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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

60 participants

Study Classification

INTERVENTIONAL

Study Start Date

2005-06-24

Study Completion Date

2010-08-15

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Arm I (lower dose 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.

Group Type EXPERIMENTAL

Genistein

Intervention Type DRUG

Given orally

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Pharmacological Study

Intervention Type OTHER

Correlative studies

Therapeutic Conventional Surgery

Intervention Type PROCEDURE

Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.

Arm II (higher dose 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.

Group Type EXPERIMENTAL

Genistein

Intervention Type DRUG

Given orally

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Pharmacological Study

Intervention Type OTHER

Correlative studies

Therapeutic Conventional Surgery

Intervention Type PROCEDURE

Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.

Arm III (placebo)

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.

Group Type PLACEBO_COMPARATOR

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Pharmacological Study

Intervention Type OTHER

Correlative studies

Placebo Administration

Intervention Type OTHER

Given orally

Therapeutic Conventional Surgery

Intervention Type PROCEDURE

Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.

Interventions

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Genistein

Given orally

Intervention Type DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type OTHER

Pharmacological Study

Correlative studies

Intervention Type OTHER

Placebo Administration

Given orally

Intervention Type OTHER

Therapeutic Conventional Surgery

Undergo cystoscopic excision, transurethral resection of the bladder tumor, or cystectomy.

Intervention Type PROCEDURE

Other Intervention Names

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4'',5, 7-Trihydroxyisoflavone Genestein Genisteol Prunetol

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Howard H Bailey

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin Chemoprevention Consortium

Locations

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University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States

Site Status

South Orange County Surgical Medical Group Inc

Laguna Hills, California, United States

Site Status

University of Iowa/Holden Comprehensive Cancer Center

Iowa City, Iowa, United States

Site Status

AccuMed Research Associates

Garden City, New York, United States

Site Status

University of Rochester

Rochester, New York, United States

Site Status

Urology San Antonio Research PA

San Antonio, Texas, United States

Site Status

Saint Vincent Hospital Cancer Center Green Bay

Green Bay, Wisconsin, United States

Site Status

University of Wisconsin Chemoprevention Consortium

Madison, Wisconsin, United States

Site Status

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Site Status

ProHealth Waukesha Memorial Hospital

Waukesha, Wisconsin, United States

Site Status

Countries

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United States

References

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Messing E, Gee JR, Saltzstein DR, Kim K, diSant'Agnese A, Kolesar J, Harris L, Faerber A, Havighurst T, Young JM, Efros M, Getzenberg RH, Wheeler MA, Tangrea J, Parnes H, House M, Busby JE, Hohl R, Bailey H. A phase 2 cancer chemoprevention biomarker trial of isoflavone G-2535 (genistein) in presurgical bladder cancer patients. Cancer Prev Res (Phila). 2012 Apr;5(4):621-30. doi: 10.1158/1940-6207.CAPR-11-0455. Epub 2012 Jan 31.

Reference Type DERIVED

PMID: 22293631 (View on PubMed)