Clinical trial NCT01205230: VEG113971: An Open-Label Study of the Effects of Ketoconazole or Esomeprazole on Pazopanib PK
Official title: An Open-Label Study to Evaluate the Effects of Ketoconazole and the Effects of Esomeprazole on the Pharmacokinetics of Orally Administered Repeat Doses of Pazopanib in Subjects With Solid Tumor Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cancer
Keywords: Esomeprazole
Pharmacogenetics
Pharmacokinetics
Ketoconazole
Pazopanib
Drug Interaction
Safety
Solid Tumors
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-09-20
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: 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
timeFrame: 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.
measure: Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
timeFrame: 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.
measure: Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
timeFrame: 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:
measure: Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole
timeFrame: 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.
measure: Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole
timeFrame: 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.
measure: Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole
timeFrame: 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.
measure: Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole
timeFrame: 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.
measure: Plasma Ketoconazole Concentration at the Indicated Time Points
timeFrame: 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.
measure: Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs)
timeFrame: From Baseline (Day 1) to a maximum of 4 weeks after the last dose of study drug was administered (on Study Day 12)
measure: Number of Participants With the Indicated Event of Dose Limiting Toxicity (DLT)
timeFrame: From Baseline (Day 1) to a maximum of 4 weeks after the last dose of study drug was administered (on Study Day 12)
Other outcomes:
Locations:
city: New Brunswick
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Greenville
country: United States
facility: GSK Investigational Site
state: South Carolina
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.