Phase II study of vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in patients with advanced transitional cell urothelial cancer (TCC) after platinum-based therapy—California Cancer Consortium/University of Pittsburgh NCI/CTEP-sponsored trial

Abstract

16058 Background: There is no defined standard second-line therapy for patients (pts) with advanced TCC. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of models including the modulation of apoptosis in bladder cancer cell lines (Earel JK Cancer Res 2006). The HDACi SAHA has recently been approved by the FDA for cutaneous T-cell lymphoma (Olson EA J Clin Oncol 2007). We evaluated the efficacy and toxicity of SAHA in patients with recurrent/metastatic TCC failing first line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease. Methods: SAHA was given orally 200 mg BID continuously until progression or unacceptable toxicity. Cycle length was 3 weeks. Primary end point was RECIST response rate (RR); a RR > 20% was deemed interesting in a 2-stage design requiring at least one response in the first 12 pts to proceed to the 2nd stage of 37 pts. Patients were imaged every 6 weeks. Results: Fourteen pts were entered. Patient characteristics: median age-65 years (43–84); Caucasian (93%); males (86%). Karnofsky performance status (> 90, <80) - 57%, 41%. Best responses: stable (3 pts), progression (8), death from other cause (1), & too early (2). Median number of cycles was 2 (range 1–11). Median disease free survival and overall survival times were 1.1 (1.0–2.1) & 4.3 (2.1–8.3) months, respectively. Toxicities were predominantly due to cytopenia and thrombocytopenic bleeding. Two early on-study deaths occurred. Five pts had grade 4/5 toxicity; 4 had grade 3. Two pts with stable disease had low grade (<2) toxicity and remained on therapy for 5+ months. The study closed to further accrual after review of first stage results. Conclusions: Suberoylanilide Hydroxamic Acid (vorinostat) in this dose-schedule proved surprisingly toxic and had limited efficacy in pts with advanced TCC. Further evaluation of lower dose regimens in combination with cytotoxic or target specific agents may be warranted but should be undertaken with caution. No significant financial relationships to disclose.