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

Phase 1
18 Years
Open (Enrolling)

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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.

Inclusion Criteria:

1. Biopsy-proven invasive adenocarcinoma of the breast 1.5cm or larger by clinical exam
or imaging including ultrasound, mammogram, CT, or MRI

2. Females at least 18 years-old,

3. Not pregnant, as demonstrated by a negative serum or urine pregnancy test in women of
child bearing potential, and not planning on becoming pregnant

4. Willing to have a biopsy at the start of study if adequate sample for gene array is
not available.

5. Willing to have a biopsy at the end of the trial if breast surgery is not planned.

6. ECOG Performance status 0-2

7. Able to provide informed consent and have signed an approved consent form that
conforms to federal and institutional guidelines

Exclusion Criteria:

1. Need for immediate chemotherapy as determined by the patients' physicians, e.g.,
present or imminent compromise of vital organs or unacceptable symptoms from the

2. Known hypersensitivity to valproic acid or its components or peanut allergy

3. Inadequate bone marrow, kidney, and liver function (greater than grade 1 by CTCAE
version 4) as defined by the protocol.

4. Immunocompromised due to medications or HIV as documented in medical history

5. Use of other antiepileptics or medications with known interactions with valproic acid
(See protocol for full list)

6. Inborn errors of metabolism (valproic acid is contraindicated in patients with known
urea cycle disorders)

7. History of pancreatitis

8. Use of a ketogenic diet

9. Inability to have an MRI due to extreme claustrophobia, possible metal fragments in
the eye, cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, carotid
artery vascular clamp, neurostimulator, insulin or infusion pump, implanted drug
infusion device, bone growth/fusion stimulator, or cochlear, otologic, or ear implant

10. Tumor that is unlikely to yield adequate tissue for genomic studies in the opinion of
the principle investigator

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine if valproic acid levels correlate with histone acetylation in leukocytes during treatment and whether either valproic acid levels or histone acetylation in leukocytes predict histone acetylation in tumor samples post treatment.

Outcome Time Frame:

December 2011

Safety Issue:


Principal Investigator

Theresa Werner, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Huntsman Cancer Institute


United States: Institutional Review Board

Study ID:




Start Date:

May 2010

Completion Date:

December 2013

Related Keywords:

  • Cancer
  • breast cancer
  • Breast Neoplasms



Huntsman Cancer InstituteSalt Lake City, Utah  84112