VEG113971: An Open-Label Study of the Effects of Ketocona... | NCT01205230

NCT01205230

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Pazonib+ketoconazole	Experimental	Administration of oral pazopanib 400mg (2 200-mg tablets) once-daily each morning for at least 7 consecutive doses during Period 1. Then administration of oral ketoconazole 400 mg (2 - 200 mg tablets) followed immediately by pazopanib 400 mg (2 -200 mg tablets) once-daily each morning for a total of 5 consecutive doses during Period 2.	Drug: pazopanib
Pazonib+esomeprazole	Experimental	Subjects will receive orally administered pazopanib 800mg (4 - 200mg tablets) once-daily each morning for at least 7 consecutive doses in Period 1. In the evening on the last day of Period 1, subjects will take their initial dose of esomeprazole 40 mg (1 - 40 mg capsule) approximately 3 hours after the evening meal. Subjects will continue to receive pazopanib (each morning) and esomeprazole each evening once-daily for a total of 5 consecutive doses.	Drug: pazopanib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
pazopanib	Drug	Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet derivative growth factor receptor (PDGFR)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	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.
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.	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.
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.

Secondary Outcomes

Measure	Description	Time Frame
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.	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.

Eligibility Module

Eligibility Criteria

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).

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		New Brunswick	New Jersey	08901	United States
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
23636448	Derived	Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, Gregory C, Suttle AB, Tada H, Botbyl J, Stephenson JJ. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol. 2013 Jun;71(6):1635-43. doi: 10.1007/s00280-013-2164-3. Epub 2013 May 1.

ID	Title	Description
FG000	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
FG001	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

ID	Title	Description
BG000	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

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Pharmacokinetic (PK) Population: all participants who underwent plasma PK sampling and had evaluable PK assay results from at least one analyte

Posted

Geometric Mean

95% Confidence Interval

Hour*micrograms/milliliters (hr*mcg/mL)

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.

ID	Title	Description

OG000	Pazopanib 400 mg QD	Pazopanib 400 milligrams (mg) (2x200 mg tablets) once daily (QD), for at least 7 consecutive days in the morning during Period 1
OG001	Pazopanib 400 mg QD + Ketoconazole 400 mg QD	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
OG002	Pazopanib 800 mg QD	Pazopanib 800 mg (4x200 mg tablets) QD, for at least 7 consecutive days in the morning during Period 1
OG003	Pazopanib 800 mg QD + Esomeprazole 40 mg QD	Pazopanib 800 mg (4x200 mg tablets) QD in the morning in combination with esomeprazole 40 mg (1x40 mg capsule) QD in the evening (administered 1 hour after the evening meal) for 5 consecutive days during Period 2