Trial Information

A Pre-Surgical Study to Evaluate Molecular Changes That Occur in Human Breast Cancer Tissue After Short Term Exposure to Dasatinib and To Correlate These Alterations With Pharmacokinetics Parameters

Primary Objective: To evaluate the molecular changes which occur in human breast cancer
tissue after short-term exposure to dasatinib.

Secondary Objectives:

" To evaluate the molecular effects of short term dasatinib exposure in peripheral blood and
on SRC (an oncogene) and EPHA2 signaling pathways in non-tumor cells (peripheral blood).

" To correlate the pharmacokinetic parameters with molecular changes detected in breast
cancer tissues and peripheral blood " To evaluate the tolerability and safety of short-term
exposure to daily dose of 100 mg twice daily of dasatinib administration

Study Design:

Eligible patients will be registered to receive dasatinib 100 mg orally twice daily starting
within 8 days from the time of registration and continuing to the time of the definitive
surgery.

Duration of Treatment " No more than 8 days should elapse from the time of registration to
the time of the first dose of dasatinib " No more than 28 days should elapse from the time
of the initial diagnosis to the time of the first dose of dasatinib " Minimum duration of
treatment with dasatinib is 14 days with a minimum of 10 consecutive days of treatment
immediately prior to the definitive surgery " Dasatinib shall be administered until the day
prior to the definitive surgery " No more than 45 days should elapse from the time of the
initial diagnosis to the time of the definitive surgery i.e. maximum duration of treatment
with dasatinib is 45 days.

Core Biopsies: Tumor sample must be collected at the time of the initial diagnosis (or in a
subsequent procedure) either by core needle or incisional biopsy. Excisional biopsy will
not be allowed. A minimum of 4 core biopsies (or the equivalent with an incisional biopsy)
is required to perform the molecular analyses. Once the core biopsies have been removed,
the samples must be immediately snap-frozen, then stored in liquid nitrogen or at -70 to -80
C at the site. Samples will be shipped to the UCLA laboratory within 30 days of collection.

Tumor Tissue at the time of Definitive Surgery: A second tumor sample (post-dasatinib) must
be collected at the time of the patient's surgery in the same manner as above.

Unstained paraffin slides: While most analyses will be performed on the frozen tissue, some
molecular testing may require paraffin embedded tissue. The pathology department will be
asked to send 4, 5 micron thick, unstained paraffin slides of each the pretreatment
(diagnosis biopsy) and from the definitive surgery (8 slides in total) Definitive Surgery:
The type of definitive surgery performed will be according to the institution's guidelines.
In the event that a sentinel node biopsy procedure is performed, the dye can be injected
into the tumor bed after tumor removal. The dye should not be injected into the tumor
itself as this may alter the tissue and affect the molecular analyses.

Pharmacokinetic plasma samples and peripheral blood mononuclear cells samples will be
collected at the following time points (5 samples each):

1. Baseline, prior to the first dose of dasatinib. Timing of collection: anytime between
registration and the first dose of dasatinib.

2. Last day of dasatinib (= on the day prior to surgery) Timing of Collection: patient
should be asked to come into the clinic before taking her last morning dose of
dasatinib. Blood can be drawn immediately prior to her taking the tablet in the
clinic.

3. Last day of dasatinib (= on the day prior to surgery) Timing of Collection: 2-3 hours
after the last morning dose

4. Last day of dasatinib (= on the day prior to surgery) Timing of Collection: 6-8m hours
after the last morning dose

5. On the day of surgery Timing of Collection: as close as possible to the surgery (+/- 1
hour) Patients will be requested to document the date and time of each dose consumed as
well as any details concerning a drug holiday in the patient diary.

Samples from all patients are required to all for the relatively large variability in
dasatinib pharmacokinetics (interpatient coefficient of variation is approximately 65 %) The
samples will be centrifuged, processed, and shipped. Results from the pharmacokinetics
analysis will be correlated with the molecular data.

Number of Patients: 60 evaluable patients

Statistical Analysis:

The primary objective of this trial is to evaluate molecular changes occurring in breast
cancer tissue following short-term dasatinib administration. Based on pre-clinical data
supporting the role of Src in "triple-negative" breast cancer, the study will aim for 50% of
evaluable patients be of this subtype defined as being negative for ER, PR, and HER2
amplification. In cases where HER2 amplification is not determined by FISH at diagnosis,
HER2 staining by IHC of 0 or 1+ will be considered negative for enrolment purposes. After
30, 40, and 50 evaluable patients have been accrued, enrolment may be adjusted to reach the
goal of 30 triple-negative patients.

Descriptive statistics will be used to compare the pre- and post-treatment molecular
findings. A statistical Analysis Plan (SAO) will be finalized at the latest prior to
database lock and the analysis details will be provided in the SAP. Descriptive statistics
will be used to describe the incidence of adverse events and toxicity, as well as the number
of patients in who the study medication was permanently stopped.

Stopping Rules:

Enrolment is completed according to protocol planned sample size, and assessments and
requirements are completed as per protocol, the stated objectives of the trial are achieved,
recommendation by DMC. Patients may withdraw from the trial at any time at their own
request, or they may be withdrawn at any time at the discretion of the investigator or
sponsor if continuation of the study would be detrimental to the patient's well being, such
as objective disease progression, unacceptable toxicity, noncompliance, second primary
malignancy, or logistical considerations