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

Study Overview
=================
Brief Summary
-----------------
Studying samples of blood, urine, and tissue from patients with cancer in the laboratory may help doctors learn more about changes that may occur in DNA and identify biomarkers related to cancer. It may also help doctors learn how genistein or placebo works in patients with bladder cancer. This randomized phase II trial is studying genistein or placebo to compare how they work in patients who are undergoing surgery for bladder cancer.

Detailed Description
-----------------
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.

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

Conditions
-----------------
Recurrent Bladder Carcinoma, Stage I Bladder Cancer AJCC v6 and v7, Stage II Bladder Cancer AJCC v6 and v7, Stage III Bladder Cancer AJCC v6 and v7

Intervention / Treatment
-----------------
* Drug: Genistein
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Placebo Administration
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
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 partical 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (lower dose genistein)<br>Patients receive oral genistein 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. | Drug: Genistein<br>* Given orally<br>* Other names: Prunetol;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.<br>|
| Experimental: Arm II (higher dose genistein)<br>Patients receive oral genistein as in arm I but at a higher dose. One day after completion of genistein or placebo, all patients undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy. | Drug: Genistein<br>* Given orally<br>* Other names: Prunetol;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.<br>|
| Placebo Comparator: Arm III (placebo)<br>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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo Administration<br>* Given orally<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epidermal Growth Factor Receptor (EGFR) Phosphorylation in Tumor Tissue, as Measured by Immunohistochemistry After the Completion of Treatment | Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days | 
| pEGFR in Benign Tissue | Detecting the signal of the biomarker, pEGFR, in the benign tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BLCA-4 in Urine by Visit | Detecting the mean amount of the biomarker BLCA-4 in the urine of patients prior to starting study agent, at Day 8 and pre-surgery time (when they have been on study agent between 14-21 days). This is measured by urine analysis at each of the time points to serve as a surrogate tumor marker. | up to 21 days | 
| Survivin in Urine by Visit (pg/ml) | Detecting the mean amount of the biomarker Survivin in the urine of patients prior to starting study agent, at Day 8 and pre-surgery time (when they have been on study agent between 14-21 days). This is measured by urine analysis at each of the time points to serve as a surrogate tumor marker. | up to 21 days | 
| Survivin in Tumor Tissue | Detecting the signal of the biomarker, Survivin, in the tumor tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| EGFR Mutations in Tumor Tissue | Detecting the signal of EGFR mutations in the tumor tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| EGFR in Benign Tissue | Detecting the signal of the biomarker, EGFR, in the benign tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| Ki-67 in Tumor Tissue | Detecting the signal of the biomarker, Ki-67, in the tumor tissue after being on study drug for between 14-21 days as a way to measuring the effects G-2535 have on it with regards to proliferation, apoptosis, and other processes relevant to bladder cancer. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| Activated Caspase 3 in Tumor Tissue | Detecting the signal of the biomarker, Activated Caspase 3, in the tumor tissue after being on study drug for between 14-21 days as a way to measuring the effects G-2535 have on it with regards to proliferation, apoptosis, and other processes relevant to bladder cancer. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| COX2 in Tumor Tissue | Detecting the signal of the biomarker, COX2, in the tumor tissue after being on study drug for between 14-21 days as a way to measuring the effects G-2535 have on it with regards to proliferation, apoptosis, and other processes relevant to bladder cancer. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| AKT in Tumor Tissue | Detecting the signal of the biomarker, AKT, in the tumor tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| pAKT in Tumor Tissue | Detecting the signal of the biomarker, pAKT, in the tumor tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| MAP Kinase in Tumor Tissue | Detecting the signal of the biomarker, MAP Kinase, in the tumor tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug | 
| pMAP Kinase in Tumor Tissue | Detecting the signal of the biomarker, pMAP Kinase, in the tumor tissue after being on study drug for between 14-21 days. Strong, Moderate, Weak, and Negative are categorized based on the signal. The measurements display the strength of the signal between the different Arms. | up to 21 days on Study Drug |