Trial Information

Phase I/II Clinical Trial of Vorinostat in Patients With Recurrent and/or Metastatic Breast Cancer

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.