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

Phase 2

Completed

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

Interventions: Other: Laboratory Biomarker Analysis
Drug: Genistein
Other: Placebo Administration
Other: Pharmacological Study
Procedure: Therapeutic Conventional Surgery

Registration Number: NCT00118040

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (higher dose genistein)	Therapeutic Conventional Surgery	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.
Arm III (placebo)	Therapeutic Conventional Surgery	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.
Arm I (lower dose genistein)	Therapeutic Conventional Surgery	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.
Arm III (placebo)	Laboratory Biomarker Analysis	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.
Arm III (placebo)	Placebo Administration	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.
Arm II (higher dose genistein)	Pharmacological Study	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.
Arm I (lower dose genistein)	Laboratory Biomarker Analysis	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.
Arm I (lower dose genistein)	Pharmacological Study	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.
Arm III (placebo)	Pharmacological Study	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.
Arm II (higher dose genistein)	Laboratory Biomarker Analysis	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.
Arm I (lower dose genistein)	Genistein	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.
Arm II (higher dose genistein)	Genistein	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.

Primary Outcome Measures

Name	Time	Method
Epidermal Growth Factor Receptor (EGFR) Phosphorylation in Tumor Tissue, as Measured by Immunohistochemistry After the Completion of Treatment	up to 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.
pEGFR in Benign Tissue	up to 21 days on Study Drug	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.

Secondary Outcome Measures

Name	Time	Method
Survivin in Tumor Tissue	up to 21 days on Study Drug	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.
EGFR in Benign Tissue	up to 21 days on Study Drug	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.
Ki-67 in Tumor Tissue	up to 21 days on Study Drug	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.
Activated Caspase 3 in Tumor Tissue	up to 21 days on Study Drug	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.
COX2 in Tumor Tissue	up to 21 days on Study Drug	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.
Survivin in Urine by Visit (pg/ml)	up to 21 days	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.
BLCA-4 in Urine by Visit	up to 21 days	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.
EGFR Mutations in Tumor Tissue	up to 21 days on Study Drug	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.
AKT in Tumor Tissue	up to 21 days on Study Drug	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.
MAP Kinase in Tumor Tissue	up to 21 days on Study Drug	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.
pMAP Kinase in Tumor Tissue	up to 21 days on Study Drug	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.
pAKT in Tumor Tissue	up to 21 days on Study Drug	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.

Trial Locations

Locations (10): University of Wisconsin Chemoprevention Consortium
🇺🇸
Madison, Wisconsin, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸
Green Bay, Wisconsin, United States
AccuMed Research Associates
🇺🇸
Garden City, New York, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
University of Rochester
🇺🇸
Rochester, New York, United States
ProHealth Waukesha Memorial Hospital
🇺🇸
Waukesha, Wisconsin, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
South Orange County Surgical Medical Group Inc
🇺🇸
Laguna Hills, California, United States
Urology San Antonio Research PA
🇺🇸
San Antonio, Texas, United States