Phase II Study of Isoflavone G-2535 (Genistein) in Patients With Bladder Cancer

PRIMARY OBJECTIVES:

I. To measure the effect of G-2535 on EGF-R phosphorylation. Two EGF-R phosphorylation sites
with functional significance are phosphotyrosine 992, which is a direct binding site for the
PLC-gamma SH2 domain, and phosphotyrosine 1068, a binding site for the Grb2/SH2 domain. The
expression of EGF-R and phosphorylated EGF-R will be determined in tumors as well as
adjacent and remote normal appearing urothelium.

SECONDARY OBJECTIVES:

I. Measuring tissue intermediate endpoint biomarkers such as EGF-R mutations (EGFR vIII,
exon 19-21), Ki67, activated Caspase 3, Akt, P-Akt, MAP kinase, P-MAP kinase, COX-2,
survivin, and BLCA-4 and we will also determine survivin and BLCA-4 levels in urine
specimens as surrogate tumor markers. Biomarkers associated with the EGF-R pathway,
including Akt and P-Akt will be studied by immunohistochemistry. Additionally, Ki67,
activated Caspase 3 (as a marker of apoptosis), and COX-2 will serve as biological endpoint
biomarkers to measure the effects of G-2535 on proliferation, apoptosis, and other processes
and molecules relevant to bladder cancer. These studies will be performed on tumors as well
as adjacent and remote normal urothelium. II. Safety will also be studied.

OUTLINE: This is a randomized, placebo-controlled, multicenter study. Patients are
stratified according to invasiveness of disease (non-invasive [stage Ta, Tis, or T1] vs
invasive [stage T2, T3, or T4]). Patients are randomized to 1 of 3 treatment arms.

Arm I: Patients receive oral genistein twice daily for approximately 14-30 days.

Arm II: Patients receive oral genistein as in arm I but at a higher dose. Arm III: Patients
receive oral placebo twice daily for approximately 14-30 days.

One day after completion of genistein or placebo, all patients undergo cystoscopic excision,
transurethral resection of the bladder tumor, or cystectomy.

Patients undergo blood, urine, and tissue sample collection for pharmacogenomic,
pharmacokinetic, and biomarker laboratory studies. Blood and urine samples are collected at
baseline, after 1 week of treatment, and at the time of surgery for pharmacokinetic and
urine biomarker (survivin and BLCA-4) studies. Pharmacogenomic studies (epidermal growth
factor receptor [EGFR] polymorphisms and CYP3A 4/5 genotypes) are performed at baseline
using blood samples. Tissue biomarker (EGFR polymorphism, EGFR mutations [EGFR vIII, exon
19-21], EGFR, phosphorylated EGFR, Ki67, activated caspase 3, Akt, P-Akt, MAP kinase, P-MAP
kinase, COX-2, survivin, and BLCA4) studies using tumor tissue and adjacent and remote
normal urothelium are performed at baseline and at the completion of treatment.

PROJECTED ACCRUAL: A total of 60 patients (20 per treatment arm) will be accrued for this
study within 1 year.

Inclusion Criteria:

- Participants eligible for this study will have been evaluated by diagnostic office
cystoscopy and found to have a bladder tumor; enrollment (signing of the consent
form) must be within 60 days of pre-study cystoscopy demonstrating bladder tumor; the
participant should have no evidence of distant metastasis and the primary tumor may
represent either an initial diagnosis or recurrent disease of any clinical stage.
Study participants must also be candidates for either subsequent
cystoscopy/transurethral resection of bladder tumor (TURBT) or complete or partial
cystectomy; histologic diagnosis is not required for enrollment; pre-enrollment
diagnostic cystoscopy must be at least 45 days after treatment of the bladder with
other agents such as BCG (participants with recurrent disease)

- ECOG performance status 0 or 1

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation

- Ability to understand and the willingness to sign a written informed consent document

- WBC >= 3000/mm^3

- Platelets >= 100,000mm^3

- Hemoglobin >= 10 g/dL

- Bilirubin =< 1.4 mg/dl

- AST =< 3x normal

- Creatinine =< 2.0mg/dl

- Serum calcium =< 10.2 mg/dl,

- Amylase =< 3 x normal

- Na >= 125 and =< 155 mmol/L

- K >= 3.2 and =< 6 mmol/L

- Cl >= 85 and =< 114 mmol/L

- CO2 >= 11 mEQ/dL

- TSH within 1.3 x the upper range of normal and normal T4

- Females of child-bearing potential must have a negative pregnancy test; patients who
have had a bilateral oophorectomy, hysterectomy, are greater than 1 year since their
last menses, or are greater than 51 years of age are not considered to be of
child-baring potential

- Participants must agree to stop soy supplements before enrolling in the study

- Patients must agree to stop taking NSAIDS before enrolling in the study; patients
may, however, take cardioprotective doses of aspirin equal to or less than 81mg per
day

Exclusion Criteria:

- Participant may not have received other treatment for bladder cancer between the
pre-enrollment cystoscopy and subsequent surgery

- Participants may not be receiving any other investigational agents

- Participant may not have received prior pelvic irradiation for any reason

- Participant may not be receiving concurrent systemic cancer treatment for other
cancers

- Participant may not be taking concurrent soy supplements while on the study
medication

- Participant may not be taking concurrent NSAIDS (aspirin doses of =< 81 mg
acceptable) while on the study medication

- Participant may not be taking thyroid medications

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to genistein, soy isoflavones or other allergies to soy-based products
will render a participant ineligible

- Uncontrolled concurrent illness will render a participant ineligible including,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, unregulated cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements

- Women may not be pregnant or lactating; the effects of G-2535 on the developing human
fetus at the recommended therapeutic dose are unknown; for this reason women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately