Molecular Signature of Valproic Acid in Breast Cancer With Functional Imaging Assessment - a Pilot (VAST)
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Purpose
The investigators' hypothesis is that valproic acid given before surgery for newly diagnosed breast cancer will increase breast tumor histone acetylation at tolerable doses and that the increase in breast tumor histone acetylation will correlate with valproic acid blood levels and changes in peripheral blood white blood cell histone acetylation. Published in vitro studies have shown sensitivity of breast cancer cells to histone deacetylase inhibitors (Fortunati et al., 2008; Fuino et al., 2003; Hodges-Gallagher et al., 2007; Olsen et al., 2004). The investigators' gene array data predict sensitivity to valproic acid in over half of breast cancers [Bild, unpublished]. The investigators hypothesize that in women with newly diagnosed breast cancers valproic acid will have an unacceptable toxicity rate less than 15% at doses that increase tumor histone acetylation and that valproic acid will decrease the Ki-67 in at least half of breast tumors by over 20%. The investigators also hypothesize that their genomically-derived signature for sensitivity to valproic acid (GDSS-VPA) can be used to predict which tumors will have a decrease proliferation as measured by Ki-67 by at least 20%. The investigators hypothesize that valproic acid levels and histone acetylation levels in peripheral leukocytes will correlate with a decrease in the Ki-67 proliferation index by 20%. The investigators hypothesize that DCE-MRI imaging studies will provide an accurate and quantitative means of assessing tumor response to valproic acid. Finally, the investigators hypothesize that response to valproic acid will not be affected by intrinsic breast cancer subtype.
| Condition | Intervention | Phase |
|---|---|---|
|
Cancer |
Drug: Valproic Acid |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Molecular Signature of Valproic Acid in Breast Cancer With Functional Imaging Assessment - a Pilot |
- 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. [ Time Frame: December 2011 ] [ Designated as safety issue: No ]
- Assess the sensitivity and specificity of the genomic sensitivity signature of VPA (GDSS-VPA) to predict histologically measured antitumor activity of valproic acid in newly diagnosed breast cancer. [ Time Frame: December, 2011 ] [ Designated as safety issue: No ]
- Analyze the change in immunohistochemical markers of proliferation, apoptosis, and tumor grade following treatment with valproic acid in newly diagnosed breast cancer. [ Time Frame: December, 2011 ] [ Designated as safety issue: No ]
- Analyze the change in radiologic markers of tumor size and vascularity following treatment with valproic acid in newly diagnosed breast cancer [ Time Frame: December, 2011 ] [ Designated as safety issue: No ]
- Analyze whether intrinsic breast subtype by the Breast Bioclassifier correlates with changes in tumor proliferation rate or changes in DCE-MRI markers of size and vascularity following treatment with valproic acid. [ Time Frame: December, 2011 ] [ Designated as safety issue: No ]
- Determine if women have dose-limiting toxicities for valproic acid over 7-12 days [ Time Frame: December, 2011 ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 33 |
| Study Start Date: | May 2010 |
| Estimated Study Completion Date: | December 2013 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: All patients
All participants enrolled.
|
Drug: Valproic Acid
Valproic Acid is FDA approved and indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Valproic Acid is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
|
Show Detailed Description Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Biopsy-proven invasive adenocarcinoma of the breast 1.5cm or larger by clinical exam or imaging including ultrasound, mammogram, CT, or MRI
- Females at least 18 years-old,
- Not pregnant, as demonstrated by a negative serum or urine pregnancy test in women of child bearing potential, and not planning on becoming pregnant
- Willing to have a biopsy at the start of study if adequate sample for gene array is not available.
- Willing to have a biopsy at the end of the trial if breast surgery is not planned.
- ECOG Performance status 0-2
- Able to provide informed consent and have signed an approved consent form that conforms to federal and institutional guidelines
Exclusion Criteria:
- Need for immediate chemotherapy as determined by the patients' physicians, e.g., present or imminent compromise of vital organs or unacceptable symptoms from the tumor.
- Known hypersensitivity to valproic acid or its components or peanut allergy
- Inadequate bone marrow, kidney, and liver function (greater than grade 1 by CTCAE version 4) as defined by the protocol.
- Immunocompromised due to medications or HIV as documented in medical history
- Use of other antiepileptics or medications with known interactions with valproic acid (See protocol for full list)
- Inborn errors of metabolism (valproic acid is contraindicated in patients with known urea cycle disorders)
- History of pancreatitis
- Use of a ketogenic diet
- 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
- Tumor that is unlikely to yield adequate tissue for genomic studies in the opinion of the principle investigator
Contacts and Locations| Contact: Mark Wade | 801-587-4284 | mark.wade@hci.utah.edu |
| Contact: Greg Lamb | 801-585-0431 | greg.lamb@hci.utah.edu |
| United States, Utah | |
| Huntsman Cancer Institute | Recruiting |
| Salt Lake City, Utah, United States, 84112 | |
| Principal Investigator: | Theresa Werner, MD | Huntsman Cancer Institute |
| Study Chair: | Adam Cohen, MD | Huntsman Cancer Institute |
More Information
No publications provided
| Responsible Party: | University of Utah |
| ClinicalTrials.gov Identifier: | NCT01007695 History of Changes |
| Other Study ID Numbers: | HCI36488 |
| Study First Received: | November 2, 2009 |
| Last Updated: | April 10, 2013 |
| Health Authority: | United States: Institutional Review Board United States: Food and Drug Administration |
Keywords provided by University of Utah:
|
breast cancer |
Additional relevant MeSH terms:
|
Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Valproic Acid Anticonvulsants Central Nervous System Agents Therapeutic Uses Pharmacologic Actions |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action GABA Agents Neurotransmitter Agents Physiological Effects of Drugs Antimanic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs |
ClinicalTrials.gov processed this record on May 23, 2013