Pilot Study of GW786034 (Pazopanib), a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Operable Breast Cancer
18 Years
N/A
Both
Male Breast Cancer, Recurrent Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer
Trial Information
Pilot Study of GW786034 (Pazopanib), a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Operable Breast Cancer
PRIMARY OBJECTIVES:
I. Determine the biologic effect of pazopanib hydrochloride, in terms of decreased
phosphorylation of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and/or
decreased microvessel density, in patients with newly diagnosed or locally and/or regionally
recurrent operable breast cancer.
II. Determine the mechanism of antitumor effect of this drug, in terms of reduced tumor cell
proliferation (Ki67) or increased apoptosis, in these patients.
SECONDARY OBJECTIVES:
I. Determine the change in levels of tissue VEGF in patients treated with this drug.
II. Determine the change in phosphorylation of epidermal growth factor receptor (EGFR),
MAPK, and AKT in patients treated with this drug.
III. Evaluate gene expression patterns in patients treated with this drug. IV. Evaluate the
change in VEGF and VEGFR-2 as circulating biomarkers in patients treated with this drug.
V. Evaluate the changes in circulating tumor cells in patients treated with this drug.
VI. Determine if steady-state plasma concentration of this drug correlates with inhibition
of phospho-VEGFR-2.
VII. Evaluate the change in vascular permeability by bilateral dynamic contrast-enhanced MRI
(DCE-MRI) of the breast in patients treated with this drug.
VIII. Compare DCE-MRI imaging of the tumor vasculature in the breast before, during, and
after treatment with this drug.
OUTLINE: This is an open-label, pilot study.
Patients receive pazopanib hydrochloride orally (PO) once daily for 12-20 days. Patients
then undergo surgical resection of tumor between days 13 and 21 (24 hours after completion
of pazopanib hydrochloride).
Blood samples are collected periodically for analysis of circulating tumor cells and
pharmacokinetic studies. Patients also undergo tumor biopsy at the time of surgery. Samples
are analyzed by immunohistochemistry, microarray (gene expression profiling), and TUNEL
assays to assess vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2),
epidermal growth factor receptor (EGFR), MAPK, AKT, phosphorylated (p) VEGFR-2, pEGFR,
pMAPK, and pAKT activity, tumor cell proliferation (Ki67) and apoptosis, and microvessel
density (using endothelial markers CD31 [PECAM-1], CD34, and CD 133).
Inclusion Criteria:
- Diagnosis of invasive adenocarcinoma of the breast by core needle biopsy or limited
incisional biopsy
- Tumor size >= 1.0 cm as assessed by physical exam or radiographic exam
- Patients with histologically verified local and/or regional recurrence of invasive
breast cancer that is amenable to surgery and meet all eligibility criteria may
participate
- No prior chemotherapy or hormonal therapy for this primary breast cancer
- Able to undergo surgical treatment with either lumpectomy or mastectomy
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- WBC >= 3,000/mm^3
- Platelet count >= 100,000/mm^3
- Bilirubin within normal institutional limits
- AST and ALT =< 2.5 times upper limit of normal (ULN)
- Creatinine normal OR creatinine clearance >= 60 mL/min
- PT/INR/PTT =< 1.2 times ULN
- Urine protein:creatinine ratio =< 1
- Blood pressure =< 140/90
- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of GW786034 (pazopanib)
will be determined following review by principal investigator
- Women of child-bearing potential and men must agree to use adequate contraception
prior to study entry and for the duration of study participation
- Any concomitant medications that are associated with a risk of QTc prolongation
and/or Torsades de Pointes should be discontinued or replaced with drugs that do not
carry these risks, if possible; patients who must take medications with a risk or
possible risk of Torsades de Pointes should be watched carefully for symptoms of QTc
prolongation, such as syncope
Exclusion Criteria:
- Patients with locally advanced breast cancer who are not candidates for surgical
resection at time of initial evaluation, including patients with:
- Tumor of any size with direct extension to chest wall or skin (T4a-c)
- Inflammatory breast cancer (T4d)
- Patients with evidence of metastatic disease
- Patients may not be receiving any other investigational agents
- Patients with history of allergic reactions attributed to compounds of similar
chemical or biologic composition to GW786034 or other agents used in the study
- Patients with any of the following conditions are excluded:
- Serious or non-healing wound, ulcer, or bone fracture
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days of treatment
- Any history of cerebrovascular accident (CVA) within the last 6 months
- Current use of therapeutic warfarin. Note: Low molecular weight heparin and
prophylactic low-dose warfarin are permitted; PT/PTT must meet the inclusion
criteria (Section 5.1.8)
- History of myocardial infarction, cardiac arrhythmia, admission for unstable
angina, cardiac angioplasty or stenting within the last 12 weeks
- History of venous thrombosis in last 12 weeks
- Class III or IV heart failure as defined by the NYHA functional classification
system (see Appendix C); a patient who has a history of Class II heart failure
and is asymptomatic on treatment may be considered eligible
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situation that would limit compliance with
study requirements
- Baseline QTc >= 480 msecs or other significant ECG abnormalities
- Patients taking certain medications that act through the CYP450 system
- Patients with any condition that impairs their ability to swallow and retain GW786034
- HIV-positive patients
- Patients who are unable or unwilling to sign a written informed consent document
Type of Study:
Interventional
Study Design:
Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Response to GW786034 defined as change in molecular parameters such as phosphorylated VEGFR-2, microvessel density, tumor proliferation (Ki67), and apoptosis
Outcome Description:
The pre-post comparison of the biologic effects in the tumor can be done by a paired t-test as they are all continuous variables. If the differences are not normally distributed, transformations or non-parametric methods will be applied. We will adjust for multiple comparisons using Bonferroni method as the biologic effects are measured by four variables. The relationship among these four variables will be analyzed using factor analysis to see if they can be reduced to one or two representative indices.
Outcome Time Frame:
Baseline to 4 years
Safety Issue:
No
Principal Investigator
Antoinette Tan
Investigator Role:
Principal Investigator
Investigator Affiliation:
Cancer Institute of New Jersey
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-00183
NCT ID:
NCT00450879
Start Date:
January 2007
Completion Date:
Related Keywords:
- Male Breast Cancer
- Recurrent Breast Cancer
- Stage IA Breast Cancer
- Stage IB Breast Cancer
- Stage II Breast Cancer
- Stage IIIA Breast Cancer
- Breast Neoplasms
- Breast Neoplasms, Male
Name | Location |
|---|---|
| Cancer Institute of New Jersey | New Brunswick, New Jersey 08901 |
