• EFFICACY MEASUREMENTS:
  
• Disease response/progression will be assessed by using CT scan and RECIST criteria.
  
• The objective response rate, response duration, and progression-free survival, duration of stable disease and time to response for Vorinostat will be determined.
  
• CT scan for measurable disease will be repeated after every 2 treatment cycles.
  
• Beyond 6 treatment cycles of Vorinostat in responding patients, the frequency of CT scan may be increased to every 12 weeks.
  
• SAFETY MEASUREMENTS:
  
• Vital signs, physical examinations, ECOG performance status, Adverse Events, lab safety tests, and electrocardiograms will be obtained or assessed prior to drug administration and at designated intervals throughout the study.
  

• CORRELATIVE STUDIES:
  
• Pharmacokinetic studies will be performed after the first and fifteenth dose of oral Vorinostat.
  
• Germline DNA from peripheral mononuclear cells will be extracted for pharmacogenetic studies for genotyping of drug metabolizing enzymes and cancer genes that may influence disposition and tumor efficacy of Vorinostat.
  
• Histone acetylation studies in peripheral mononuclear cells will be performed at baseline and after 3 weeks of treatment.
  
• Plasma proteomics studies using SELDI-MS with the Ciphergen technology will be collected serially to identify protein markers that are associated with Vorinostat response.
  
• OPTIONAL CORRELATIVE STUDIES:
  
• Tumor histone acetylation studies, genomics and proteomics studies will be optional.
  
• Patients with tumor that is easily assessable for biopsy with minimal risks (eg skin nodules, breast tumor, axillary lymph node) will be recruited to participate in the optional correlative studies.
  
• Tumor tissues will be obtained at baseline, and after 3 weeks of oral Vorinostat.
  

Breast cancer is sensitive to a range of chemotherapeutics agents, but despite initial sensitivity, resistance typically emerges, resulting in disease relapse or progression. Exploration of novel classes of agents in the treatment of breast cancer is therefore in urgent need. Vorinostat or SAHA, a potent inhibitor of histone deacetylase (HDAC) activity, represents a novel class of anti-cancer agents in early stages of development.

Vorinostat is active in inducing differentiation, cell growth arrest, and/or apoptosis in a wide variety of transformed cells in culture, and has shown activity against breast cancer in cell lines and animal models.

Exploratory pharmacokinetic analysis has demonstrated that oral Vorinostat has excellent bioavailability. Oral Vorinostat has been administered to more than 300 patients enrolled in completed or ongoing clinical studies. The maximum tolerated dose (MTD) is 400 mg q.d. or 200 mg b.i.d. continuously, or 300 mg b.i.d. x 3 consecutive days per week. Dose-limiting toxicities (DLT) are non-hematologic (anorexia, dehydration, diarrhea and fatigue), that resolve quickly once drug administration is interrupted. This study will evaluate the safety and efficacy of Vorinostat in breast cancer patients who have failed anthracyclines and taxanes, and if proven active, will add an important new class of agents to the treatment armamentarium of breast cancer. The study will be divided into 2 phases: phase I to determine the MTD in our population, starting with 400mg q.d. continuously, with progressive dose decrements in the event of DLT; and phase 2 to determine efficacy of Vorinostat at MTD in 12-37 evaluable patients. Correlative studies (pharmacokinetics, pharmacogenetics, plasma proteomics, tumor histone acetylation, genomics and proteomics) will be carried out to identify markers that will predict treatment response and/or toxicity to Vorinostat, to achieve the future goal of tailored therapy.