertension | 2 participants |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Lymphopenia | 0 participants |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs) | Hypokalemia | 0 participants |
Secondary
Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole
Blood samples for PK analysis of the metabolites of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter AUC(0-24) was determined by standard non-compartmental analysis using WinNonlin. Plasma AUC(0-24) is a measure of the amount of drug a participant has been exposed to in 24 hours.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration.
Population: PK Population. One participant from the Pazopanib + Ketoconazole treatment arm was not analyzed for GSK1071306 due to mishandling of PK samples during shipping. Only those participants providing samples were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pazopanib 400 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992, n=21, 16, 12, 12 | 30.3 hr*mcg/mL |
| Pazopanib 400 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306, n=21, 15, 12, 12 | 7.61 hr*mcg/mL |
| Pazopanib 400 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997, n=20, 13, 12, 12 | 17.4 hr*mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992, n=21, 16, 12, 12 | 30.3 hr*mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306, n=21, 15, 12, 12 | 4.26 hr*mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997, n=20, 13, 12, 12 | 6.67 hr*mcg/mL |
| Pazopanib 800 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997, n=20, 13, 12, 12 | 21.6 hr*mcg/mL |
| Pazopanib 800 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306, n=21, 15, 12, 12 | 11.7 hr*mcg/mL |
| Pazopanib 800 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992, n=21, 16, 12, 12 | 35.5 hr*mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306, n=21, 15, 12, 12 | 8.14 hr*mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997, n=20, 13, 12, 12 | 11.2 hr*mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992, n=21, 16, 12, 12 | 20.8 hr*mcg/mL |
Secondary
Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole
Blood samples for PK analysis of the metabolites of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. The concentration-time curve is the result of time points of blood sampling and its measured concentration of pazopanib in the plasma.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration.
Population: PK Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pazopanib 400 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 0.39 mcg/mL |
| Pazopanib 400 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 1.55 mcg/mL |
| Pazopanib 400 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 1.02 mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 0.22 mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 0.31 mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 1.52 mcg/mL |
| Pazopanib 800 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 0.61 mcg/mL |
| Pazopanib 800 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 1.65 mcg/mL |
| Pazopanib 800 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 1.95 mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 0.42 mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 0.84 mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 1.13 mcg/mL |
Secondary
Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
Pazopanib plasma concentration-time data were analyzed by non-compartmental methods with WinNonlin. Calculations were based on the actual sampling times. From the plasma concentration-time data, the PK parameter C24 was determined.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained 24 hours after administration of pazopanib.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pazopanib 400 mg QD | Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 26.9 mcg/mL |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 48.7 mcg/mL |
| Pazopanib 800 mg QD | Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 27.2 mcg/mL |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole | 17.3 mcg/mL |
Secondary
Plasma Ketoconazole Concentration at the Indicated Time Points
Blood samples for the determination of plasma ketoconazole concentrations were collected before (pre-dose \[within 60 minutes prior to pazopanib administration\]) and after the final pazopanib and ketoconazole dose (fifth dose) during Period 2 at the indicated time points, relative to pazopanib administration (at 1 and 2 hours after pazopanib administration). Blood samples were obtained via peripheral intravenous cannula or central line. Concentrations of ketoconazole were determined in plasma samples using the currently approved analytical methodology.
Time frame: Day 5 of Period 2 (combination therapy). Blood samples were collected within 60 minutes prior to pazopanib administration and 1 and 2 hours after pazopanib administration.
Population: PK Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pazopanib 400 mg QD | Plasma Ketoconazole Concentration at the Indicated Time Points | 1 hr | 4.21 mcg/mL |
| Pazopanib 400 mg QD | Plasma Ketoconazole Concentration at the Indicated Time Points | Pre-dose | 0.53 mcg/mL |
| Pazopanib 400 mg QD | Plasma Ketoconazole Concentration at the Indicated Time Points | 2 hr | 4.82 mcg/mL |
Secondary
Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole
Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Nominal data collection time points (TPs) were defined in the protocol; however, the actual data collection TP often differed slightly from the nominal TP for various reasons. This leads to medians and ranges that don't coincide with planned nominal data collection TPs.
Time frame: Day 7 of Period 1 (monotherapy) and Day 5 (Study Day 12) of Period 2 (combination therapy). Blood samples were obtained within 60 minutes prior to pazopanib administration and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration.
Population: PK Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pazopanib 400 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 3.12 hr |
| Pazopanib 400 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 4 hr |
| Pazopanib 400 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 3.02 hr |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 24.1 hr |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 13.4 hr |
| Pazopanib 400 mg QD + Ketoconazole 400 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 24 hr |
| Pazopanib 800 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 3 hr |
| Pazopanib 800 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 2.2 hr |
| Pazopanib 800 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 3.9 hr |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1071306 | 6 hr |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268992 | 3 hr |
| Pazopanib 800 mg QD + Esomeprazole 40 mg QD | Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole | GSK1268997 | 2.4 hr |