Phase II trial of tamoxifen for progressive advanced urothelial carcinoma following prior chemotherapy.

Abstract

e15003 Background: Urothelial carcinoma (UC) expresses estrogen receptor (ER)-β, which increases with stage and grade. The selective estrogen receptor modulators, tamoxifen and raloxifene have displayed anti-tumor activity in preclinical UC. Effective therapy for progressive UC following chemotherapy is lacking. A rationale can be made to evaluate the activity of tamoxifen following prior chemotherapy for advanced UC. Methods: A non-randomized two-center 2-stage phase II trial was planned. Eligible patients were required to have bladder or upper tract urothelial cancer, measurable metastatic disease, 1-2 prior chemotherapy regimens, adequate organ function and ECOG performance status (PS) 0-2. The primary endpoint was freedom from progression (FFP) at 4 months (mo), with secondary endpoints of response, survival, toxicities and association of tumor ER studies with FFP. FFP of ≥30% was considered important and ≤10% was felt to reflect poor activity. Twenty-five evaluable subjects were required, 15 during stage 1 and 10 during stage 2 for α=0.05 and power =0.8. If ≥2 patients attained FFP during stage-1, the trial proceeded to stage-2. Tamoxifen was administered as 20 mg orally once daily until progression by RECIST or intolerable toxicities. Clinical assessments were performed every 4 weeks and imaging every 8 weeks or earlier if indicated. ER isoforms were measured in archival formalin fixed tumor. Results: The trial has completed accrual with 28 patients enrolled of whom 18 are currently evaluable (16 male and 2 female). Number of prior chemotherapy regimens was 2 in 15, ≥3 in 2 and unknown in 1 patient. ECOG-PS was 0 in 9, 1 in 7 and 2 in 2 patients. Liver metastasis was present in 4 and anemia (Hb <10 gm/dL) in 7 patients. Four patients (22.2%) attained FFP at 4 mo. Minor tumor regression was seen in 1 patient. One grade 3 toxicity (deep vein thrombosis) possibly related to therapy was observed. Tumor ER isoform studies and correlation with FFP will be presented. Conclusions: Tamoxifen exhibited potential activity in a subset of patients with advanced UC following chemotherapy. Given the excellent tolerability, further study may be warranted to identify factors predictive of benefit in less heavily pretreated patients.