VEG113971: An Open-Label Study of the Effects of Ketoconazole or Esomeprazole on Pazopanib PK

NCT01205230 | Completed Phase 4 Results

• 1 other identifier: 113971
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 2

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.

Conditions

Cancer

Keywords

Esomeprazole; Pharmacogenetics; Pharmacokinetics; Ketoconazole; Pazopanib; Drug Interaction; Safety; Solid Tumors

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

Secondary Outcomes (7)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (2)

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

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)

Also known as: Votrient

Pazonib+esomeprazole; Pazonib+ketoconazole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed, written informed consent
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

New Brunswick, New Jersey, 08901, United States

Location

GSK Investigational Site

Greenville, South Carolina, 29605, United States

Location

Related Publications (1)

• 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.

  PMID: 23636448 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

pazopanib

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2010
• First Posted: September 20, 2010
• Study Start: September 1, 2010
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: May 22, 2012
• Results First Posted: April 24, 2012

Record last verified: 2012-05

Locations

US (2)