The major objective of this two-stage phase II study is to determine whether tamoxifen is deserving of further study in metastatic bladder cancer. Tamoxifen is expected to function as a cytostatic (and not cytotoxic) agent, and may produce more disease stability than regression. Sustained stable disease is considered to be clinically important and the more likely event. Hence, 4-month freedom from progression is chosen as the primary end-point instead of response rate. Freedom from progression is defined as the period from start of therapy to the time of objective radiologic progression. A total of 25 subjects will be enrolled, 15 during stage 1 and 10 during stage 2 of a two-stage minimax design phase II study.

Pre-therapy evaluation (within 3 weeks of initiation of therapy):

• History and physical examination (H and P)
• Performance status (PS) assessment
• CBC (complete blood counts)
• CMP (complete metabolic profile)
• Pregnancy test (in women younger than 50)
• Computed tomography (CT) scan of the chest, abdomen and pelvis
• Bone scan if bone pain or raised alkaline phosphatase
• Biopsy (may use previous biopsy specimen)
• Samples of plasma from the routine CBC and CMP will be banked indefinitely for future biomarker studies at the Scott Department of Urology.

Treatment plan: Therapy will be administered as an outpatient. Tamoxifen is administered at 20 mg/day as a single daily oral dose. Clinical assessment of patients by a history and physical examination will be performed every 4 weeks (one cycle). Objective radiological assessment of response will be made every 8 weeks or earlier if clinically indicated. A CT (computerized tomography) scan of the abdomen, pelvis and chest will be performed at baseline and every 2 cycles. A response is confirmed by repeating the scans in 4 weeks. Bone scan is performed if the patient complains of new bone pain or has raised alkaline phosphatase. A radiologist who is blinded to the treatment regimen reads the scans. The RECIST criteria are used to define response. Tamoxifen is continued until progressive disease or intolerable side effects occur.

• Kim HT, Kim BC, Kim IY, Mamura M, Seong DH, Jang JJ, Kim SJ. Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. J Biol Chem. 2002 Sep 6;277(36):32510-5. Epub 2002 Jun 25.
• Shen SS, Smith CL, Hsieh JT, Yu J, Kim IY, Jian W, Sonpavde G, Ayala GE, Younes M, Lerner SP. Expression of estrogen receptors-alpha and -beta in bladder cancer cell lines and human bladder tumor tissue. Cancer. 2006 Jun 15;106(12):2610-6.

Inclusion Criteria:

• Patients previously diagnosed with bladder cancer who have already received 1-2 systemic therapy regimens (chemotherapy or biological therapy or both) but including at least one chemotherapy regimen.
• Patients who have had the cancer spread to other parts of the body.
• Patients must have adequate liver function.

Exclusion Criteria:

• Patients who have uncontrolled nervous system metastasis
• Patients who are pregnant
• Patients who have had systemic therapies within the past 4 weeks
• Patients who plan to have major surgery within 2 weeks
• Patients who have Grade III/IV heart problems
• Patients who have severe and/or uncontrolled medical disease.
• Patients who might be at high risk for deep vein thrombosis

• AstraZeneca
• Cytogen Corporation