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

NCT01007695 | Terminated Phase 1 DMC

• 1 other identifier: HCI36488
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

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 The investigators' gene array data predict sensitivity to valproic acid in over half of breast cancers \[Bild, unpublished\].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.

Conditions

Cancer

Keywords

breast cancer

Outcome Measures

Primary Outcomes (1)

• 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.

  December 2013

Secondary Outcomes (5)

• 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.

  December, 2013

• Analyze the change in immunohistochemical markers of proliferation, apoptosis, and tumor grade following treatment with valproic acid in newly diagnosed breast cancer.

  December, 2013

• Analyze the change in radiologic markers of tumor size and vascularity following treatment with valproic acid in newly diagnosed breast cancer

  December, 2013

• 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.

  December, 2013

• Determine if women have dose-limiting toxicities for valproic acid over 7-12 days

  December, 2013

Study Arms (1)

All patients

EXPERIMENTAL

All participants enrolled.

Drug: Valproic Acid

Interventions

Valproic Acid DRUG

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.

All patients

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Utah: lead

Study Sites (1)

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Neoplasms; Breast Neoplasms

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Theresa Werner, MD

  Huntsman Cancer Institute

  PRINCIPAL INVESTIGATOR

• Adam Cohen, MD

  Huntsman Cancer Institute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2009
• First Posted: November 4, 2009
• Study Start: May 1, 2010
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: July 20, 2016

Record last verified: 2016-07

Locations

US (1)