Trial Information

Molecular Signature of Valproic Acid in Breast Cancer With Functional Imaging Assessment - a Pilot

Before treatment each woman needs a DCE-MRI and a biopsy of the breast mass. For women who
have had diagnoses of breast cancer outside our institution, the study procedures are
illustrated in figure 1. Following screening labs and enrollment, a DCE-MRI will be
performed followed by a biopsy to obtain two cores for study immunohistochemistry studies
and one core for the GDSS-VPA. The biopsy will be examined by the pathologist to confirm
diagnosis and stained for markers of histone acetylation, proliferation, and apoptosis.

For women who are coming to the HCI for a breast biopsy for a suspicious mass that is
greater than 1.5 cm by exam, mammogram, ultrasound, CT, or MRI, study procedures are
illustrated in figure 2. A DCE-MRI will be done on the same day prior to the biopsy under
existing research MRI consents, if possible. Biopsy material is already obtained for
research purposes using a tissue collection consent. One of these cores will be placed in
liquid nitrogen for storage. If no breast cancer is seen on other cores, then the frozen
core will be used by the clinical pathologist and the woman will not be eligible for the
study. If the diagnosis of cancer is confirmed, the woman will then be consented for this
trial. If she consents, then the frozen core may have one section taken to confirm the
presence of tumor, and the rest will be sent for GDSS-VPA. Once clinical examination of the
non-frozen parts of core biopsy is completed, then study immunohistochemistry will be done
on the remaining tissue in the paraffin block. If the DCE-MRI was not done prior to the
biopsy, then it should be done as soon as possible after the biopsy.

Once the biopsy and DCE-MRI have been obtained, all women will receive therapy according to
the following schedule.

Valproic acid 30mg/kg/day divided BID starting AM of day 1. We will assess toxicity after
2.5 days. If grade 2 side effects are present, continue at the same dose, reassessing every
three days. When all side effects are grade 1 or less, then increase dose by 10 mg/kg/day
every three days to a maximum of 50mg/kg/day. If a grade 3 side effect is encountered, then
hold medicine until side effect resolves and restart at previous dose level for remainder of
time. The highest tolerated dose will be continued until the day of surgery, which will not
be before 7 days of valproic acid therapy or after 12 days of valproic acid therapy. If a
dose-limiting toxicity is encountered, then the patient will be removed from the study. See
appendix 18.2 for schedule based on what day of the week treatment is started.

On day 3 and 6, a valproic acid level and PWBC histone acetylation will be drawn prior to
the dose increase. These labs are used for secondary endpoints and as such are optional for
women for whom transportation here to obtain blood may be difficult.

The proportion of patients that experience a dose limiting toxicity is expected to be low.
Dose limiting toxicity would be grade 4 confusion, grade 3 encephalopathy, grade 3 cognitive
dysfunction, grade 3 somnolence, grade 3 dizziness, grade 3 tremor that does not improve
with beta-blocker therapy, or any other grade 4 non-hematologic adverse event. A 2% rate of
dose limiting toxicity would be considered acceptable, while a 15% rate of dose limiting
toxicity would be considered unacceptable. The stopping rule will allow a maximum of one (1)
patient to experience a dose limiting toxicity per eight (8) patients accrued. Patient
accrual will be stopped for excessive toxicity if this level of toxicity is exceeded. More
detail is provided in section 11.1. With this stopping rule, the probability of stopping the
trial for excessive toxicity is 0.16 if the true rate of DLT is 2%, and the probability of
stopping the trial for excessive toxicity is 0.88 if the true rate of DLT is 15%.

Between day 7 and day 12, once the subject has been on the highest tolerated dose of
valproic acid treatment for at least two days, a DCE-MRI will be performed followed by
surgical excision of the primary tumor per standard of care. If surgery is to be delayed
for neoadjuvant therapy or other non-study related reasons, then a repeat biopsy will be
performed. The last dose of valproic acid will be taken on the morning of surgery or
biopsy. Following the surgery or biopsy, there will be one end of study visit with the
subject to assess for any lingering toxicity. Data on subjects will then be taken from
clinical appointments for 6 months after surgery to assess for relapse rates.