Phase II study of FK228 in patients with hormone refractory prostate cancer (HRPC)

Abstract

14554 Background: FK228 is a bicyclic depsipeptide that inhibits histone deacetylase (HDAC). HDAC inhibition results in accumulation of hyperacetylated histone proteins resulting in G1 and G2/M arrest, differentiation of transformed cells and apoptosis. FK228 can also inhibit HSP90, ablating androgen receptor expression. Methods: FK228 was administered intravenously at 13mg/m2 on days 1, 8 and 15 of a 28-day schedule for up to 6 cycles. Sixteen patients were treated in stage 1. If ≥ 1 response was seen, an additional 9 patients were to be recruited. Eligibility criteria included: no prior chemotherapy, metastatic disease, ≤3 lines of hormonal therapy, QTcB <500 msec, Karnofsky PS ≥80. The primary endpoint was to measure rate of disease control (complete response [CR], partial response [PR], stable disease [SD] for 6 months). Secondary endpoints were PSA response rate, time to PSA and objective disease progression, safety profile, effect on disease related symptoms and pharmacokinetics (PK) of FK228. Results: Interim results are available after 16 patients were enrolled in stage 1 and 5 patients in stage 2. Median age (n = 21): 65 years (range 43–77). 3 patients have completed 6 cycles of treatment, 4 are ongoing and 14 have discontinued. 16 patients are evaluable for radiological response and 18 for PSA response: 1 has achieved a confirmed radiological PR (6 months [m]), and 6 have confirmed SD (2 for 6m, 1 for 5 m, 1 for 4 m+, 1 for 3 m+). 2 of 18 have had a 50% fall in PSA (6 m, 4 m+) and another a 40% fall (5m). Most common drug related adverse events are (grade [gr],%): fatigue (gr 1–2, 88%), nausea (gr 1–2, 77%; gr 3, 10%), anorexia (gr 1–2, 72%), vomiting (gr 1–2, 55%; gr 3, 10%), non-specific asymptomatic ECG changes (gr 1–3, 44%), diarrhoea (gr 1–2, 38%), thrombocytopaenia (gr 1–2, 33%) and weight loss (gr 1, 20%). Conclusions: Interim results of treatment with FK228 suggest clinically relevant antitumor activity with an 18% disease control rate and a 11% PSA response rate. Toxicity is manageable. Accrual into the study continues. [Table: see text]