Phase II Randomized Placebo-Controlled Clinical Trial of Genistein in Reducing the Toxicity and Improving the Efficacy of Intravesical Therapy
Phase: PHASE2
Conditions: Bladder Cancer
Sponsor: Emory University

 
 
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Title: PHASE II RANDOMIZED PLACEBO-CONTROLLED CLINICAL TRIAL OF GENISTEIN IN 
REDUCING THE TOXICITY AND IMPROVING THE EFFICACY OF INTRAVESICAL THERAPY 
Study Principal Investigator: Omer Kucuk MD  
Study Sponsor:  Omer Kucuk, MD 
Study Co-Principal Investigator: Viraj Master, MD PhD 
Study Supporter: DSM Nutritional Products 
Version Date: 16 Jul 2019 
 
Schema: 
E
n
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o
ll
m
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44 TaT1 Tis superficial bladder 
cancer patients scheduled to 
receive BCG intravesical therapy 
will be consented 
 
Estimated Timeline: until 44 
subjects are enrolled 
(approximately 2 years) 
R
a
n
d
o
m
iz
a
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Arm 1: BCG 
intravesical 
therapy with 
placebo pills 
for 10 weeks 
(22 subjects) 
F
o
ll
o
w
-
u
p 
Arm 1: Followed-up according to 
standard after-treatment care: one-
month post-treatment appointment 
and subsequent doctor visits. 
Arm 2: BCG 
intravesical 
therapy with 
30 mg 
genistein 
supplement 
PO TID for 10 
weeks 
(22 subjects) 
Arm 2:  Followed-up according to 
standard after-treatment care: one-
month post-treatment appointment 
and subsequent doctor visits. 
Patients will take either 30 mg tablets of placebo or genistein supplement PO TID, for 6 weeks during 
BCG intravesical therapy and will continue for 4 weeks following therapy. 
 
 

 
 
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1. Abstract:   
Patients who are treated with BCG intravesical therapy for TaT1 Tis superficial bladder 
cancer often develop adverse effects (urinary tract symptoms) which limit the dose (and 
therefore the efficacy) of therapy and result in poor quality of life. Genistein is a nutritional 
supplement with anti-inflammatory properties which might help alleviate adverse effects of 
intravesical therapy that are due to inflammation. Additionally, genistein also has anti-tumor 
and immunopotentiating properties and has been shown to have no known side effects. Our 
hypothesis is that genistein given together with BCG intravesical therapy will reduce its 
adverse effects and improve the efficacy of therapy. Patients (N=44) scheduled for 
intravesical therapy will be randomly assigned to take 30 mg tablets of genistein supplement 
(N=22) or placebo (N=22) PO TID during therapy and one month post therapy.  
2. Introduction and Background: 
BCG intravesical therapy is a form of immunotherapy commonly used to prevent the 
recurrence of noninvasive bladder cancer, which occurs in approximately 50-80% of bladder 
cancer patients within 5 years. 10-20% of all superficial bladder cancer patients will progress 
beyond superficial recurrence within 5 years.  Smoking, poor diets, and large body weights 
are all potential risk factors for recurrence, but there is also a high propensity for bladder 
cancer recurrence in general due to its aggressive nature. As treatment, BCG intravesical 
therapy is instilled in the bladder using a urinary catheter.  The intravesical therapy remains 
in the bladder for about two hours until the patient urinates.  The treatment is usually once 
a week for six weeks and then repeated every 3-6 months for two years.  However, 
intravesical therapy typically causes urinary tract symptoms, such as pain, frequency, 
burning, inflammation, and bleeding in patients. Symptoms may occur after the very first 
treatment or become worse over time as therapy continues. As a result, the dose of therapy 
is often reduced so that symptoms can be treated symptomatically with antibiotics or pain 
medication. Dose reduction is generally done in 50% increments, and the decision to reduce 
the treatment dosage is often subjective based on each patient’s perception of symptoms. 
 
The isoflavone genistein (4,7,4'-trihydroxyisoflavone) is a phytoestrogen found in high levels 
in soy products and can be taken as a nutritional supplement for its antioxidant benefits and 
its estrogenic properties. The genistein supplement is sold over the counter and has less soy 
isoflavone than commonly found in many healthy diets. For comparison, an 8 ounce glass of 
soy milk has 15 mg of genistein. Studies have used up to 300 mg of genistein supplement 
daily, and it has been shown as safe, well accepted, and well tolerated with no known 
significant toxicities.  
 
Recent epidemiologic reports show that some Asian countries with high soy consumption 
have a smaller incidence of prostate carcinoma and studies suggest it might be due to the 
anticancer effects of soy. A study of 41 subjects in 2003 showed that there was a significant 
slow in the rate of PSA rise in prostate cancer patients after taking 100 mg of genistein 
supplement daily for 6 monthsi A recent study of 52 subjects in 2010 showed that the short-

 
 
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term, neoadjuvant synthetic aglycone genistein supplement was comparable to high 
soybean consumption and indicated a possible therapeutic benefit in early CaP, a borderline 
significant serum PSA reduction, and normalization of PSA in malignant prostate tumors.ii 
Genistein has been reported to have both anticancer and anti-inflammatory effects that 
may inhibit prostate cancer cell growth and metastasis, as well as an effect on decreased 
incidence of urinary, gastrointestinal, and erectile dysfunctions when 42 patients were 
given 100 mg genistein supplement daily for 6 months in conjunction to radiation.iii 
Additionally, a small pilot study of 8 children receiving chemotherapy and/or radiation were 
given 8 mg of the genistein supplement daily and findings suggest that the genistein 
supplement reduced the adverse effects of treatment while causing no side effects.iv The 
results from these studies suggest that further clinical investigation should be warranted to 
apply soy phytochemicals, as a potential prevention regimen for cancer progression . 
 
In a large prospective cohort of 2000 Chinese men, the association between dietary 
isoflavone and lower urinary tract symptoms (LUTS) were studied using standardized 
structured questionnaires.  A total of 96.2 % of subjects reported some consumption of 
genistein, glycitein, or daidzein. In ordinal multinominal logistic regression, subjects with 
dietary total isoflavone of more than 5.1 mg were significantly less likely to suffer from 
more severe LUTS.v The aforementioned studies suggest that the use of genistein in 
combination with intravesical therapy will allow for more effective treatment of bladder 
cancer. 
 
3. Investigational Product Information: 
 
This study will use the synthetic non-soy genistein supplement,  BonisteinTM .  BonisteinTM 
has been compounded into tablets named I-Cool ®.  Each I-Cool tablet contains 30 mg of 
genistein (BonisteinTM).  I-Cool ® and the corresponding placebo tablets are supplied by 
DSM Nutritional Products.  DSM Nutritional Products as the study product supplier, 
provides Certificate of Analysis to Study Sponsor.  Patients enrolled in the study will be 
receiving I-Cool ® tablets or the corresponding placebo tablets. 
 
4. Objectives: 
 
4.1 Primary objective 
The primary study endpoint is the change in severity of urinary symptoms over time as 
determined by the IPSS questionnaire score, specifically comparing the symptoms at the 
1st BCG treatment (baseline) to the symptoms at the 6th week of treatment. The 
difference in the degree of urinary symptoms between the placebo and genistein 
supplement arms will help reflect whether genistein supplement can improve the quality 
of life in BCG intravesical therapy patients. 
 
 
4.2 Secondary objective 

 
 
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a) A secondary study endpoint will be the presence of cancer and the rate of recurrence 
as determined by the 10-week biopsy or subsequent standard follow-up visits. 
 
b) A second secondary study endpoint will be the total dose of intravesical therapy 
administered over the 6 weeks of treatment. If subjects develop fewer urinary tract 
symptoms as a result of the genistein supplement, then hypothetically, intravesical 
therapy dosing would not have to be reduced as much. This will be measured by 
looking at the level of dose reduction for each treatment week and comparing it 
across the two arms. 
 
5. Study Design and Methods: 
At the pre-operative office visit before intravesical therapy, eligible patients will be screened 
and enrolled into the study by going through the consent process and signing the consent 
and HIPAA forms. Each patient will need to report all other medications so that the study 
team can assess whether certain medications might affect trial outcome. 
 
Patients will be randomized into Arm 1 (placebo) or Arm 2 (genistein supplement) at a ratio 
of 1:1 stratified by one dichotomized prognostic factor, age. The dichotomization will take 
place based on whether they are age 60 and above or whether they are age 59 and below. 
This will allow for similar age groups to be placed in each arm, so that the degree of urinary 
symptoms while receiving treatment is not skewed depending on the patient’s age. 
 
Patients are treated with intravesical therapy once a week for 6 weeks and then return to 
the office approximately four weeks later for a post-operative visit and biopsy, as is standard 
care. Study subjects will take their genistein or placebo tablets for a total of 10 weeks, which 
includes the length of their treatment, as well as the 4 weeks before the post-op visit. Each 
patient will fill out an International Prostate Symptom Score (IPSS) questionnaire at their 
baseline office visit when consented.  Patients will fill out an IPSS questionnaire at each 
subsequent intravesical therapy session and their final one-month follow-up appointment (at 
10 weeks) either in person or via phone call with a study team member. The IPSS 
questionnaire will gauge their urinary symptoms throughout their therapy and provide 
measurable symptom scores for the two arms. The biopsy at 10 weeks, as well as standard 3 
months follow-up appointments, is standard care for superficial bladder patients and will 
help determine cancer rate of recurrence. 
 
 

 
 
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Baseline 
BCG Week 1-6b 
10 Week c 
Placebo Arm 
• Screening 
(Physical Exam,a 
Vitals, a 
complete blood 
count and serum 
chemistry 
analyses, a Urine 
Dipstick, IPSS 
Questionnaire)  
• Enrollment 
• Randomization 
 
• Urine Dipstick, 
Interval History, Vitals, 
IPSS Questionnaire*, 
• BCG Intravesical 
Therapy 
• 6 weeks of placebo 
(30 mg, PO TID) 
• Continue taking 
placebo for remaining 
4 weeks before biopsy 
• Bladder Cystoscopy 
(Biopsy 
recommended, but 
not mandatory )  
• Urinary cytology (if 
inidicated) 
• Interval History 
• IPSS Questionnaire* 
• Physical Exam 
• Vital signs  
• Complete blood 
count and serum 
chemistry panel is 
recommended, but 
not mandatory 
 
 
Genistein 
Supplement 
Arm 
• Screening 
(Physical Exam, a 
Vitals, a 
complete blood 
count and 
serum 
chemistry 
analyses, a Urine 
Dipstick, IPSS 
Questionnaire) ,  
• Enrollment,  
• Randomization 
 
• Urine Dipstick, 
Interval History, Vitals, 
IPSS Questionnaire*, 
• BCG Intravesical 
Therapy 
• 6 weeks of genistein 
Supplement (30 mg,  
PO TID) 
• Continue taking 
genistein Supplement  
for remaining 4 weeks 
before biopsy 
 
• Bladder Biopsy 
(pathology)  
• Urinary cytology 
• Interval History 
• IPSS Questionnaire* 
• Physical Exam 
•  Vital signs 
• Complete blood 
count and serum 
chemistry panel is 
recommended, but 
not mandatory  
 
a Within 2 months before the first dose of study treatment.  
b A range of 7 days before or after the scheduled visit is allowed or per standard of care. If 
BCG treatment is interrupted or discontinued Urine Dipstick, Interval History, and Vitals may 
not be collected per standard of care.  
c A range of 2-3 weeks before or after the 10 week is allowed or per standard of care.  
*IPSS Questionnaire may be collected via phone call.  
6. Participant Selection: 
44 patients will be enrolled in the trial, with 22 subjects on each arm. Potential subjects will 
be superficial bladder cancer patients in the Department of Urology who are scheduled for 
their standard-of-care BCG intravesical therapy. 

 
 
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Inclusion Criteria:  
1. Male or female gender 
2. 18 years or older 
3. Diagnosis of superficial bladder cancer 
4. Scheduled for induction BCG intravesical therapy 
5. Willing and able to give blood sample 
6. Willing and able to fill out a pill diary to ensure compliance 
7. Willing and able to sign informed consent 
***Birth Control is not required for this study!  
Exclusion Criteria: 
1. Patients who are pregnant 
2. Diagnosis of muscle-invasive bladder cancer 
3. Unwillingness to follow study protocol and compliance procedures 
4. HIV positive or immunocompromised 
5. Receiving concurrent immunotherapy or chemotherapy 
6. Presence of concurrent second cancer (active, not history) 
7. Quality of Life:  
This study follows standard of care for all superficial bladder cancer subjects. All subjects 
will receive standard BCG intravesical therapy for six weeks and return for a one-month 
post-operative visit and biopsy. Both the control and intervention arms will receive the 
same care, other than taking the genistein supplement or placebo. While genistein 
supplement is not a standard part of treatment, it has been shown to not have any 
significant toxicities. It is expected that the subjects taking genistein supplement will have a   
better quality of life due to a possible reduction in urinary symptoms, such as hematuria, 
infection, frequency, urgency,  and retention, when compared to those subjects receiving 
standard treatment without the genistein supplement. Each patient’s perception of quality 
of life will be seen indirectly throughout the BCG treatment, as it is a supplemental question 
on the IPSS Questionnaire. 
Quality of life will be assessed for both arms during an interim analysis and stopping criteria 
will be determined on the degree of individual AEs as well as an interim analysis of both 
arms. Subjects with toxicities of Grade 3 or higher according the NCI CTCAE Version 4.0 will 
be immediately discontinued from the study pill. Additionally, the interim analysis will take 
place after 22 patients (11 on each arm) have been enrolled, treated, and biopsied. If the 
genistein supplement arm has statistically significant toxicities reported or greater degree 
of bladder cancer biopsies then we will immediately discontinue any future study 
enrollment. If the genistein supplement arm has significant Grade 3 toxicities, we will 
reduce the genistein supplement given by 1 tablet for 10 more patients, and if the toxicities 
persist after that, the study will be stopped.  

 
 
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8. Statistical Consideration: 
 
8.1 Power analysis 
We hypothesize that, at 6 weeks, the symptom score will increase by 6 (SD = 3.5) relative 
to the baseline in the placebo arm, while it will only increase by 3 (SD = 3.5) in the 
synthetic genistein supplement arm. A sample size of 20 patients in each arm can reach 
83% power to detect the hypothesized difference at the significance level of 0.05 by one-
sided Mann-Whitney test. 
 
In an effort to reach a sample size of 20 patients on each arm, we also hypothesize that 
there will be a 10% drop-out or non-compliance rate. We will accrue 44 patients, 22 
subjects on each arm, for this study with the expectation that 10% will drop out. With a 
10% drop out rate included, this would result in a total of 40 compliant patients. 
 
8.2 Statistical analysis plan 
 
8.2.1 Primary analysis 
The IPSS score change at 6-week from baseline will be calculated with 95% confidence 
interval and compared between two experiment groups through Mann-Whitney test. 
The baseline, minimum three treatment period IPSS scores, and the 10-week biopsy IPSS 
scores are required in order for the patient to be evaluable.  
 
8.2.2 Secondary analysis 
a) For the secondary end point of recurrence rate defined by 10-week biopsy, the 
Chi-squares test is used to test the rate difference between the two arms, and a 
logistic regression is needed to further adjust potential covariates, e.g. total BCG 
therapy dose. 
b) For the secondary end point of the total dose of intravesical therapy administered 
over 6 weeks, we consider the two-sample t test and/or sum rank test to test the 
difference between two arms. If genistein supplement works by reducing 
symptoms and maintaining the therapy dose, we expect to see a higher total 
therapy dose in its arm than in the placebo arm. 
c) We will also explore the change of IPSS score over time by the GEE model in 
which the repeated measurements of IPSS score are treated as outcome.  
Treatment, time, interaction between treatment and time, and intravesical 
therapy dose enter the model as predictors and time-dependent covariate. 
 
 
9. Adverse Event Reporting:   
 
According to 21 CFR 312.32, Adverse event means any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related. A 
Serious adverse event or serious suspected adverse reaction is an adverse event or 
suspected adverse reaction is considered "serious" if, in the view of either the 

 
 
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investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Adverse events will be recorded at each study visit via direct patient communication as 
well as through patient questionnaires. The severity of the AEs will be graded according 
to NCI CTCAE Version 4.0. Subjects with toxicities of Grade 3 or higher will be 
immediately discontinued from the study pill for the remainder of treatment. Any BCG 
intravesical therapy modifications will be done according to doctor analysis with an effort 
on alleviating toxicities as needed. In order to be evaluable, patients will need to receive 
at least three BCG instillations. If BCG treatment is interrupted or discontinued, only IPSS 
scores will be obtained via phone call. If a SAE occurs, we will promptly report it to our 
IRB upon discovery and follow the subject until the SAE is resolved. Adverse events will 
be reported to the IRB according to their requirements. 
 
IND safety reports will be sent to the FDA in accordance with 312.32 the FDA’s Guidance 
for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE 
studies. IND safety reports will document any aggregate adverse events, adverse 
reactions suspected adverse reactions, or serious adverse events. If the event is 
considered to be unexpected fatal or life-threatening, the IND safety report will be sent 
as soon as possible and within 7 business days of the investigator being notified. If 
necessary, the investigator will report any serious or life-threatening event initially by 
facsimile or telephone prior to formal submission. IND safety reports will also be 
submitted to the FDA if any related safety information is released from other sources. 
Any nonserious adverse events will be reported to the FDA in aggregate on an annual 
basis. 
 
 
10. Data and Safety Monitoring Plan (DSMP):  
 
Once the study has reached 50% accrual, investigators will plan to initially evaluate the 
results.  A group of physicians from the Winship Cancer Institute at Emory University will 
review the data and questionnaires to see how patients are reacting to the genistein 
supplement arm or whether there are drug compliance issues, such as failure to take the 
pills per protocol.  If the genistein supplement arm has statistically significant toxicities 
reported or greater degree of bladder cancer biopsies then we will immediately 

 
 
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discontinue any future study enrollment. If the genistein supplement arm has significant 
Grade 3 toxicities, we will reduce the genistein supplement given by 1 tablet for 10 more 
patients, and if the toxicities persist after that, the study will be stopped. 
Also, per Winship Cancer Institute’s Data Safety Monitoring Plan, their Data Safety 
Monitoring Committee will review the study conduct annually as well as monitor for 
regulatory compliance. 
 
 
11. References and Appendices 
i Soy Isoflavones in the Treatment of Prostate Cancer. Nutrition and Cancer. 2003 Nov;47(2):111-117. Hussain M, 
Banerjee M, Sarkar FH, Djuric Z, Pollak MN, Doerge D, Fontana J, Chinni S, Davis J, Forman J, Wood DP, Kucuk 
O. 
ii Efficacy and  safety of short-term genistein intervention in patients with localized prostate cancer prior to radical 
prostatectomy: a randomized, placebo-controlled, double-blind phase 2 clinical trial. Nutrition and Cancer IN 
PRESS. Lazarevic B, Boezelijn G, Diep LM, Kvernrod K, Ogren O, Ramberg H, Moen A, Wessel N, Berg RE, 
Egge-Jacobsen W, Hammarstrom C, Svindland A, Kucuk O, Saatcioglu F, Tasken KA, Karlsen, SJ.  
iii Soy Isoflavones in Conjunction with Radiation Therapy in Patients with Prostate Cancer. Nutrition and  Cancer. 
2010 Oct;62(7):996-1000. Ahmed IU, Forman JD, Sarkar FH, Hillman GG, Heath E, Vaishampayan U, Cher ML, 
Andic F, Rossi P, Kucuk O. 
iv Soy Isoflavones Ameliorate the Adverse Effects of Chemotherapy in Children. Nutrition and Cancer. 2010 Oct; 
62(7): 1001-1005. Tacyildiz N, Ozyoruk D, Yavuz G, Unal E, Dincaslan H, Dogu F, Sahin F, Kucuk, O. 
v The association between isoflavone and lower urinary tract symptoms in elderly men. Br J Nutr. 2007 
Dec;98(6):1237-42. Wong SY, Lau WW, Leung PC, Leung JC, Woo J.