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

Recurrent Bladder Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00118040
• Other study ID #: NCI-2013-00453
• Secondary ID: NCI-2013-00453CD
• Status: Completed
• Phase: Phase 2
• Start date: June 24, 2005
• Est. completion date: August 15, 2010

Study information

• Verified date: March 2021
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: August 15, 2010
• Est. primary completion date: August 15, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• 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
• Urinary Bladder Neoplasms

Intervention

Drug:
• Genistein
Given orally

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies
• Placebo Administration
Given orally

Procedure:
• Therapeutic Conventional Surgery
Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	AccuMed Research Associates	Garden City	New York
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	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	University of Wisconsin Chemoprevention Consortium	Madison	Wisconsin
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of Rochester	Rochester	New York
United States	Urology San Antonio Research PA	San Antonio	Texas
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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