Clinical trial NCT00118040: Phase II Study of Isoflavone G-2535 (Genistein) in Patients With Bladder Cancer
Official title: Phase II Study of Isoflavone G-2535 (Genistein) in Patients With Bladder Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2005-07-11
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Epidermal Growth Factor Receptor (EGFR) Phosphorylation in Tumor Tissue, as Measured by Immunohistochemistry After the Completion of Treatment
timeFrame: up to 21 days
measure: pEGFR in Benign Tissue
timeFrame: up to 21 days on Study Drug
Secondary outcomes:
measure: BLCA-4 in Urine by Visit
timeFrame: up to 21 days
measure: Survivin in Urine by Visit (pg/ml)
timeFrame: up to 21 days
measure: Survivin in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: EGFR Mutations in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: EGFR in Benign Tissue
timeFrame: up to 21 days on Study Drug
measure: Ki-67 in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: Activated Caspase 3 in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: COX2 in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: AKT in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: pAKT in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: MAP Kinase in Tumor Tissue
timeFrame: up to 21 days on Study Drug
measure: pMAP Kinase in Tumor Tissue
timeFrame: up to 21 days on Study Drug
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Laguna Hills
country: United States
facility: South Orange County Surgical Medical Group Inc
state: California
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Garden City
country: United States
facility: AccuMed Research Associates
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: San Antonio
country: United States
facility: Urology San Antonio Research PA
state: Texas
city: Green Bay
country: United States
facility: Saint Vincent Hospital Cancer Center Green Bay
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Chemoprevention Consortium
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Waukesha
country: United States
facility: ProHealth Waukesha Memorial Hospital
state: Wisconsin
Study officials:
affiliation: University of Wisconsin Chemoprevention Consortium
name: Howard H Bailey
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.