Safety and tolerability of oral halofuginone hydrobromide in refractory recurrent transitional cell carcinoma of the bladder

Abstract

4757 Background: Halofuginone hydrobromide (Tempostatin) is an orally bioavailable quinazolinone derivative that acts as a signal transduction inhibitor in stromal cells and susceptible tumor cells. In animal models of bladder cancer, halofuginone inhibits growth of primary tumor and metastases at exposures (AUC) of 4–8 ng*hr/ml by supressing angiogenesis, tumor cell proliferation, and invasion. Methods: A phase II dose-intensity study in refractory recurrent TCC with halofuginone administered orally at 0.5 mg BID for 6 months. Treatment is started immediately following TUR and continues until tumor recurrence or unacceptable tolerability. Patients are monitored for tumor recurrence by cystoscopy and cytology at 3-month intervals. Results: 11 patients (5 M, 6 F), median age 77 yrs (range 52–87), have been enrolled. Total treatment days is >1200. Two patients are relapse-free and continue taking study drug beyond 6 months. Adverse events possibly related to therapy: nausea and/or vomiting grade 1–2 (resolved spontaneously or with anti-emetics) (4 patients). One patient each reported headache grade 2, fatigue grade 1, and indigestion grade 3. One patient experienced transient anemia that resolved while continuing therapy. No other significant changes in laboratory parameters were observed. Pharmacokinetic samples were analyzed for 7 of the 11 patients. Mean plasma AUC on Day 1 was 2.4ng.h/ml (1.16–3.09 ng.h/ml) and on Day 15 10.26 ng.h/ml (4.4–15.8ng.h/ml). Mean Cmax on Day 1 was 0.47 ng/ml and on Day 15 was 2.087 ng/ml. Drug concentration in urine on Day 15 was 87.87–197.95 ng/ml (mean 139.8 ng/ml). Conclusions: Split-dose oral halofuginone 0.5 mg is well tolerated, concentrated in the urine, and achieves AUC values exceeding those that inhibit bladder cancer in animal models. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Collgard Biopharmaceuticals Collgard Biopharmaceuticals Collgard Biopharmaceuticals