Invasive Breast Cancer
Conditions
Keywords
breast cancer, TKI, tyrosine kinase inhibitor, vandetanib, Ki-67
Brief summary
The purpose of this project is to examine whether treatment with vandetanib has an effect on the tumor cells in breast cancer by examining tissue markers.
Detailed description
The purpose of this research study is to test whether vandetanib has an effect on tumor growth markers. Vandetanib is not approved by the FDA for use in treating breast cancer. This study will compare vandetanib to a placebo. The proposed study is designed to determine the change in Ki-67 expression on paired breast cancer samples obtained before and after treatment with vandetanib. Other tumor markers including RET, TUNEL and phosphorylation specific levels of ERK1/2, AKT and mTOR will also be assessed on the paired samples. Those who have a core biopsy of the breast which demonstrates invasive breast cancer and requires surgical excision of the lesion will be eligible for inclusion in the study. The tyrosine kinase inhibitor, vandetanib 300 mg, will be given once a day for 7-14 days prior to surgery. Following surgery, tissue markers would be analyzed on each of the paired samples, allowing for rapid assessment of in vivo response to TKI treatment.
Interventions
DRUGVandetanib
OTHERPlacebo
Sponsors
AstraZeneca
Ronald Weigel
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Patients with core breast biopsy that, on pathology review, demonstrates invasive breast cancer and are determined to need surgical excision of the lesion. All subtypes of invasive breast cancer will be enrolled. Core biopsy specimens of enrolled patients will be stained for RET by immunohistochemistry and scored, however, patients will not be excluded according to RET expression. * Female gender * Age \>/= 18 years of age * ECOG performance status \</= 2 * Life expectancy of greater than 6 months * Ability and willingness to provide informed consent to participate in study
Exclusion criteria
* Prolonged QT interval (QTc \> 480 milliseconds) on screening EKG or congenital long QT syndrome * Any concomitant medications that are known to be associated with Torsades de Pointes or QT elongation (see appendix 2). * Hypertension not controlled by medical therapy (systolic BP greater than 160 millimeters of mercury \[mmHg\] or diastolic blood pressure great than 100 mmHg). * Patients taking metformin or digoxin. * History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted. * Significant cardiac event (e.g., myocardial infarction), superior vena cava syndrome, New York Heart Association (NYHA) classification of heart disease ≥2 within 12 weeks, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia. * Serum calcium or magnesium outside the institutional range of normal. * Serum Potassium \< 4.0 mmol/L or above 5.0 mmol/L * Creatinine clearance \< 50 ml/min * PT \> 12 seconds or PTT \> 31 seconds * Platelet count of \< 100,000 * Serum bilirubin greater than 1.5 mg/dl * Alanine aminotransferase (ALT) \> 50 U/L, aspartate aminotransferase (AST) \> 65 U/L, or alkaline phosphatase (ALP) \> 250 U/L * Any cytotoxic treatments, such as neoadjuvant chemotherapy, planned before subsequent surgical procedure. * Previous exposure to Vandetanib * Previous enrollment or randomization in this study * Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and staff at UIHC). * Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin. * Patients who have received prior surgical site radiation. * Patients on CYP3A4 inhibitors or inducers (see appendix 1). * Inability to test core biopsy for study markers * Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards for women of childbearing potential.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Ki-67 Cells Observed 2 Weeks Post-treatment | 2 weeks | Pre- and post-treatment samples will be assessed by immunohistochemistry for positivity for Ki-67. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in TUNEL Observed 2 Weeks Post-treatment | 2 weeks | Pre- and post-treatment samples will be assessed by immunohistochemistry for positivity for TUNEL. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in RET Expression Observed 2 Weeks Post-treatment | 2 weeks | Results will be stratified by RET gene expression, a negative prognostic indicator in breast cancer, to demonstrate that RET is a marker of response. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vandetanib Vandetanib, 300 mg, PO, q day for 7-14 days prior to surgery
Vandetanib | 7 |
| Placebo Placebo, PO, q day for 7-14 days prior to surgery.
Placebo | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Vandetanib | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 8 Participants |
| Age, Continuous | 55.5 years | 62.9 years | 58.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 5 Participants | 12 Participants |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 |
| other Total, other adverse events | 5 / 6 | 1 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 |
Outcome results
Primary
Percent Change From Baseline in Ki-67 Cells Observed 2 Weeks Post-treatment
Pre- and post-treatment samples will be assessed by immunohistochemistry for positivity for Ki-67.
Time frame: 2 weeks
Population: 10 subjects took study drug and completed surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vandetanib | Percent Change From Baseline in Ki-67 Cells Observed 2 Weeks Post-treatment | 0.3 percentage of positivity for Ki-67. | Standard Deviation 0.08 |
| Placebo | Percent Change From Baseline in Ki-67 Cells Observed 2 Weeks Post-treatment | 2 percentage of positivity for Ki-67. | Standard Deviation 0.05 |
p-value: 0.51t-test, 2 sided
Secondary
Percent Change From Baseline in TUNEL Observed 2 Weeks Post-treatment
Pre- and post-treatment samples will be assessed by immunohistochemistry for positivity for TUNEL.
Time frame: 2 weeks
Population: 10 subjects took study drug and completed surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vandetanib | Percent Change From Baseline in TUNEL Observed 2 Weeks Post-treatment | 0.48 percentage of for positivity for TUNEL | Standard Deviation 0.71 |
| Placebo | Percent Change From Baseline in TUNEL Observed 2 Weeks Post-treatment | 1.02 percentage of for positivity for TUNEL | Standard Deviation 89 |
p-value: 0.35t-test, 2 sided
Other Pre-specified
Percent Change From Baseline in RET Expression Observed 2 Weeks Post-treatment
Results will be stratified by RET gene expression, a negative prognostic indicator in breast cancer, to demonstrate that RET is a marker of response.
Time frame: 2 weeks
Population: 6 patients that got the study drug and completed surgery by RET expression were analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vandetanib | Percent Change From Baseline in RET Expression Observed 2 Weeks Post-treatment | TUNEL | 0.77 percent change of RET positive samples | Standard Deviation 0.32 |
| Vandetanib | Percent Change From Baseline in RET Expression Observed 2 Weeks Post-treatment | Ki-67 | -0.3 percent change of RET positive samples | Standard Deviation 0.03 |
| Placebo | Percent Change From Baseline in RET Expression Observed 2 Weeks Post-treatment | Ki-67 | 1.0 percent change of RET positive samples | Standard Deviation 0.12 |
| Placebo | Percent Change From Baseline in RET Expression Observed 2 Weeks Post-treatment | TUNEL | 0.2 percent change of RET positive samples | Standard Deviation 0.12 |
p-value: 0.43t-test, 2 sided