Genistein Combined With FOLFOX or FOLFOX-Avastin for Treatment of Metastatic Colorectal Cancer: Phase I/II Pilot Study
Phase: PHASE1
Conditions: Colon Cancer, Rectal Cancer, Colorectal Cancer
Sponsor: Sofya Pintova

Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment 
of Metastatic Colorectal Cancer: Phase I/II Pilot Study
PI: Dr. Sofya Pintova
NCT01985763
Document Date: Sept 12, 2016

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
1 
Revised 7/20/12 
Brief Summary of Research (250-400 words):  
Colorectal neoplasms are the third most common malignancies in the United States and a major 
cause of mortality in our population. Patients with metastatic (stage IV) colorectal cancer have a 
median life expectancy of 2 years but in the vast majority of cases have incurable disease.  
Response rates to chemotherapy range from 35-40%.   
Epidemiologic evidence suggests that soy compounds may reduce the incidence of colorectal 
cancers. Further, preclinical data support the concept that genistein, a soy-derived substance, may 
serve a role in prevention of colorectal cancers. Laboratory analyses demonstrate that genistein 
inhibits Wnt signaling, a pathway activated in majority of colon cancers. Additionally, in vitro 
observations suggest that combining genistein with chemotherapeutic agents augments growth 
inhibition of colon cancer cell lines.  The primary agents that have improved activity in the 
laboratory with the addition of genistein are platinum compounds and 5-fluorouracil. 
Based on pre-clinical data, the purpose of the study is to combine genistein with standard of care 
treatment in patients with metastatic colorectal cancers. We hypothesize that combining genistein 
with standard of care FOLFOX or FOLFOX-Avastin chemotherapy regimens will lead to reduced 
chemotherapy resistance and improve response rates in patients with metastatic colorectal cancer.  
FOLFOX and FOLFOX-avastin are standard first line chemotherapy regimens for patients with 
metastatic colorectal cancer.  Each contains 5-fluorouracil (F) and a platinum agent, oxaliplatin 
(OX). 
Genistein is classified by the FDA as a GRAS compound – generally recognized as safe.  It is a 
derivative of soy and classified as a nutritional supplement; therefore, it is not regulated as a drug 
by the FDA.  It has minimal side effects at dosages which have been studies (up to 600mg/day) 
and there no evidence that this compound has any effect on the toxicity of standard chemotherapy.   
The aim of the study is to recruit newly diagnosed patients with colon or rectal cancers who have 
already been identified to receive either FOLFOX or FOLFOX-A by their treating oncologist.  
Genistein will be administered in the pill form with every chemotherapy treatment. Patients will 
be carefully monitored for toxicity. Response rates in all patients will be measured by radiologic 
RECIST criteria.  We hypothesize that genistein will improve response rates over published 
historical control response rates for these regimens. 
 
1) Objectives 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
2 
Revised 7/20/12 
We hypothesize that genistein will reduce chemotherapy resistance and lead to improved response 
rates in colon and rectal cancer patients receiving 5FU and oxaliplatin based therapy as first line 
treatment for metastatic disease. The aim of the study is to treat patients with newly diagnosed stage 
IV colorectal cancer with genistein in addition to standard of care treatments FOLFOX or FOLFOX-
Avastin. 
 
2) Background 
Colorectal cancers (CRC) are the third most common malignancy in United States and represent a 
significant cause of cancer related mortality.  While therapeutic options for patients with 
metastatic colorectal cancer have improved over the past decade, the vast majority of these 
patients, up to 90%, die from their metastatic disease.  Therefore, it is important that new 
approaches for the treatment of metastatic colorectal cancer continue to be explored. 
 
Colorectal malignancies are less common in East Asia where diet is thought to contain more soy. 
Soy products have some estrogenic properties and evidence suggests that estrogen may play a 
protective role in colon cancer prevention and that women are less likely than men to develop 
CRC [1].  Additionally, hormone replacement therapy has demonstrated colon cancer risk 
reduction in post-menopausal women [2].  Epidemiologic data evoke a correlation between soy 
consumption and colon cancer risk reduction, as well as reduction in adenomatous polyposis [3-7].  
In vitro data and in vivo animal studies have demonstrated that the soy-derived compound, 
genistein has colon cancer prevention activity [8-10].  This provides a rationale for the study of 
genistein, which is a naturally derived product classified as a nutritional supplement, in the 
treatment of human colorectal cancer. Genistein is classified as a GRAS (generally recognized as 
safe) substance by the FDA. 
 
Prior studies and recent data from our laboratory demonstrate that colon cancer cell growth is 
inhibited when cell lines are treated with genistein [11-13].  The mechanism by which genistein 
inhibits proliferation of colon cancer cells is still under investigation though it may be due in part 
to inhibition of signaling through the Wnt pathway.  The Wnt signaling is activated in >85% of 
patients with colon cancer [14]. Genistein inhibits Wnt signaling by inhibiting the production of 
soluble Wnt inhibitory molecules such as sFRP2 and other mechanisms may also be operative 
[15].  The uniform activation of Wnt signaling in colon cancer, and the activity of genistein to 
inhibit Wnt signaling, makes its use in patients with colorectal cancer potentially rewarding. 
 
There is also strong in vitro evidence suggests that genistein reduces chemotherapy resistance in 
cancer cell lines treated in combination with genistein and either 5FU or platin-class 
chemotherapeutic agents [16-18].  The primary chemotherapeutic regimen utilized for the 
treatment of metastatic colorectal cancer is a combination of 5FU and oxaliplatin (FOLFOX), with 
or without the anti-angiogenic agent bevacizumab (Avastin®).  Genistein may therefore be 
beneficial for patients treated with these agents. 
 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
3 
Revised 7/20/12 
Although preclinical data suggest that genistein may improve inhibition of colon cancer cells, no 
clinical trial has been undertaken to date to test this hypothesis in colorectal cancer patients.  We 
hypothesize that genistein will reduce chemotherapy resistance and lead to improved response 
rates in colon and rectal cancer patients receiving 5FU and oxaliplatin based therapy as first line 
treatment for metastatic disease. We hope that if genistein improves response rate in patients with 
metastatic colorectal cancers, it may lead to observation of improved survival if tested in larger 
randomized control trials.  
 
 
 
3) Setting of the Human Research 
Patients will be recruited at Mount Sinai in the inpatient and outpatient facilities,  including 
the 
 
medical oncology practices at the Ruttenberg Treatment Center. 
4) Resources Available to Conduct the Human Research 
Approximately 130-150 new cases of colorectal cancer are seen at Mt Sinai every year. 
Our goal is to recruit 24 patients. Enrollment in the study would be carried out by the PI 
and co-investigators. Patients will be identified by gastroenterological medical oncologists, 
surgical oncologists and gastroenterologists at Mt Sinai and evaluated for the study by the 
investigators. 
All chemotherapy is standard of care.  Genistein will be distributed through the oncology 
research pharmacy at the Ruttenberg Treatment Center. 
 
All personnel participating in the project has completed the IRB education requirements. 
 
5) Study Design 
 
a) Recruitment Methods 
Potential subjects will be identified at Mount Sinai – on the inpatient wards and in 
 
outpatient clinics. 
The study has been presented at and approved by the GI Oncology disease focus  group 
of 
the 
 
Tisch  Cancer Institute, which includes medical oncologists, surgeons, radiation oncology 
 
physicians and gastroenterologists.  Information about the  availability of the study will be 
 
distributed to the hematology and medical oncology faculty at standard research forums. 
 
b) Inclusion and Exclusion Criteria 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
4 
Revised 7/20/12 
Inclusion:  
• Adult male and female patients ≥18 years old, willing and able to understand and 
sign Informed Consent Form.  
• Have pathologically confirmed colon or rectal adenocarcinoma. 
• Have metastatic disease (stage IV) confirmed surgically, by imaging or 
pathologically. 
• No prior chemotherapy for metastatic disease 
• Have a plan by treating physician to receive FOLFOX or FOLFOX-Avastin 
standard therapy for colorectal cancer as a first-line chemotherapy treatment. 
• Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 
• Have adequate hematopoietic, hepatic and renal function (these represent standard 
criteria for administration of FOLFOX or FOLFOX-A): 
o Hematopoietic function 
 Hemoglobin ≥10g/dL 
 Absolute Neutrophil Counts (ANC) ≥1,500cells/mm2   
 Platelet Count ≥ 100 x 103/µL 
o Hepatic Function 
 Total bilirubin ≤ 1.5x the upper limit of normal 
 
ALT and AST must each be ≤2,5x the upper limits of normal 
o Renal Function 
 Estimated creatinine clearance (Clcr) ≥30 mL/minute 
• Are not pregnant and do not plan to become pregnant during the clinical trial. 
• Women of childbearing age must provide a negative pregnancy test within the 
screening period and must be using adequate contraception (oral or injectable 
[depot] estrogen and/or progesterone, or intrauterine contraceptive device or double 
barrier method [e.g., condom and diaphragm or spermicidal gel]). Non-child 
bearing potential is defined as post-menopausal for at least 1 year or surgical 
sterilization or hysterectomy at least 3 months before clinical trial start. 
Exclusion:  
• Prior systemic chemotherapy for metastatic disease.  
• History of breast cancer, endometrial cancer or ovarian cancer or taking aromatase 
inhibitors or selective estrogen receptor modulators.  
• Patients taking MAO-inhibitors or antipsychotic medications.  
• History of myocardial infarctions or cardiac stent placement less than 1 year before 
recruitment into the study. 
• Unable to give informed consent or comply with clinical trial requirements. 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
5 
Revised 7/20/12 
• Have any past or current, acute or chronic concurrent medical condition/illness or 
therapy that, in the opinion of the investigator, would make the subject unsuitable 
for the clinical trial or unable to comply with follow up visits. 
• 
Uncontrolled hypertension 
• 
History of clinically significant GI bleeding within prior 2 months prior to enrollment 
• 
Presence of GI fistula 
• 
Prior history of bowel perforation 
• History of CNS thrombotic/embolic or ischemic event(s) 
c) Number of Subjects 
The published Response Rates (RR) to FOLFOX and FOLFOX-A are 38% [19].  We plan to treat 
24 patients treated this pilot study.  Since FOLFOX RR and FOLFOX-A have identical RR, both 
groups will be analyzed together for RR.  However, PFS is longer for FOLFOX-A than FOLFOX 
so analysis will be stratified for this secondary endpoint and also for toxicity evaluation.  RR will 
be compared to previously published data [19].   Should a trend toward improved response rate be 
seen, and genistein well tolerated without significant toxicities, then this pilot study will provide a 
rationale for a larger, placebo-controlled trial to confirm the effect of genistein on response rate in 
this patient population. 
 
d) Study Timelines 
We anticipate all enrolment to be complete in 12 months. Patients will complete 6-12 cycles of 
chemotherapy (approximately 3-6 months of treatment) with genistein.  Response rate will be 
determined based on standard-of-care radiographic testing performed at standard time points.  
Patients will have follow up for progression and survival for 1 year following completion of 
treatment on this protocol to record progression free survival.  Data analysis and publication will 
occur subsequently by the end of year 2. 
e) Endpoints 
Primary Endpoint:  
- 
Evaluation of tolerability of genistein treatment. 
o A brief survey about side effects will be conducted with every  
chemotherapy/genistein cycle. 
Secondary Endpoints: 
- 
Response Rate (RR) as measured by radiologic RECIST criteria.  
o Under RECIST criteria Complete Response (CR) is defined as disappearance of 
all target lesions and reduction in the short axis measurement of all pathologic 
lymph nodes to ≤10mm.  

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
6 
Revised 7/20/12 
o Under RECIST criteria Partial Response (PR) is defined as ≥30% decrease in 
the sum of the longest diameters of the target lesions compared with baseline.) 
o Progression of disease (Progression of Disease (PD) defined by RECIST 
criteria as  ≥ 20% increase of at least 5mm in the sum of the longest diameters 
of the target lesions compared with the smallest sum of the longest diameter 
recorded OR the appearance of new lesions)  
o No patients will be treated longer than 12 cycles (6 months) on this protocol. 
o Progression of disease will lead to a change in chemotherapy regimen and will 
result in termination of the subject’s participation in this study. 
- 
Progression Free Survival (PFS) 
o Patients will be monitored for progression during the study period and for 1 
year following. 
f) Procedures Involved in the Human Research 
FOLFOX or FOLFOX-A will be given every 2 weeks for 3 days as standard of care. The 
chemotherapy administration is in itself not a component of research for this study. 
 
It is recommended that the FOLFOX regimen utilized is mFOLFOX-6 either alone, or in 
combination with bevacizumab (Avastin).  The dosages and schedule for medications utilized with 
mFOLFOX-6 and mFOLFOX-6-A, given on a q14 day cycle, are as follows: 
 
Oxaliplatin 
85mg/m2 
250cc D5W over 2 hours IVPB 
 
Day 1 
Leucovorrin 
400mg/m2 
250cc D5W over 2 hours IVPB 
 
Day 1 
Fluorouracil 
400mg/m2 
50cc D5W IVPB over 15 minutes or IVP over 2-4 minutes Day 1 
Fluorouracil 
2400mg/m2 
In D5W IV Continuous Infusion over 46 hour 
Start Day 1 
 
With or without: 
Bevacizumab 5mg/kg 
 
250cc NS over 30 minutes IVPB 
 
Day 1 
 
 
 
Genistein will be administered orally for 7 days every 2 weeks, beginning 4 days prior to 
FOLFOX or FOLFOX-A and continuing during the 3 days of chemotherapy.  This schedule is 
chosen because genistein achieves steady state in the serum within 4 days based on prior 
pharmacokinetic studies [20-26]. Elimination half life approximately 8-10 hours postulating 
complete elimination of genistein within 2 days of completion of this agent. Genistein has been 
administered to humans at dosages of 30-600mg/day without any significant adverse effects [24].  
The dose to be utilized will be 60mg/day. 
 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
7 
Revised 7/20/12 
Toxicity assessment will be performed prior to every cycle of FOLFOX or FOLFOX-A by phone 
survey or in person to evaluate: 1) any toxicity from 4 days of genistein alone and 2) any toxicities 
from prior cycle of FOLFOX or FOLFOX-A with genistein. Toxicity will be evaluated by 
surveying patients regarding adverse effects.  Blood work performed by treating clinician prior to 
administration of chemotherapy, which is standard practice and not part of the study, will also be 
reviewed and recorded. 
 
Response rates will be assessed during restaging evaluations by CEA serum levels and PET-CT or 
CT scan radiologic imaging at routine time points.  The specific type of staging test utilized will 
be at the discretion of the treating clinician. Results of laboratory and radiologic studies will be 
extracted from EPIC or paper records. All this testing is standard of care. 
 
Compliance with self-administration of genistein will also be evaluated prior to every cycle 
through phone survey at the time of toxicity assessment done prior to each chemotherapy cycle. 
 
Subjects will receive 1-6 (3 months) cycles of FOLFOX or FOLFOX-Avastin every 2 weeks in 
combination with Genistein as described above.  It is recommended that efficacy of the 
chemotherapy be assessed as follows, though final decisions regarding the timing of assessment 
will be left to the discretion of the treating oncologist: 
1. CEA determination q 6 weeks (standard-of-care) 
2. Radiographic staging post cycle 6  (standard-of-care) 
3. If CR, PR or stable disease treatment may be continued for 6 more cycles (3 months)  with 
FOLFOX or FOLFOX-Avastin in combination with Genistein. 
4. Radiographic staging post cycle 12 or at cessation of FOLFOX or FOLFOX-Avastin for 
either progression, intolerance or patient preference  
 
 
Study Calendar 
 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
8 
Revised 7/20/12 
SCHEDULE OF ASSESSMENTS  
 
 
 
 
 
 
 
 
 
 
 
 
Note: timing of radiographic staging and CEA are recommendations.  Decision of exact 
time points left to treating physician. 
 
g) Specimen Banking 
No specimens will be banked. 
 
h) Data Management and Confidentiality 
All individual patient data will be kept strictly confidential. Each subject will be given and then 
identified only by a study number. The key will be available only to the principal investigator and 
co-investigators.  All files will be stored in a locked cabinet located in a locked office with keys 
available only to the PI and co-investigators. All electronic data will be password protected and 
encrypted.  
 
i) Provisions to Monitor the Data to Ensure the Safety of Subjects 
All DSMP standards of the PPHS will be adhered to.  
Part I: Elements of a Data and Safety Monitoring Plan 
MSSM Principal Monitor: 
Principal Investigator
Pre-Study 
Radiographic staging of target lesions & CEA 
Standard-of-Care (SOC) 
Post cycle 3 
CEA 
SOC 
Post cycle 6 
Radiographic staging of target lesions & CEA 
SOC 
Post cycle 9 
CEA 
SOC 
Post cycle 12 or at 
cessation of protocol Rx 
Radiographic staging of target lesions & CEA 
SOC 
 
 
 
Toxicity evaluation 
Prior to each cycle 
 
Genistein compliance 
Prior to each cycle 
 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
Neha Kumarley  
 
Date Revised: 
9/12/2016 
Study Number: 
GCO# 13-1697 
 
9 
Revised 7/20/12 
Last Name: Pintova  
First Name: Sofya 
Academic Title: Assistant Professor 
Department: Medicine (Heme/Onc) 
 
E-mail: sofya.pintova@mssm.edu  
Phone: 212-824-8858 
Fax: 212-659-5599 
Mailing Address: 
 Mount Sinai School of Medicine 
Tisch Cancer Institute 
One Gustave L. Levy Place 
Box 1128 
New York, NY 
10029-6574 
MSSM Additional Monitor: 
Co-investigator  
Last Name: Ang 
First Name: Celina 
Academic Title: Assistant Professor 
Department: Medicine (Heme/Onc) 
Mailing Address:  
Mount Sinai School of Medicine 
Tisch Cancer Institute 
One Gustave L. Levy Place 
Box 1079 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
 
10 
Revised 7/13/12 
 
New York, NY 
10029-6574 
Phone: 212 241 6631 
Fax: 212 241 5425 
E-mail: 
 
2. Principal monitor has expertise in conducting clinical research and vast experience in treating 
patients with colorectal malignancies. (Please see attached CV). 
The principal investigator can safely serve as principal monitor since genistein is regarded as 
safe with minimal side effects. 
3. Adverse events assessment will be assessed prior to each cycle of FOLFOX or FOLFOX-A to 
evaluate: 1) any toxicity from 4 days of genistein alone and 2) any toxicities from prior cycle of 
FOLFOX or FOLFOX-A with genistein. Toxicity will be evaluated by surveying patients 
regarding adverse effects. 
The adverse events are assessed in a standard way according to CTCAE 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Abdominal 
Distension 
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; 
limiting 
instrumental ADL 
Severe discomfort; 
limiting self-care 
ADL 
- 
- 
Abdominal Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self-care ADL 
- 
- 
Bloating 
No change in 
bowel function 
Symptomatic, 
decreased oral 
intake; change in 
bowel function 
- 
- 
- 
Constipation 
Occasional or 
intermittent 
symptoms; 
occasional use of 
stool softeners, 
laxatives, dietary 
Persistent 
symptoms with 
regular use of 
laxatives or 
enemas; limiting 
instrumental ADL 
Obstipation with 
manual evacuation 
indicated; limiting 
self-care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
 
11 
Revised 7/13/12 
 
modification, or 
enema 
Nausea 
Loss of appetite 
without alteration 
in eating habits 
Oral intake 
decreased 
without 
significant weight 
loss, dehydration 
or malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube feeding, 
TPN, or 
hospitalization 
indicated 
- 
- 
Vomiting 
1-2 episodes 
(separated by 5 
minutes) in 24 
hours 
3-5 episodes 
(separated by 5 
minutes) in 24 
hours 
>= 6 episodes 
(separated by 5 
minutes) in 24 hrs; 
tube feeding, TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders – Other, 
specify 
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate; 
minimal, local or 
noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental ADL 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; disabling; 
limiting self-care 
ADL 
 
 
 
 
 
 
 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Edema Limbs 
5-10% inter-limb 
discrepancy in 
volume or 
circumference at 
point of greatest 
visible difference; 
swelling or 
obscuration of 
anatomic 
architecture on 
close inspection 
>10-30% inter-
limb discrepancy 
in volume or 
circumference at 
point of greatest 
visible difference; 
readily apparent 
obscuration of 
anatomic 
architecture; 
obliteration of 
skin folds; readily 
apparent 
deviation from 
normal anatomic 
contour, limiting 
>30% inter-limb 
discrepancy in 
volume; gross 
deviation from 
normal anatomic 
contour, limiting 
self-care ADL 
- 
- 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
 
12 
Revised 7/13/12 
 
instrumental ADL 
Allergic Reaction 
Definition: A 
disorder 
characterized by 
an adverse local 
or general 
response from 
exposure to an 
allergen. 
Transient flushing 
or rash, drug fever 
<38 degrees C 
(<100.4 degrees 
F); intervention 
not indicated 
Intervention or 
infusion 
interruption 
indicated; 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for 
<=24hrs 
Prolonged (e.g., not 
rapidly responsive 
to symptomatic 
medication and/or 
brief interruption of 
infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for clinical 
sequelae (e.g., renal 
impairment, 
pulmonary 
infiltrates) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Anaphylaxis  
- 
- 
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
intervention 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Life threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Back pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self-care ADL 
- 
- 
Myalgia 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self-care ADL 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
Headache 
Definition: A 
disorder 
characterized by a 
sensation of 
marked 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self-care ADL 
- 
- 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
 
13 
Revised 7/13/12 
 
discomfort in 
various parts of 
the head, not 
confined to an 
area of 
distribution of any 
nerve 
Breast pain 
Definition: A 
disorder 
characterized by 
marked 
discomfort 
sensation in the 
breast region. 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self-care ADL 
- 
- 
Gynecomastia 
Definition: A 
disorder 
characterized by 
excessive 
development of 
the breasts in 
males.  
Asymptomatic 
breast 
enlargement 
Symptomatic 
(e.g., pain or 
psychosocial 
impact).  
Severe symptoms; 
elective operative 
intervention 
indicated 
- 
- 
Hot flashes 
Definition: A 
disorder 
characterized by 
an uncomfortable 
and temporary 
sensation of 
intense body 
warmth, flushing, 
sometimes 
accompanied by 
sweating upon 
cooling 
Mild symptoms; 
intervention not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL 
- 
- 
Other 
 
 
 
 
 
 
Routine blood work performed by the treating clinician prior to administration of chemotherapy as 
routine care of a patient with colorectal neoplasms will be reviewed. 
Genistein compliance will be assessed prior to each cycle via the phone or in person survey. 
Drop outs will be recorded and assessed at every clinic visit. 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
 
14 
Revised 7/13/12 
 
 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
15 
Revised 7/13/12 
 
4. A faculty-level review committee of experienced clinical trials investigators will 
be convened to analyze toxicities and risks of the study.  This Review Committee 
will be comprised of: 
 
PI: Sofya Pintova, MD 
      
Independent faculty members: Matthew Galsky, MD, Philip Friedlander, MD 
 The Review Committee will evaluate the safety of the first 3 recruited subjects after 
2 cycles of chemotherapy. Recruitment will continue unless 1) unanticipated 
toxicities of greater than grade 2 or 2) any grade 4 toxicities occur.  If either of these 
situations arise, accrual will be placed on hold and data will be presented to the 
DSMC for additional recommendations.  Identical analysis will occur at at 6 months 
or at recruitment of 12 patients (half of total cohort) whichever comes first (Interim 
Analysis). 
The Tisch Cancer Institute Data Safety and Monitoring Committee will also provide 
additional and independent oversight of the conduct of the study. 
5. The study will be discontinued if an increased number of adverse effects is seen as 
outlined in section 4, above and this is recommended by either the Review Committee 
or the DSMC.  The study will also be discontinued if there is a 20% or greater 
increase in the number of deaths compared to expected number in patients with newly 
diagnosed metastatic colorectal cancer population based on prior published data [19].  
Any treatment-related death while on study will lead to an immediate hold on accrual and 
review by the data safety and monitoring committee established for this protocol.  The 
study will be reopened to accrual only with permission from this committee.  If two 
treatment-related deaths occur for patients while on study, the protocol will be 
permanently closed to accrual. 
6. Genistein has been administered to humans at dosages of 30-600mg/day without any 
significant adverse effects [24].  The dose to be utilized will be 60mg/day which is a 
dose previously utilized in trials for men with prostate cancer where no clinically 
significant side effects were noted and for which prolonged administration schedules 
have had documented pharmacokinetic analysis [25]. 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
16 
Revised 7/13/12 
 
7. Toxicity will be evaluated with a questionnaire based on previously published adverse 
effects of genistein.  Any other toxicities will be graded according to the National 
Cancer Institute Common Toxicity Criteria. 
8. Data accuracy and completeness will be ensured by review of the principal monitor 
(PI) and the Data Safety and Monitoring Committee. 
9. In case of suspension of the study, occurrence will be reported to the IRB and the 
sponsor (DSM pharmaceuticals) 
10. Chemotherapy treatment delays: 
 
Planned delay in treatment – for planned delays in treatment, genistein administration 
will be delayed concurrently so as to be administered along with the standard 
chemotherapy as outlined. 
Unplanned delays in treatment – For unplanned delays in treatment, such as when 
neutrophil or platelet counts are insufficient to administer chemotherapy, patients will 
have already taken 4 days of genistein.  Genistein will be stopped for this cycle and 
resumed in conjunction with the rescheduled treatment, beginning 4 days prior to the 
rescheduled treatment date and continuing for 7 days as outlined. 
Part II. Data Monitoring Committee/Data Safety Monitoring Board 
(DMC/DSMB) 
j) Please refer to Section F-i-4. Withdrawal of Subjects 
Participation in the study is voluntary. Subjects may choose to withdraw at any point. 
Participation in the study may be stopped by the research team if the study drug is 
ineffective, harmful or has medically unacceptable side effects.  
6) Risks to Subjects 
Previous studies in healthy volunteers and patients with prostate cancer treated with 
genistein demonstrate low risk of adverse events with this medication and previously 
reported adverse events were described as mild.20-26  Risks to subjects include side effects 
from the study drug such as increased  hot flashes, headache, edema, constipation, 
gynecomastia, nipple tenderness, nausea and rarely increased amylase/lipase levels. 
Patients of childbearing age are advised not to get pregnant as the effect of the drug on 
the fetus is unknown.  Patients who are currently pregnant or breastfeeding will be 
excluded from the study. Patients with personal history of breast, ovarian or uterine 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
17 
Revised 7/13/12 
 
malignancy are excluded because genistein has soy-based estrogen properties. Patients 
with any psychiatric disorders on MAO inhibitors or anti-psychotic medication may 
experience exacerbation of symptoms and will be excluded. Patients with history of 
cardiovascular diseases requiring antiplatelet therapy may theoretically experience an 
increased risk of cardiovascular events while on genistein and patients with MI or cardiac 
stent within past year are therefore excluded. 
There is no published evidence to suggest that genistein increases the risks of 
chemotherapy associated toxicities. 
 
7) Provisions for Research Related Harm/Injury 
Subjects will be followed routinely by an oncologist and other medical specialists. 
Adverse events will be routinely evaluated at each office and chemotherapy visit. Should 
any adverse effects occur, they will be immediately evaluated and managed by the 
treating physician. 
In case of injury or adverse event related to participating in this research study, the 
facilities at Mount Sinai Hospital and professional attention will be made available to 
subjects at their expense or billed to their insurance. Financial compensation from Mount 
Sinai will not be provided. 
8) Potential Benefits to Subjects 
Response rate in metastatic colorectal cancer treated with FOLFOX or FOLFOX-
Avastin is approximately 38%. The hypothesis of the study is that addition of genistein 
to standard of care chemotherapeutic regimen will improve response rates. This may 
translate into longer progression free survival (PFS) and/or longer overall survival (OS) 
which may be of great benefit to individual patients. 
9) Provisions to Protect the Privacy Interests of Subjects 
Written Informed consent will be obtained in the Investigators’ private offices in order to 
maintain confidentiality.  If patients find any procedures, tests or questionnaires 
uncomfortable they may speak with the investigator and can decline to get the test done. 
Patients will be informed about health information and confidentiality. Subjects will be 
informed that certain parties will have access to confidential health information including 
the treating team, research team and also possibly IRB, governmental regulatory agencies 
and the sponsor. Patients will be made aware that participation in the study is purely 
voluntary and should they wish to withdraw their consent at any point, the subjects will 
not be penalized at any point. 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
18 
Revised 7/13/12 
 
All members who will have access to subjects’ private information will have HIPPAA 
training. The study team will ask permission and obtain authorization from each 
participant regarding access to personal health information including demographics, past 
and present medical records, research records, records about phone calls made as part of 
the study and records about study visits. 
10) 
Economic Impact on Subjects 
Genistein will be provided free of charge by the sponsor. The rest of clinical care is part 
of routine standard-of-care in patients with metastatic colorectal cancer.  Data 
management costs will be covered by Mount Sinai internal accounts and will not be 
charged or the patient or their insurance.  We do not anticipate that subjects will incur 
any additional costs through participation in the trial. 
 
11) 
Payments to Subjects 
Subjects will not be paid for participation in this trial. 
12) 
Consent Process 
 
Subjects will be identified and screened during clinic visits and on inpatient wards. For 
subjects interested in study participation informed consent will be obtained by PI or co-
investigator. 
 
Informed consent will be obtained following HRP-090-SOP - Informed Consent Process for 
Research. The patients will have an opportunity to discuss the clinical trial, read through the 
consent form at their leisure, and ask questions of the treating Investigator. To ensure that the 
subjects understand they would be asked to reiterate in their own words the purpose of the 
research, what they will need to do as participants in the study, and what the potential risks, 
potential benefits and alternatives are. 
 
If the patient does not speak or read English, then the consent will be provided in patient’s 
native language.  If a translated consent becomes necessary, one will be submitted for review 
and approval to the IRB with a letter of attestation.  To ensure that the study procedures are 
adequately explained to non-English speaking subjects, a translator will be present at the time 
of the consent process to explain and obtain consent, and answer questions that the subject 
may have. 
Short Form Consent Policy 
The patient population for this study will include English speaking subjects. 
However, it is possible that a patient may be approached for consent who does not 
speak these languages. In such cases, PPHS/CCTO Short Form Policy procedures 
will be followed. 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
19 
Revised 7/13/12 
 
The short form consent will be translated in the potential subject's native language and will be approved 
by the IRB prior. A translator will be present at the time of consent to address any questions the 
subject may have. 
 
13) 
Process to Document Consent in Writing 
Consent will be obtained using the procedures outline in HRP-091-SOP – Written 
Documentation of Consent. 
14) 
Vulnerable Populations 
Indicate specifically whether you will include or exclude each of the 
following populations: 
Include 
Exclude 
Vulnerable Population Type 
 
X 
Adults unable to consent 
 
X 
Individuals who are not yet adults (e.g. infants, children, 
teenagers) 
 
X 
Wards of the State (e.g. foster children) 
 
X 
Pregnant women 
 
X 
Prisoners 
 
15) 
Multi-Site Human Research (Coordinating Center) 
This is a single institution/single site study.  
16) 
Community-Based Participatory Research 
N/A 
17) 
Sharing of Results with Subjects 
Results will be shared with patients including incidental finding and overall study 
findings upon completion of the study. 
18) 
External IRB Review History 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
20 
Revised 7/13/12 
 
None 
19) 
Control of Drugs, Biologics, or Devices 
Please see attached FORM 211.  Genistein will be distributed through the Mount Sinai 
Research Pharmacy. 
 
 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
21 
Revised 7/13/12 
 
References 
 
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1779  
4. Hu JF, at al Diet and cancer of the colon and rectu,: A case-control study in China 1991 Int J 
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5. Nishi M, at al Eating habits and colorectal cancer. 1997 Oncology Rep:995-998 
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12. Linsalata M, et al Effects of Genistein on the Polyamine Metabolism and Cell Growth in 
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NF-kappaB. 2008 J Ovarian Research:1-11 
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the cell cycle progression in vitro. J Medical Colleges of PLA:125-135 

 
Protocol Name: 
Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of 
Metastatic Colorectal Cancer: Phase I/II Pilot Study 
Principal Investigator:  
Sofya Pintova, MD 
Primary Contact 
Name/Contact Info: 
 
Date Revised: 
09/01/2016 
Study Number: 
GCO# 13-1697 
 
22 
Revised 7/13/12 
 
19. Saltz LB, Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line 
Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. 2008 JCO:2013-
2019 
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21. Ullman U, et al, Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of 
Synthetic Genistein (Bonistein) in Healthy Volunteers. 2005 Advances in Therapy:65-78 
22. Setchell KDR, et al, Comparing the pharmacokinetics of daidzein and genistein with the use 
of 13C-labeled tracers in premenopausal women. Am J Clin Nutr:411-420. 
23. Takimoto CH, et al, Phase I Pharmacokinetic and Pharmacodynamic Analysis of 
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24. Fischer L, et al, Clinical Characteristics and Pharmacokinetics of Purified Soy Isoflavones: 
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25. Ullmann U, et al, Repeated Oral Once Daily Intake of Increasing Doses of the Novel 
Synthetic Genistein Product Bonistein in Healthy Volunteers. 2005 Planta Med:891-896 
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