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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


Phase 4
18 Years
N/A
Not Enrolling
Both
Cancer

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Trial Information

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


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.


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).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome 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

Outcome Description:

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.

Outcome 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.

Safety Issue:

No

Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:

GlaxoSmithKline

Authority:

United States: Institutional Review Board

Study ID:

113971

NCT ID:

NCT01205230

Start Date:

September 2010

Completion Date:

August 2011

Related Keywords:

  • Cancer
  • Esomeprazole
  • Pharmacogenetics
  • Pharmacokinetics
  • Ketoconazole
  • Pazopanib
  • Drug Interaction
  • Safety
  • Solid Tumors

Name

Location

GSK Investigational SiteColumbia, South Carolina  29210
GSK Investigational SiteEdison, New Jersey  08837