Clinical trial NCT02624388
Conditions: Lymphoma Childhood Lymphoma Solid Tumor Childhood Solid Tumor Neuroblastoma Ewing Sarcoma Hodgkin Lymphoma Non-Hodgkin Lymphoma Rhabdomyosarcoma Soft Tissue Sarcoma Medulloblastoma Germ Cell Tumor Wilms Tumor Brain Neoplasms Medulloblastoma, Childhood Neuroectodermal Tumors, Primitive
Keywords: Genistein Soy Chemotherapy side-effects Pediatric Cancer Isoflavone
Sponsor: University of Virginia
Start date: 2016-08-01; Completion date: 2021-09-01
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Toxicities related to pediatric cancer treatment can lead to significant illness, organ damage, treatment delays, increased health care cost, and decrease in quality of life. Such toxicities are largely due to tissue damage sustained by chemotherapy, and strategies designed to limit such cellular damage to normal tissues may reduce therapy-related morbidity and mortality. In addition to their in vitro and in vivo anti-cancer effects, naturally occurring soy isoflavones have anti-inflammatory and anti-oxidant properties, and have been shown to reduce side effects of therapy in adult oncology clinical trials. This study will examine the effect of genistein, the major isoflavone component in soybeans and the most extensively studied of the soy isoflavones, on short-term side effects of myelosuppressive chemotherapy in pediatric cancer patients. Subjects will be randomized to receive either: a) 30 mg genistein daily throughout chemotherapy Cycles 1 and 2 and placebo during chemotherapy Cycles 3 and 4; or b) placebo daily during chemotherapy Cycles 1 and 2 and 30 mg genistein daily during chemotherapy Cycles 3 and 4. Investigators hypothesize that subjects will have fewer short-term therapy-related side effects during cycles of chemotherapy given in conjunction with genistein supplementation than cycles given with placebo.

Detailed description:
This is a multi-center, randomized, double blind, placebo-controlled crossover study to evaluate the effect of soy isoflavones on the short term untoward effects of myelosuppressive chemotherapy used to treat pediatric cancers. Newly diagnosed cancer patients aged 1-21 years will be registered to the study and informed consent will be obtained prior to any study-related procedures. Stratification will be based on length of chemotherapy cycles, between 14 day and 21 day cycles. Within strata registered subjects will be randomized 1:1 to one of two schedules:

Arm A: Subjects will receive genistein daily throughout chemotherapy cycles 1 and 2, and placebo during chemotherapy cycles 3 and 4

Arm B: Subjects will receive placebo daily throughout chemotherapy cycles 1 and 2, and genistein during chemotherapy cycles 3 and 4

Subjects will be assessed for safety and efficacy during each cycle with clinical labs, cytokine panels, and physical exams. Drug compliance will be monitored by use of a patient diary as well as monitoring of serum genistein levels. Adverse events will be monitored starting on Cycle 1 Day 1 through 30 days following the last day of protocol therapy (genistein/placebo).

Arms: arm 1: Genistein daily throughout chemotherapy cycles 1 and 2, and placebo daily during chemotherapy cycles 3 and 4 arm 2: Placebo daily throughout chemotherapy cycles 1 and 2, and genistein daily during chemotherapy cycles 3 and 4
Interventions: intervention 1: Genistein intervention 2: Placebo
Intervention descriptions: intervention 1: Estrogen-like compound (isoflavone) derived from soybeans intervention 2: Pill that contains no medicine

Protocol documents:
Prot_SAP_000.pdf: 
UVa-Gen001: Randomized, Controlled Pilot Study of Genistein in Pediatric Cancer Patients 
Version 3.0, 30Jun2017 
i 
Study Title 
A Randomized, Placebo-Controlled Pilot Study of Genistein 
Supplementation 
in 
Pediatric 
Cancer 
Patients 
Receiving 
Myelosuppressive Chemotherapy 
Protocol Number 
UVA-Gen001 
Study Intervention 
Genistein 
Indication Studied 
Pediatric Cancer 
Development 
Phase of Study 
Pilot 
Study Sponsor 
University of Virginia 
NCT # 
NCT02624388 
IND # 
122755 
Protocol Version 
3.0 
Amendment 
4.0 
Protocol Date 
30Jun2017 
GCP Statement 
This study is to be performed in full compliance with acceptable 
Good Clinical Practices (GCP) and regulations. All required study 
documentation will be archived as required by regulatory authorities. 
Confidentiality 
This document is confidential and the property of the University of 
Virginia. No part of it may be transmitted, reproduced, published, or 
used by other persons without prior written authorization from the 
study sponsor. 
Study Chair 
 
William Petersen, Jr., MD (UVa PI) 
Assistant Professor, Division of Hematology/Oncology 
Department of Pediatrics 
P.O. Box 800386 
Charlottesville, VA 22908 
P:  434-924-8499 
F: 434-982-3509 
wcp3g@virginia.edu 
Biostatistician  
 
Gina Petroni, PhD 
Professor, Division of Translation Research and Applied Statistics 
Department of Public Health Sciences 
grp4c@virginia.edu 
 


UVa-Gen001: Randomized, Controlled Pilot Study of Genistein in Pediatric Cancer Patients 
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ii 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Changes from the previous version are listed below.  The affected sections are listed in 
parentheses. 
• 
Version and date updated throughout 
• 
Study inititation specified (Synopsis) 
• 
Repaired formatting error in Inclusion Criteria, resulting in renumbering of list 
(3.1) 
• 
Complete blood count with differential collected during Baseline (Days -7 to 1) 
and removed from Cycle 1 Day 1 assessments (6.1, 6.2) 
• 
Cytokine panel removed from baseline assessments and added to Cycle 1 Day 1 
assessments (6.1, 6.3) 
• 
Acceptable window for visits and assessment indicated for Treatment Phase 
Assessments (6.3) 
• 
AE details no longer required for antineoplastic agent dose modifications, 
antineoplastic agent treatment delays, or antimicrobial agent use (6.3) 
• 
Data reporting for concomitant medications revised and clarified (6.3) 
• 
Clarification of reporting for soy-based products (6.3) 
• 
Expectedness clarified for reporting purposes (9.2.1, 9.2.2) 
• 
Target AE subsection (9.2.3.1) added to Additional Reporting Requirements and 
other subsections renumbered 
• 
Excluded certain toxicities from single-event FDA IND safety reporting (9.2.3.3, 
Appendix C) 
• 
DSMC review changed from unblinded to blinded (10.2) 
• 
Addition of scheduled AE review by study staff (10.3) 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Randomized, Placebo-Controlled Pilot Study of Genistein in Pediatric Cancer Patients 
Receiving Myelosuppressive Chemotherapy 
 
 
 
INVESTIGATORS’ AGREEMENT 
 
I confirm that I have read this protocol and agree to conduct the study as outlined herein. I will 
also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with good clinical practices and the applicable laws and 
regulations.  
 
 
Site Name: 
 
 
 
 
 
 
Principle 
Investigator: 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
Printed Name 
 
 
 
 
 
Instructions to the Investigator: Please sign and date this signature page. File the original 
signature page in the study file at the site and send a copy of the signed and dated page to the 
Study Manager.  
 
 
Signature: 
 
 
 
 
 
 
 
William Petersen, Jr, MD 
Study Chair  
 
Date 
 


UVa-Gen001: Randomized, Controlled Pilot Study of Genistein in Pediatric Cancer Patients 
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STUDY DESIGN SCHEMATIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemo: chemotherapy 
PE: physical exam 
ANC: absolute neutrophil count 
 
 
Diagnosis; 
Baseline 
labs and PE 
Genistein 
Genistein 
Placebo 
Placebo 
Arm B 
Arm A 
Randomize 
Day -2 
to 1 
Day 1 
End of reporting 
(Data collected an 
additional 30 days) 
Weekly labs and PE for toxicity assessment 
Twice weekly ANC until recovery 
Cytokine panel last day of each chemo cycle 
Chemo 
begins 
Chemo Cycles 1 & 2 
Chemo Cycles 3 & 4 
(2-day 
buffer) 


UVa-Gen001: Randomized, Controlled Pilot Study of Genistein in Pediatric Cancer Patients 
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SYNOPSIS 
Title of Study: A Randomized, Placebo-Controlled Pilot Study of Genistein Supplementation in Pediatric 
Cancer Patients Receiving Myelosuppressive Chemotherapy 
Study Chair/ UVa Principal Investigator (PI): William Petersen, Jr., M.D. 
Study center(s): University of Virginia Cancer Center (coordinating center) and participating US sites  
Phase of study: Pilot 
Study Initiation:  August 2016 
Objectives:  
Primary: 
• 
To estimate the effect of supplementation with genistein on the time to neutrophil count recovery 
following myelosuppressive chemotherapy  
Secondary: 
• 
To estimate the effect of supplementation with genistein on short-term side effects of  
myelosuppressive chemotherapy  
• 
To estimate levels of the serum markers of inflammation during cycles of chemotherapy given in 
conjunction with genistein supplementation versus placebo 
Methodology: This is a multi-center, randomized, double-blind, placebo-controlled crossover study to 
evaluate the effect of the isoflavone genistein on the short-term untoward effects of myelosuppressive 
chemotherapy used to treat pediatric cancers.  Newly diagnosed cancer patients aged 1 - 21 years will be 
registered to the study and informed consent will be obtained prior to any study-related procedures. 
Stratification will be based on length of chemotherapy cycles: 14 days or 21 days.  Subjects will be 
randomized 1:1 to one of two schedules within each stratum: 
Arm A:  Subjects will receive genistein daily throughout chemotherapy Cycles 1 and 2, and placebo 
during chemotherapy Cycles 3 and 4 
Arm B:  Subjects will receive placebo daily throughout chemotherapy Cycles 1 and 2, and genistein 
during chemotherapy Cycles 3 and 4 
The safety and efficacy of genistein will be assessed during each cycle through clinical laboratory tests, 
cytokine panels, and physical exams. Study supplement compliance will be monitored by use of a subject 
diary, drug reconciliation, and serum isoflavone levels. Adverse events will be monitored starting on Cycle 
1 Day 1 through 30 days following the last day of study supplementation (genistein/placebo). Serious 
adverse events will be collected through 6 months post-study intervention. 
Number of subjects (planned): Up to 50 subjects will be accrued to obtain 44 eligible subjects. 
Main Eligibility Requirements:  
Inclusion criteria: 
1. New diagnosis of a solid tumor or lymphoma, with histologic verification of malignancy 
2. Age 1 - 21 years at the time of diagnosis 
3. Able to tolerate enteral medication administration 
4. Performance score minimum requirement ≥ 50 on Karnofsky/Lansky scale 
5. Planned chemotherapy regimen involves at least four consecutive cycles of chemotherapy that is 
known to be myelosuppressive     
Exclusion criteria: 
1. Known allergy to soy or any soy-based food or supplement 
2. Pre-existing neutropenia or neutrophil qualitative or quantitative disorder 
3. Pre-existing cytopenia or bone marrow failure syndrome 
4. Subject will not receive myelosuppressive chemotherapy 
5. Current acute or chronic leukemia diagnosis 
6. Enrolled on another therapeutic or supportive care clinical trial within the last 30 days 
7. Secondary malignancy  


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Investigational intervention:  
• 
Genistein: 30 mg/day, oral tablets 
• 
Placebo: oral tablets 
Both genistein and placebo tablets will be provided by DSM Nutritional Products Europe Ltd, Switzerland. 
Other study intervention(s): The chemotherapeutic regimen for each subject will be determined by the 
treating physician and must contain a combination of at least two agents from the following list during 
each of the four cycles administered in this study:  actinomycin, carboplatin, cisplatin, cyclophosphamide, 
daunorubicin, doxorubicin, etoposide, ifosfamide, topotecan.  
Criteria for evaluation (i.e. endpoints): 
Efficacy: To evaluate the effectiveness of genistein administration during myelosuppressive 
chemotherapy, the following endpoints will be compared between genistein cycles and placebo cycles:   
Primary endpoint: 
• 
Duration of grade 4 neutropenia, defined as an absolute neutrophil count (ANC) of < 500 cells/µl 
Secondary endpoints (per cycle): 
• 
Severity of neutropenia  
• 
Duration of grade 4 neutropenia during hospital admissions for febrile neutropenia  
• 
Frequency and duration of unplanned hospital admissions due to (an) adverse event(s) 
• 
Days with fever (temperature > 101.5° F, or > 100° F more than once in a 24-hour period) 
• 
Incidence and severity of infections 
• 
Duration of antimicrobial agent use 
• 
Duration and severity of oral mucositis  
• 
Duration and severity of peripheral motor neuropathy (in subjects receiving vincristine) 
• 
Incidence and severity of hearing impairment and tinnitus (in subjects receiving a platinum-based 
chemotherapy agent) 
• 
Number of days delayed and percent reduction of full, planned doses of anti-neoplastic agents 
due to (an) adverse event(s) 
• 
Incidence of primary and secondary G-CSF use  
• 
Number of required blood product transfusions 
• 
Cytokine, growth factor, C-reactive protein, and homocysteine levels as well as erythrocyte 
sedimentation rates 
Safety: Safety will be assessed by incidence and severity of AEs and changes in physical examinations. 
Statistical methods: 
Graphical and repeated measure models will be used to describe the complete pattern of ANC over all 
four cycles. Between group (e.g. Cycles 1 & 2) and crossover differences (Cycles 1 - 4) form the structure 
for treatment comparisons. Repeated measure models will be used to assess differences in raw ANC, 
daily ANC, days with fever, duration of hospitalization, and duration of antimicrobial use for subjects 
admitted with febrile neutropenia. The Cochran–Mantel–Haenszel test statistics will be used in the 
analysis of stratified categorical data. The Cochran–Mantel–Haenszel test will be used to compare grade 
and repeated measure models for duration of mucositis between cycles containing genistein versus 
placebo.  Safety data will be summarized and compared during genistein versus placebo cycles. 
 
 
 


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vii 
TABLE OF CONTENTS 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ________________________ ii 
PROTOCOL SIGNATURE PAGE ______________________________________________ iii 
STUDY DESIGN SCHEMATIC ________________________________________________ iv 
SYNOPSIS _________________________________________________________________ v 
1 
BACKGROUND AND RATIONALE ________________________________________ 1 
1.1 
Study Synopsis ____________________________________________________________ 1 
1.2 
Background ________________________________________________________________ 1 
1.2.1 
Toxicities Associated With Chemotherapy for Pediatric Cancers ________________________ 1 
1.2.2 
Anti-cancer/Anti-Inflammatory Effects of Soy Isoflavones ______________________________ 2 
1.2.3 
Genistein Reduces Chemotherapy-Induced Side Effects_______________________________ 3 
1.3 
Study Design and Rationale _________________________________________________ 4 
2 
STUDY OBJECTIVES ____________________________________________________ 6 
2.1 
Primary Objectives _________________________________________________________ 6 
2.1.1 
To estimate the effect of supplementation with genistein on the time to neutrophil count 
recovery following myelosuppressive chemotherapy _________________________________________ 6 
2.2 
Secondary Objectives_______________________________________________________ 6 
2.2.1 
To estimate the effect of supplementation with genistein on short-term side effects of 
myelosuppressive chemotherapy _________________________________________________________ 6 
2.2.2 
To estimate levels of the serum markers of inflammation during cycles of chemotherapy 
given in conjunction with genistein supplementation versus placebo ___________________________ 6 
3 
SUBJECT ELIGIBILITY __________________________________________________ 7 
3.1 
Inclusion Criteria ___________________________________________________________ 7 
3.2 
Exclusion Criteria __________________________________________________________ 8 
3.3 
Enrollment Exceptions ______________________________________________________ 8 
4 
TREATMENT PLAN______________________________________________________ 9 
4.1 
Subject Status Definitions ___________________________________________________ 9 
4.2 
Recruitment _______________________________________________________________ 10 
4.3 
Informed Consent _________________________________________________________ 10 
4.4 
Registration _______________________________________________________________ 10 
4.5 
Randomization or Arm Assignment _________________________________________ 11 
4.6 
Unblinding ________________________________________________________________ 11 
4.7 
Dosage and Administration ________________________________________________ 11 
4.7.1 
Chemotherapeutic Regimen ______________________________________________________ 11 
4.7.2 
Genistein/Placebo Supplementation _______________________________________________ 11 
4.7.3 
Treatment Delays _______________________________________________________________ 12 


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4.7.4 
Dose Modifications ______________________________________________________________ 12 
4.8 
Concomitant Medications/Treatments _______________________________________ 13 
4.8.1 
Prohibited Medications ___________________________________________________________ 13 
4.8.2 
Concomitant Medications _________________________________________________________ 14 
4.9 
Discontinuation of Protocol Therapy ________________________________________ 14 
4.10 
Withdrawal from Study _____________________________________________________ 15 
5 
SUPPLEMENT INFORMATION___________________________________________ 16 
5.1 
Genistein _________________________________________________________________ 16 
5.1.1 
Chemical Name _________________________________________________________________ 16 
5.1.2 
Other Names ___________________________________________________________________ 16 
5.1.3 
Classification ___________________________________________________________________ 16 
5.1.4 
Molecular Formula _______________________________________________________________ 16 
5.1.5 
Manufacturer ___________________________________________________________________ 16 
5.1.6 
Dosage and Administration _______________________________________________________ 16 
5.1.7 
Expected Adverse Events ________________________________________________________ 16 
5.2 
Placebo ___________________________________________________________________ 17 
5.2.1 
Formulation _____________________________________________________________________ 17 
5.2.2 
Manufacturer ___________________________________________________________________ 17 
5.2.3 
Dosage and Administration _______________________________________________________ 17 
5.2.4 
Expected Adverse Events ________________________________________________________ 17 
5.3 
Clinical Supplies/Study Supplement Ordering _______________________________ 17 
5.4 
Storage and Stability_______________________________________________________ 17 
5.5 
Agent Accountability ______________________________________________________ 17 
6 
EVALUATIONS AND ASSESSMENTS ____________________________________ 19 
6.1 
Study Procedures and Assessments Table __________________________________ 19 
6.2 
Pre-treatment Assessments ________________________________________________ 20 
6.2.1 
Medical History and Physical Examination __________________________________________ 21 
6.3 
Treatment Phase Assessments (Cycles 1 – 4)________________________________ 22 
6.4 
Post-Treatment/Follow-up Assessments ____________________________________ 25 
7 
EVALUATION CRITERIA ________________________________________________ 26 
7.1 
Primary Endpoint __________________________________________________________ 26 
7.2 
Secondary Endpoints (per cycle) ___________________________________________ 26 
7.3 
Toxicity and Safety ________________________________________________________ 27 
8 
STATISTICAL CONSIDERATIONS _______________________________________ 28 
8.1 
Study Design ______________________________________________________________ 28 
8.2 
Sample Size and Accrual ___________________________________________________ 28 
8.3 
Stratification Factors/ Randomization _______________________________________ 28 
8.4 
Data Analyses Plans _______________________________________________________ 28 


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9 
ADVERSE EVENTS AND REPORTING ___________________________________ 30 
9.1 
Definitions ________________________________________________________________ 30 
9.1.1 
Adverse Event [72] ______________________________________________________________ 30 
9.1.2 
Persistent or Recurrent Adverse Events ____________________________________________ 31 
9.1.3 
Secondary Adverse Events _______________________________________________________ 31 
9.1.4 
Abnormal Laboratory Values/Clinical Assessments __________________________________ 31 
9.1.5 
Death __________________________________________________________________________ 31 
9.1.6 
Pre-existing Medical Conditions ___________________________________________________ 32 
9.1.7 
Expectedness ___________________________________________________________________ 32 
9.1.8 
Severity ________________________________________________________________________ 32 
9.1.9 
Serious Adverse Event [72] _______________________________________________________ 33 
9.1.10 
Attribution Assessment ________________________________________________________ 35 
9.2 
Required Reporting ________________________________________________________ 35 
9.2.1 
UVa Cancer Center DSMC Reporting Requirements _________________________________ 35 
9.2.2 
IRB Reporting Requirements ______________________________________________________ 36 
9.2.3 
Additional reporting Requirements _________________________________________________ 38 
10 
DATA SAFETY MONITORING PLAN ___________________________________ 40 
10.1 
Data Collection/CRF Completion ____________________________________________ 40 
10.2 
UVa Cancer Center Data Safety Monitoring Committee _______________________ 40 
10.3 
Review of Adverse Events by the Study Team _______________________________ 40 
11 
STUDY MANAGEMENT _______________________________________________ 42 
11.1 
IRB Approval and Consent _________________________________________________ 42 
11.2 
Adherence to the Protocol _________________________________________________ 42 
11.2.1 
Emergency Modifications _______________________________________________________ 42 
11.2.2 
Protocol Deviations/Violations __________________________________________________ 42 
11.3 
Record Retention __________________________________________________________ 43 
11.4 
Obligations of Investigators ________________________________________________ 43 
12 
REFERENCES _______________________________________________________ 45 
13 
APPENDICES ________________________________________________________ 49 
APPENDIX A: CTCAE ____________________________________________________________ 50 
APPENDIX B: STUDY MEDICATION INFORMATION ________________________________ 51 
GenVida™ TG Product Data Sheet _______________________________________________________ 52 
GenVida™ TG Product Safety Sheet _____________________________________________________ 54 
Genistein Fact Sheet ___________________________________________________________________ 61 
APPENDIX C: TOXICITIES EXCLUDED FROM SINGLE-EVENT IND SAFETY REPORTING 
TO THE FDA ____________________________________________________________________ 65 


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1 
 
 
 
 
1 BACKGROUND AND RATIONALE 
1.1 Study Synopsis 
Toxicities related to pediatric cancer treatment can lead to significant illness, organ 
damage, treatment delays, increased health care cost, and decrease in quality of life.  
Such toxicities are largely due to tissue damage sustained by chemotherapy, and 
strategies designed to limit such cellular damage to normal tissues may reduce therapy-
related morbidity and mortality.  In addition to their in vitro and in vivo anti-cancer effects, 
naturally occurring soy isoflavones have anti-inflammatory and anti-oxidant properties, 
and have been shown to reduce side effects of therapy in adult oncology clinical trials.  
This study will examine the effect of genistein, the major isoflavone component in 
soybeans and the most extensively studied of the soy isoflavones, on short-term side 
effects of myelosuppressive chemotherapy in pediatric cancer patients.  Subjects will be 
randomized to receive either: a) 30 mg genistein daily throughout chemotherapy Cycles 
1 and 2 and placebo during chemotherapy Cycles 3 and 4; or b) placebo daily during 
chemotherapy Cycles 1 and 2 and 30 mg genistein daily during chemotherapy Cycles 3 
and 4.  We hypothesize that subjects will have fewer short-term therapy-related side 
effects during cycles of chemotherapy given in conjunction with genistein 
supplementation than cycles given with placebo.   
1.2 Background 
1.2.1 Toxicities Associated With Chemotherapy for Pediatric Cancers 
While cure rates for pediatric cancers have steadily improved over the last several 
decades, toxicities associated with cancer therapy continue to cause significant 
morbidity and mortality [1, 2].  Serious side effects of chemotherapy and radiation are 
common and are thought to be due to a variety of factors, including depletion of 
glutamine and glutathione, free radical generation, cytokine release, and oxidative 
damage [1, 3-9].  Unlike certain targeted anti-cancer agents, most chemotherapeutic 
drugs have nonspecific mechanisms of action that damage both normal tissue and 
cancer cells [1].  Similarly, the mechanism of action of radiation is nonspecific and can 
cause oxidative DNA damage to normal tissues that are within the radiation field [1].  
These nonspecific effects of chemotherapy and radiation tend to be more severe in 
tissues that contain rapidly dividing, mitotically active cells such as those found in the 
bone marrow [1].  Myelosuppressive regimens cause a predictable decline in peripheral 
blood cell counts, usually 7 - 10 days after exposure to therapy.  Highly-suppressed 
absolute neutrophil counts during this period put patients at an elevated risk for serious 
infection [10].  The standard of care at most institutions is to admit neutropenic patients 
with fever to the hospital and treat with empiric intravenous broad-spectrum antibiotics 
until their febrile neutropenia resolves.  This is due to the high mortality associated with 
serious bacterial infections in this population, reported to be around 1% [11, 12].  Such 
patients also often require packed red blood cell and platelet transfusions for 
chemotherapy-induced anemia and thrombocytopenia, respectively, which are 


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2 
 
 
 
 
associated with hemolytic transfusion reactions and transfusion-transmitted infections.  
Other common acute toxicities due to cancer treatment include mucositis caused by 
chemotherapy and radiation as well as neurotoxicity due to vincristine and other tubulin-
inhibiting chemotherapeutic agents [13-15].   
Many long-term side effects of therapy cause significant morbidity and mortality [2].  One 
problematic long-term side effect of therapy is the irreversible ototoxicity due to platinum-
based chemotherapy [16, 17] that is estimated to occur in up to 61% of patients 
receiving cisplatin and postulated to be due to cochlear oxidative damage [3-5, 16].  
Ototoxicity negatively impacts patients’ quality of life by impairing their social and 
cognitive function and overall development [5].  It can also indirectly lead to increased 
risk of cancer recurrence if the cumulative dose of cisplatin is significantly reduced due 
to ototoxicity [5].  Cardiac toxicity caused by anthracycline-induced oxidative damage is 
another common dose-limiting side effect of therapy [18, 19].  Up to 40% of patients who 
receive anthracyclines will have an abnormal echocardiogram and survivors of childhood 
cancers who were treated with anthracyclines have a 15-fold increased relative risk of 
congestive heart failure compared to adults who were not treated for a childhood cancer 
[2].  Such therapy-related toxicities significantly impact patients’ quality of life and cause 
treatment-related mortalities.  Therapies that limit normal tissue damage without 
negatively impacting the therapeutic effects of chemotherapy and radiation are needed 
to improve outcomes and quality of life for childhood cancer patients. 
1.2.2 Anti-cancer/Anti-Inflammatory Effects of Soy Isoflavones 
Soy isoflavones are naturally-occurring components of soybeans that have both anti-
neoplastic and antioxidant properties.  Their in vitro and in vivo anti-cancer effects have 
been tested in varied cancer model systems and include apoptotic induction [20, 21], 
growth inhibition [22-24], cell cycle regulation [25], and sensitization to chemotherapy 
[26, 27] and radiation [28].  Soy isoflavones inhibit growth in preclinical studies of 
multiple pediatric solid tumors, including Wilms, rhabdoid renal tumors, and 
neuroblastoma [20-22, 24], as well enhance the cytotoxicity of chemotherapy in 
medulloblastoma cells [27].   
One mechanism by which soy isoflavones exert a protective effect is by inhibiting 
oxidative damage in healthy cells [29-31].  Oxidative DNA damage is significantly 
reduced in men and women who receive soy milk supplementation, as determined by 8-
isoprostane plasma levels and DNA strand breakage [32-34], which is consistent with in 
vitro and in vivo experiments demonstrating antioxidant properties of isoflavones [35-37].  
Isoflavones also reduce hydrogen peroxide-induced DNA damage in sperm [38] and 
neutrophils [39].   
Of the three main soy compounds, genistein, daidzein, and glycitein, the major 
component in soybeans (about 50%) and the most extensively studied of the soy 
isoflavones is genistein [40].  Genistein has been shown in vitro to increase antioxidant 
gene expression in colon cancer [41] and inhibit induced oxidative stress in epidermal 


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carcinoma [37, 42] and terminally differentiated leukemia [37].  It also inhibits oxidation 
of low density lipoprotein in the presence of copper ions and superoxide free radicals, 
and protects vascular endothelial cells from damage by oxidized lipoproteins [43].  In an 
experimental model of acute liver damage, genistein-treated rats had lower liver tissue 
malondialdehyde levels, higher levels of glutathione, and reduced inflammation and 
necrosis compared to rats that were not exposed to genistein.  The protective effect 
correlated with reduced markers of lipid peroxidation, suggesting that genistein inhibits 
reactive oxygen species-induced membrane damage [44].  Genistein administration is 
associated with increased activity of several antioxidant enzymes, including superoxide 
dismutase, glutathione peroxidase, glutathione reductase, catalase, and glutathione-S-
transferase in a mouse model [45]. Additionally, in a guinea pig asthma model, genistein 
treatment was associated with fewer total white blood cells (WBCs) and eosinophils in 
bronchoalveolar lavage fluid and reduced airway eosinophilia.  Subsequent experiments 
demonstrated decreased eosinophil peroxidase activity and epidermal growth factor-
induced tyrosine phosphorylation, suggesting mechanisms for genistein-mediated 
inhibition of inflammation [46].  Interestingly, several preclinical studies suggest that 
genistein may have opposing mechanisms of action and biological effects on some 
paired normal and malignant cell lines.  For example, it has little impact on the 
generation of reactive oxygen species in astrocytes or hyperdiploidy in normal breast cell 
models, but they increase in paired malignant cell lines [37, 47].  These and other paired 
in vitro models show a minimal or pro-survival impact of genistein in non-malignant cells 
but poorer survival in their cancerous counterparts [47-52]. 
While genistein may promote inflammatory processes, including increased IFN-γ 
secretion, in the context of some cancers [62-64], data suggest that soy isoflavone 
consumption may lower pro-inflammatory proteins in non-malignant cells.  In vitro 
studies suggest a mechanism whereby genistein may attenuate homocysteine 
inflammatory signaling through IL-1, reactive oxygen species, and NF-B, thereby 
inhibiting expression of C-reactive protein and its downstream effectors, IL-6 and TNF-
 [53-56]. Supporting this, genistein supplementation was associated with reduced 
serum IL-6 and IFN-γ in a mouse autoimmune encephalitis model [57].  Soy intake 
inversely correlated with serum TNF- α, IL-6, and IL-1β levels in rats [58], which is 
consistent with data showing lower serum IL-6 and TNF-α levels in Chinese women who 
consumed soy-rich diets [59].  Serum CRP and homocysteine levels have been found to 
be inversely related to soy isoflavone intake in U.S. adults [60, 61]; CRP also inversely 
correlates with serum genistein levels in adults receiving flavonoid supplementation [60].  
Inhibition of cytokine production may be another mechanism by which soy isoflavones, 
and specifically genistein, reduce inflammation in healthy tissues.   
1.2.3 Genistein Reduces Chemotherapy-Induced Side Effects  
Genistein’s anti-inflammatory and antioxidant properties may counteract the oxidative 
damage and inflammation induced by anti-neoplastic therapy in healthy tissues, thereby 
reducing untoward toxicities.  Adult men with localized prostate cancer who received 200 
mg daily soy isoflavone supplementation (including about 96 mg genistein per day) 


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concomitant with their radiation therapy had reduced urinary, intestinal, and sexual 
adverse effects compared to subjects treated with placebo.  Compliance was 100% with 
the study tablets and no side effects from soy supplementation were reported [28].  A 
small pediatric pilot study found a similar reduction in chemotherapy and radiation 
therapy-related toxicities with genistein supplementation [65].  In this study, eight solid 
tumor and brain tumor patients received the first course of therapy without soy 
supplementation and then received a 0.3 g tablet containing 82% soy isoflavone extract 
and 2.7% (8 mg) genistein daily with subsequent courses of chemotherapy.  No 
isoflavone-related toxicities were noted and none of the children stopped taking the 
supplement.  While these data were not statistically significant, subjects receiving 
genistein in conjunction with chemotherapy appeared to have less myelosuppression, 
less mucositis, shorter durations of antimicrobial therapy, and fewer blood product 
transfusions compared to cycles of chemotherapy without genistein.  Furthermore, 
subjects who received abdominal radiation reported less pain and diarrhea while taking 
the genistein supplement, although this was also not statistically significant.  While 
encouraging, these data are preliminary and additional randomized trials are needed to 
evaluate genistein’s effect on anti-neoplastic therapy-related toxicities.   
1.3 Study Design and Rationale 
Although recent studies have demonstrated the ability of genistein supplementation to 
reduce chemotherapy-related acute toxicities in a limited number of pediatric cancer 
patients, data regarding safety and efficacy of soy isoflavones in pediatric cancer 
patients are scant. The purpose of this study is to evaluate the efficacy and safety of 
genistein supplementation in pediatric cancer patients receiving myelosuppressive 
chemotherapy. The study plans to accrue 44 eligible subjects at University of Virginia 
(coordinating center) and additional participating sites (affiliates).  
Genistein safety, efficacy, pharmacokinetics, and pharmacodynamics have been 
determined in adult clinical trials [66,67].  While much of the soy isoflavone data does 
not specify which of the soy components are responsible for the clinical effects seen, 
genistein is known to be the major component in soybeans (about 50%) and the most 
extensively studied of the soy isoflavones [40].   This study will employ purified genistein 
rather than a mixture of soy components so as to more clearly define genistein’s safety 
and efficacy in the context of myelosuppressive chemotherapy and a pediatric 
population. 
A dose of 30 mg purified genistein was chosen for this clinical trial based on prior safety 
and efficacy studies in pediatric and adult populations. In a study of eight solid and brain 
tumor pediatric patients, subjects received  a 0.3 g tablet containing 82% soy isoflavone 
extract and 2.7% (8 mg) genistein daily [65], which corresponded to a daily genistein 
dose of approximately 130 mg.  No isoflavone-related toxicities were observed and no 
subjects discontinued supplementation during that study. The findings support the safety 
of genistein supplementation at a dose up to 130 mg in a pediatric population.  In 
addition, De Ruijter and colleagues [68] recently studied the effects of genistein in 30 


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subjects with Sanfillipo disease with a median age of 11 – 13 years. They demonstrated 
that genistein could be administered in this population at doses of 10 mg/kg/day with no 
observed treatment-related adverse events (AEs). The safety of soy isoflavones in the 
pediatric population has been evaluated by researchers studying the effects of soy 
formula intake in infants.   Infants who were exposed to an estimated 4 to 16 mg/kg/day 
of soy isoflavones (approximately 2 to 8 mg/kg/day of genistein, which is equal to about 
32 mg daily for a 4 kg infant) in soy formula during their first 4 months of life had no 
evidence of any significant short- or long-term deleterious effects, including no 
differences in puberty or fertility compared to infants receiving cow’s milk formulas [71].   
A dose of 30 mg genistein has been established as a minimal effective dose in adults; it 
demonstrated elevated serum levels of genistein and was associated with reduced 
prostate-specific antigen levels in adults with prostate cancer  [69, 70].  Most AEs were 
mild and significant events were rare in those studies.  Together, toxicity data do not 
suggest a need for a dose-finding pediatric trial or that the dose of purified genistein 
selected for this study will compromise the safety of pediatric subjects.  As a reference, 
two eight-ounce glasses of soy milk contain roughly 30 mg of genistein. 
Eligibility is limited by a patient’s intended chemotherapeutic regimen.  Qualifying 
regimens must be known to be myelosuppressive and have at least four cycles (14 or 
21-day cycles). The sequence of protocol therapy will be randomized in a double-blind 
fashion to control for bias. This study will also employ a crossover design to limit any 
period effects and to allow for intra-subject comparisons. Efficacy will be retrospectively 
evaluated using clinical laboratory results and the incidence of pre-specified AEs. 
Subjects will be monitored for safety starting on Cycle 1 Day 1 through 30 days following 
the last day of genistein supplementation.  


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2 STUDY OBJECTIVES 
2.1 Primary Objectives 
2.1.1 To estimate the effect of supplementation with genistein on the time to neutrophil 
count recovery following myelosuppressive chemotherapy  
2.2 Secondary Objectives  
2.2.1 To estimate the effect of supplementation with genistein on short-term side 
effects of myelosuppressive chemotherapy  
2.2.2 To estimate levels of the serum markers of inflammation during cycles of 
chemotherapy given in conjunction with genistein supplementation versus 
placebo 
 
 


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3 SUBJECT ELIGIBILITY 
Eligibility must be reviewed and confirmed by a study investigator prior to subject 
enrollment. 
3.1 Inclusion Criteria 
[1]  
Newly diagnosed solid tumor or lymphoma with histological verification 
[2]  
Age 1 - 21 years at time of diagnosis 
[3]  
Karnofsky/Lanksy performance score of ≥ 50  
[4]  
Able to tolerate enteral medication administration 
[5]  
Planned chemotherapeutic regimen for a patient must meet all of the following 
criteria: 
a. A known myelosuppressive regimen which includes at least two of the 
following agents: actinomycin, carboplatin, cisplatin, cyclophosphamide, 
daunorubicin, doxorubicin, etoposide, ifosfamide, topotecan 
b. At least four consecutive cycles 
c. Cycle length is either 14 or 21 days 
d. Regimen must either alternate myelosuppressive chemotherapeutic 
agents in an X-Y-X-Y format, such that the same chemotherapy is given 
every 
other 
cycle 
(e.g. 
vincristine/doxorubicin/cyclophosphamide 
│ 
ifosfamide/etoposide), or repeat the same chemotherapeutic agents each 
cycle 
in 
an 
X-X-X-X 
format 
(e.g. 
repeated 
cycles 
of 
cisplatin/etoposide/bleomycin).  Courses eligible for this trial may occur at any 
time during treatment provided that they are consecutive and follow the one 
of the described patterns. Non-myelosuppressive anti-neoplastic treatments 
will not be considered for the purposes of determining eligibility.   Questions 
regarding whether or not a patient’s chemotherapy plan meets inclusion 
criteria will be decided by the Study Chair. 
[6]  
Informed consent or parental permission and assent obtained prior to trial-related 
activities (Section 4.3) 
[7]  
Able and willing to comply with all study related procedures 
[8]  
Women of childbearing potential must agree to use adequate contraception 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. 
 
 


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3.2 Exclusion Criteria 
[1]  
Known allergy to soy or any soy-based food or supplement 
[2]  
Unable or unwilling to discontinue consuming prohibited soy-based food or 
supplements while participating in this study (Section 4.8.1) 
[3]  
Pre-existing neutropenia or neutrophil qualitative or quantitative disorder (Section 
6.3) 
[4]  
Pre-existing cytopenia or bone marrow failure syndrome 
[5]  
History of gastric or duodenal ulcers or hyperacidity syndromes  
[6]  
History of Human Immunodeficiency Virus (HIV)  
[7]  
Has an active infection requiring systemic therapy 
[8]  
Planned treatment does not include myelosuppressive chemotherapy 
[9]  
Enrolled on a therapeutic or supportive care clinical trial within the last 30 days 
[10]  Current acute or chronic leukemia diagnosis 
[11]  Requires medication dosing via an enteral feeding tube that terminates in the 
duodenum or jejunum.  (Enteral feeding tubes that terminate in the stomach are 
acceptable for study medication delivery.) 
[12]  Pregnant or breastfeeding woman  
[13]  Incarceration 
[14]  Secondary malignancy, i.e. the cancer for which the patient is presently or will be 
receiving treatment may not be a malignancy related to prior cancer therapy  
[15]  Any condition which might be worsened by estrogen, such as breast cancer, 
uterine cancer, ovarian cancer, endometriosis or uterine fibroids 
[16]  Any condition, in the investigator’s opinion, that would compromise patient safety 
or study outcomes 
[17]  Anyone who, in the investigator’s discretion, would be unwilling or unable to 
comply with study procedures 
3.3 Enrollment Exceptions 
An enrollment exception is the sponsor’s prospective approval for the enrollment of a 
single research subject that fails to meet current approved protocol inclusion criteria or 
satisfies protocol exclusion criteria. Enrollment exceptions will not be granted on this 
study. 


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4 TREATMENT PLAN 
4.1 Subject Status Definitions 
Enrolled: All subjects who sign an informed consent will be considered enrolled on the 
study.  
Screen Failure: A subject who is withdrawn or discontinues from the study prior to 
receiving any protocol therapy (genistein or placebo) is considered a screen fail. Screen 
failures do not count toward accrual and will be replaced.  
On Study: An enrolled subject is considered on-study/registered when a site investigator 
has determined that the subject has met all of the inclusion and none of the exclusion 
criteria, and the Study Chair, Study Research Coordinator, or designee has confirmed 
the eligibility.  The on study date is the date that eligibility is confirmed at UVa. 
Randomized: A subject that has been assigned to an arm is considered randomized.  
On Treatment: A subject is considered on-treatment on the date that the protocol 
therapy (genistein/placebo) is initiated (i.e. Cycle 1 Day 1).  
Off Treatment: The off-treatment date is the date that the subject, for any reason, is no 
longer receiving protocol therapy (genistein or placebo).  It begins the day after the last 
dose of study supplement. 
On Follow-up: A subject is considered on follow-up on the date that the protocol therapy 
is completed or discontinued for any reason listed in Section 4.9.   The on follow-up date 
is described below. 
• 
Protocol therapy completed per protocol: date after Cycle 4 Last Day, same as 
off-treatment date 
• 
Early discontinuation of protocol therapy: same as off-treatment date 
• 
Screen failure: date determined to be ineligible 
Off Follow-up: A subject is considered off follow-up when he or she has completed the 
follow-up period or the last date of follow-up if withdrawn during this period 
 
Off-Study: A subject is considered off-study if he or she is removed from the study for 
any of the reasons listed in Section 4.10 or if he or she has completed follow-up.  It 
begins the date that the subject’s participation in protocol activities has ended and 
typically coincides with the off-follow-up date. 
• 
Follow-up period completed per protocol: date of six months post-treatment 
review  
• 
Screen failure: date determined to be ineligible 
• 
Withdrawn from study: date withdrawn 


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4.2 Recruitment 
Recruitment will be managed by each site’s local Institutional Review Board (IRB) with 
oversight by the Sponsor.  See Procedure Manual for additional information.   
4.3 Informed Consent 
In obtaining and documenting informed consent, the investigator must comply with the 
applicable regulatory requirement(s), and must adhere to all ICH E6 principles, Good 
Clinical Practice (GCP), and ethical principles that have their origin in the Declaration of 
Helsinki. 
Before recruitment and enrollment onto this study, the subject and/or his or her 
parent(s)/guardian(s) will be given a full explanation of the study and will be given the 
opportunity to review the consent form. Each consent form must include all the relevant 
elements currently required by the FDA Regulations and local or state regulations. Once 
this essential information has been provided to the subject/parent(s)/guardian(s) and the 
investigator is assured that the subject/parent(s)/guardian(s) understand(s) the 
implications of participating in the study, the adult subject will be asked to give consent 
or parent(s)/guardian(s) to provide permission to participate in the study by signing an 
IRB-approved consent form.  
Prior to a subject’s participation in the trial, the written informed consent form must be 
signed and personally dated by the subject/parent(s)/guardian(s) and by the person who 
conducted the informed consent discussion. 
Oral assent will be obtained from minor subjects ≥ 7 years old, unless more stringent 
requirements are imposed by a site’s IRB.  In addition, consent must be requested from 
subjects who become pregnant during the course of the study for the purposes of 
following the subject and fetus.  The format of consent from a pregnant subject will 
determined by the site’s IRB policies.  The Sponsor will provide oversight of all 
consent/permission/assent activities (see Protocol Section 3.1 criterion #6, Procedure 
Manual). 
4.4 Registration  
Subjects who have consented to the study must be registered in OnCore (an online 
clinical trials management system) in accordance with the UVa Cancer Center OnCore 
standard operating procedures, which can be found on the UVa OnCore Resources 
webpage (see the OnCore Help tab). General guidelines are provided in the Procedure 
Manual for reference, but registration must follow the OnCore SOP in case of any 
discrepancy. 
Subject eligibility must be confirmed by the site PI and the eligibility packet must include 
at a minimum the informed consent and eligibility worksheet. All sites will then submit an 


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eligibility packet for each eligible subject to the Study Manager for review (Procedure 
Manual).   
4.5 Randomization or Arm Assignment 
Following completion of subject registration as described in Section 4.4, the subject will 
be randomized by the Study Manager at UVa using custom randomization software 
developed at UVa. The software incorporates the randomization scheme generated by 
the Biostatistician and assigns the subject to one of the two arms. The arm assignment 
will only be available to unblinded site personnel for the purposes of dispensing protocol 
therapy, the Core Investigational Pharmacist, Study Manager, and Biostatistician.  See 
the Procedure Manual for additional information.      
Randomization must occur within the 2 days prior to the anticipated Cycle 1 Day 1. 
4.6 Unblinding 
Subjects and the study team, with the exception of the site Investigational Pharmacist or 
designee, will be blinded to the randomization assignment.  In the event that an 
Investigator believes that for the safety of the subject the blind must be broken, the 
Investigator may contact the site Investigational Pharmacist or designee to unblind the 
subject. When a subject unblinding occurs, the Study Chair, Biostatistician, and Study 
Manager must be notified in writing within 5 business days, and the reason must be fully 
documented and recorded on a Case Report Form (CRF).  
Unblinded subjects must immediately discontinue protocol therapy (Section 4.9) and will 
be considered to be in Follow-up. 
4.7 Dosage and Administration 
4.7.1 Chemotherapeutic Regimen 
The chemotherapeutic regimen must meet the inclusion criteria described in Section 3.1. 
Administration of anti-neoplastic therapy must follow standard clinical practices, 
including dosing delays and dose modifications to anti-neoplastic therapy. See Section 
4.7.3 for information pertaining to treatment delays. 
If the pre-treatment audiogram for subjects scheduled to receive platinum-based 
chemotherapy is indicative of severe hearing loss, the chemotherapeutic dose should be 
adjusted according to standard clinical practices.  Any change(s) to the anticipated 
cancer treatment regimen must be captured in OnCore. 
4.7.2 Genistein/Placebo Supplementation 
For the purposes of this study, the duration of treatment cycles will coincide exactly with 
chemotherapy cycles.  “Cycle 1” here refers to the first chemotherapy cycle during which 
the subject receives genistein or placebo, though this may not be the actual first cycle of 
the subject’s chemotherapeutic treatment.  


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Subjects will receive 30 mg genistein (Arm A) or placebo (Arm B) daily throughout 
Cycles 1 & 2, beginning on the first day of the first cycle of chemotherapy coinciding with 
this study (Cycle 1 Day 1) and ending two days prior to the predicted start date of Cycle 
3. Following a 2-day washout, subjects will then receive placebo (Arm A) or 30 mg 
genistein (Arm B) throughout chemotherapy Cycles 3 & 4, beginning on the first day of 
Cycle 3 and ending on the last day of Cycle 4.  The treatment schedule is 
summarized on Roadmaps, located in the Procedure Manual appendices.  For the 
purposes of this clinical trial, “study supplement” will refer to both genistein and placebo. 
The study supplement will be delivered orally by the subject or a parent, and a diary will 
be kept to document dose administration.  For doses given at home, subjects and 
parents will be instructed to bring unused pills to study visits.  For children who are 
unable to swallow tablets, instructions for crushing and administering will be given to the 
families (Procedure Manual).  Tablets may be crushed and delivered via feeding tube 
only if subjects are unable to take the medication orally and the feeding tube terminates 
in the stomach.  Delivery to the duodenum or jejunum may alter genistein 
pharmacokinetics. 
Subjects will record study treatments on a daily Pill Diary to indicate number of doses 
and time of dosing (Procedure Manual). If a subject misses a dose by less than 12 
hours, he or she must be instructed to take the missed dose.  If a subject misses a dose 
by more than 12 hours, he or she must be instructed to skip the missed dose and 
continue with regular dosing schedule. However, he or she must redose if vomiting 
occurs within the first 20 minutes after study supplement ingestion. Redosing may occur 
only once per 24 hour period. 
4.7.3 Treatment Delays 
A treatment delay is when scheduled therapy is postponed, typically due to toxicity or 
scheduling difficulties.  This trial contains no scheduled treatment delays.  Subjects must 
continue to take the genistein/placebo supplementation if an anti-neoplastic treatment 
delay occurs, except in the following circumstance: If the anti-neoplastic treatment delay 
occurs after the subject has stopped taking the study supplement because of the 
scheduled washout between Cycles 2 and 3, then genistein/placebo must be held until 
Cycle 3, Day 1.   
See Section 6.3 for additional information on study assessments during treatment 
delays. 
4.7.4 Dose Modifications 
Dose modifications for AEs which are at least possibly treatment-related are must follow 
Table 1. Dose modifications for reasons other than treatment-related AEs are not 
permitted.  See Section 9 for information pertaining to the severity and attribution of AEs. 
 
 


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Table 1.  Dose Modifications by Adverse Event Grade for Initial Presentation 
Grade 
Action 
Grade 0 - 1 
No change 
Grade 2 
Reduce dose of the study supplement to 50% (½ tablet)  
Grade 3 - 4 
Suspend treatment  
 
 
Return to prior dose after three consecutive days of resolution/baseline grade, or the 
beginning of Cycle 3.  If the rechallenge results in toxicity possibly/probably/definitely 
attributed to the study supplement, reduce the supplement to 50% of full dose (grade 2) 
or discontinue treatment (grades 3 – 4) until the start of Cycle 3 or the end of Cycle 4, 
whichever comes first. 
The study supplement must be started at the full dose at the beginning of Cycle 3, 
regardless of any dose modifications during Cycles 1 and 2.  This is because the agent 
used during Cycles 1 and 2 differs from that which is used during Cycles 3 and 4. 
Table 2.  Dose Modifications by Adverse Event Grade Following Rechallenge 
Grade 
Action 
Grade 0 - 1 
No change 
Grade 2 
Reduce study supplement dose to 50% (½ tablet) until the start of Cycle 3 or the 
end of Cycle 4, whichever comes first 
Grade 3 - 4 
Suspend treatment until the start of Cycle 3 or the end of Cycle 4, whichever 
comes first 
 
If treatment-related AEs are concurrent, modify the dose based upon the highest grade 
demonstrated.  Rechallenge with the previous dose only after all treatment-related AEs 
have resolved or returned to baseline. 
Pill splitting may be necessary and will not alter genistein pharmacokinetics.  The 
Procedure Manual contains further information about pill splitting. 
4.8 Concomitant Medications/Treatments 
4.8.1 Prohibited Medications 
Over-the-counter soy-based foods, drinks, and supplements are not permitted for 
consumption during this study as they may confound study results. Any subject 
consuming soy-based food or supplements as part of his or her daily diet must 
discontinue consumption prior to taking protocol therapy on Cycle 1 Day 1. The study 
team will provide guidance to the subject to help determine whether his or her diet is 
consistent with this requirement of the study.  A subject handout summarizing 
prohibited food and drinks can be found in the Procedure Manual appendices. 
Soy consumption prior to and during treatment must be reported according to Section 
6.2 and 6.3.  Consumption of prohibited soy products during the treatment period 
constitutes a protocol deviation and must be handled according to the Procedure Manual 


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and site IRB policy.  Subjects will receive a “warning” and additional education for a first 
offense; ingestion a second time will result in discontinuation of protocol therapy (Section 
4.9). 
4.8.2 Concomitant Medications 
For the purposes of this study, anti-neoplastic agents (i.e. chemotherapy, hormonal 
therapy, immunotherapy, other small molecule inhibitors, and gene therapy), 
antimicrobials (i.e. antibiotics, antifungals, antivirals), transfused blood products, G-CSF, 
and soy products will be the only collected concomitant medications.  Antimicrobial 
agent use will be designated as prophylactic or for the treatment of a presumed or 
known infection.  See Section 6 for additional information about what data will be 
collected during the trial. 
A platelet or packed red blood cell transfusion must be provided if any of the below 
criteria are met: 
• 
Hemoglobin of < 7 g/dl or if symptomatic 
• 
Platelets of < 10,000 cells/µl or abnormal bleeding  
• 
Treating physician determines it is in the subject’s best clinical interest 
4.9 Discontinuation of Protocol Therapy 
Subjects will receive genistein or placebo for four 14- or 21-day cycles of chemotherapy, 
depending upon chemotherapeutic regimen, or until any of the following occur: 
• 
Development of a secondary condition which, in the investigator’s opinion, would 
compromise patient safety or study results  
• 
A female subject becomes pregnant  
• 
Non-compliance with study procedures or protocol therapy (missing more than 
20% of prescribed doses of genistein/placebo) since the first dose of study 
supplement treatment 
• 
Consumption of prohibited soy-based products more than once during the 
Treatment Phase (Section 4.8.1) 
• 
Unacceptable AE(s). Subjects who experience National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4 grade 3 or 
higher AE that is possibly, probably, or definitely related to the genistein/placebo 
during Cycle 3 or 4  
• 
Chemotherapy regimen is altered such that it no longer meets Inclusion Criterion 
#5 (Section 3.1) 
• 
Subject’s treatment assignment is unblinded (Section 4.6) 
• 
Subject decides to discontinue protocol therapy 
If a subject discontinues protocol therapy for any of the above reasons, the subject will 
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from protocol therapy for (an) unacceptable AE(s) will be followed until resolution or 
stabilization of the AE. 
Should a pregnant subject consent, the subject will also be followed to determine the 
outcome of her pregnancy (including any premature termination of the pregnancy).  
Generally, follow-up will be requested by the Sponsor no longer than 8 weeks following 
the delivery or termination date.   
4.10 Withdrawal from Study  
Subjects may withdraw or be withdrawn from study at any time for any of the following 
reasons: 
• 
Subject decides to withdraw from study 
• 
Discretion of the investigator 
• 
Death  
The primary reason for discontinuation or withdrawal from protocol therapy or study must 
be recorded in both the study and medical records, including an explanation if removed 
due to an investigator’s discretion.  All subjects that discontinue or withdraw from the 
study will continue to receive standard of care treatment.    
A subject’s participation is considered completed when the subject has received all study 
procedures and has completed all follow-up visits. Subjects that discontinue from the 
study prior to receiving any dose of protocol therapy (genistein or placebo) will be 
replaced. A subject who is withdrawn or discontinues from the study after receiving 
protocol therapy (genistein/placebo) is considered a discontinuation and will not be 
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5 SUPPLEMENT INFORMATION  
5.1 Genistein 
5.1.1 Chemical Name 
5, 7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one 
5.1.2 Other Names 
i-cool tablets containing 30 mg geniVida™ TG (Product code 5011590) 
5.1.3 Classification 
Plant derived estrogen-like compound, Isoflavone 
5.1.4 Molecular Formula 
C15H10O5 
5.1.5 Manufacturer 
DSM Nutritional Products Europe Ltd, Switzerland. 
5.1.6 Dosage and Administration 
A dose is one tablet (30 mg genistein) per oral daily. Subjects or parents/guardians will 
be instructed to bring in unused pills to study visits. For children who are unable to 
swallow tablets, instructions for crushing and administering will be given to a caregiver 
(Procedure Manual). Tablets may be crushed and delivered via feeding tube only if 
subjects are unable to take the medication orally and the feeding tube terminates in the 
stomach.  Delivery to the duodenum or jejunum may alter genistein pharmacokinetics. 
Refer to the Procedure Manual for additional administration instructions and Section 
4.7.4 for dose modification instructions. 
5.1.7 Expected Adverse Events 
The side effects of usage of genistein reported in the literature are mild. The most 
common effect is abdominal pain (≤ grade 2).  This is the only AE that will be considered 
to be expected for the purposes of this study.  
Genistein may have estrogenic properties. Therefore any condition which might be 
worsened by estrogen, such as breast cancer, uterine cancer, ovarian cancer, 
endometriosis or uterine fibroids, may also be worsened by administration of genistein.  
The effect of genistein in someone who is pregnant or breast-feeding is not known.  
 
 


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5.2 Placebo 
5.2.1 Formulation 
The formulation includes: microcrystalline cellulose, dicalcium phosphate, and 
magnesium stearate in a ratio of 10:20:1.   Tablets will weigh about 300 mg.  
5.2.2 Manufacturer 
DSM Nutritional Products Europe Ltd, Switzerland. 
5.2.3 Dosage and Administration 
Subjects will take one tablet per oral daily. Tablets are approximately 260 mg of placebo 
(cellulose).  
Refer to the Procedure Manual for additional administration instructions and Section 
4.7.4 for dose modification instructions. 
5.2.4 Expected Adverse Events 
None. 
5.3 Clinical Supplies/Study Supplement Ordering 
Genistein and placebo tablets will be provided to the Core Investigational Pharmacy by 
DSM Nutritional Products. The Core Investigational Pharmacy will supply each site with 
full bottles of 100 tablets to be dispensed in smaller quantities as defined in the 
Procedure Manual based upon cycle length.  Site pharmacies must distribute the study 
supplement in accordance to institutional and state regulations. 
Undispensed clinical supplies, including missed doses, must be returned to the Core 
Investigational Pharmacy.  Bottles must not be transferred from one subject to another 
subject or from one protocol to another protocol.   
Details regarding study supplement ordering are provided in the Procedure Manual. 
5.4 Storage and Stability 
The study supplement may be stored for up to 36 months from the date of manufacture 
at < 25 ºC. Keep container tightly closed. See the Procedure Manual for directives 
should a temperature excursion occur. 
5.5 Agent Accountability 
Subject Pill Diaries must be collected and study medication reconciled at the end of each 
cycle.  Record agent accountability on the Investigational Agent Accountability Record.  
Both forms are located in the Procedure Manual appendices. 


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Each site will be responsible for providing periodic study supplement reconciliation 
reports to the Study Manager. 


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6 EVALUATIONS AND ASSESSMENTS 
6.1 Study Procedures and Assessments Table 
Table 3: Schedule of Events 
Assessment1 
Pre-Treatment 
Treatment Phase 
Follow-up2 
Day -28 to Day 13 
Cycle 1 
Cycles 1 - 4 
Cycles 2 - 4 
Cycle 4 
Day 13,4 
Weekly5 
Day 1 
Last Day6 
Informed Consent 
X 
 
 
 
 
 
Eligibility Determination 
X 
 
 
 
 
 
Baseline7 and Demographic8 Data 
X 
 
 
 
 
 
Randomization9 
X 
 
 
 
 
 
Medical History/Baseline Condition 
X 
 
 
 
 
 
Physical Exam10 
X 
X 
X 
X 
 
 
Height and Weight 
 
X 
 
X 
 
 
Chemistry/Metabolic Panel11  
X 
X 
 
X 
 
 
CBC with Differential12 
X 
 
X 
X 
 
 
CRP, ESR, and Homocysteine13 
X 
 
 
X 
X 
 
Cytokine and Isoflavone Panels14  
 
X 
 
X 
X 
 
Audiogram15 
X 
 
 
X 
X 
 
Concomitant Medications Review16 
X17 
X 
X 
X 
X 
 
Adverse Events Review 
 
X 
X 
X 
X 
X 
Study Medication Dispensing 
 
X 
 
X 
 
 
Subject Pill Diary18 
 
X 
X 
X 
X 
 
Study Medication Reconciliation 
 
 
 
X 
X 
 
 
 
 
 
1 All visits and assessments must be completed within ± 72 hours of the milestone date unless otherwise specified. 
2 Subjects must be followed for 30 days following the last study intervention for AEs and for 6 months for SAEs, unless consent is withdrawn. 
3 Cycles begin on Day 1.  There is no Day 0. 
4 Cycle 1 Day 1 assessments do not need to be repeated if completed in the 7 days prior (i.e. Day -7 to Day 1) unless otherwise stated. 
5 Weekly visits are to occur at 7-day intervals between Day 1 and the cycle’s last day. 
6 The last day of a cycle corresponds to the Day 1 of the next cycle.  The last day’s number will vary by cycle length. 
7 Diagnosis, stage, grade, site(s) of disease, anti-neoplastic treatment +/- radiation regimen 
8 Age, sex, race, and ethnicity 
9 Randomization must occur within the 2 days prior to the anticipated Cycle 1 Day 1. (Section 4.5) 
10 Full physical exam at the beginning of each cycle of chemotherapy, and a symptom-directed physical exam at each of the weekly  
treatment visits. Collect height, weight and BSA on Day 1 of each cycle. 
11 Chemistry labs to assess for general safety must be conducted on Day 1 of each cycle.  They must include serum creatinine, total  
bilirubin, AST, and ALT. 
12 CBC must be collected once during Baseline (Day -7 to 1), and then Day 1 of Cycles 2, 3, and 4, and Day 8 of Cycles 1, 2, 3, and 4.  Once 
ANC begins to decrease each cycle, obtain twice a week until ANC recovery (see Section 7.1 for definition of ANC recovery).  CBC must 
include the following: hemoglobin, hematocrit, platelet count, total white blood cell count and automated differential (manual differential if 
automated not available).   
13 Blood sample must be drawn at Baseline (Day -7 to Day 1), Day 1 of Cycles 2, 3, and 4, and the last day of Cycle 4. 
14 Blood sample must be drawn on Day 1 of Cycles 1, 2, 3, and 4, and the last day of Cycle 4. 
15 In subjects receiving platinum based chemotherapy only, an audiogram must be resulted at baseline (Day -7 to Day 1) and again  
0 - 4 days prior to Day 1 of Cycles 2, 3, 4, and the last day of Cycle 4. If hearing loss is detected then adjust dose per Section 4.7.4. 
16 G-CSF, antimicrobials, blood product transfusions, anti-neoplastic agents, and soy-based products (Section 4.8 and 6.4) 
17 Concomitant medications used in the 28 days prior to the initiation of the study intervention 
18 Dispense Day 1 of each cycle.  Weekly review recommended but not required.  Collect and review on the last day of each cycle. 


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6.2 Pre-treatment Assessments 
Informed consent will be obtained from a parent or guardian of eligible minor subjects, or 
the patient if ≥ 18 years old.  Oral assent will be obtained from minor subjects ≥ 7 years 
old, unless more stringent requirements are imposed by a site’s IRB.  Consent and 
assent must be obtained prior to any study-related procedures. (Section 4.3, Procedure 
Manual) 
Subject eligibility must be confirmed prior to subject enrollment using the inclusion and 
exclusion criteria (Section 3.1 – 3.2). The following data must also be collected pre-
treatment: 
• 
Clinical data: diagnosis, stage, grade, site(s) of disease 
o Stage (extent of spread): in situ, localized, regional, distant, unknown 
o Grade (differentiation level): well differentiated/low grade, moderately 
differentiated/moderate 
grade, 
poorly 
differentiated/high 
grade, 
undifferentiated/highest grade 
• 
Anticipated anti-neoplastic treatment regimen for courses coinciding with this 
trial: therapeutic agents (i.e. chemotherapy, hormonal therapy, immunotherapy, 
other small molecule inhibitors, gene therapy), doses expressed per kilogram 
body weight, duration of cycle (14 or 21 days), radiation dose and number of 
fractions (if applicable)  
• 
Demographic data: date of birth, sex, race, and ethnicity 
• 
Blood sample collection for serum homocysteine, C-reactive protein (CRP), and 
erythrocyte sedimentation rate (ESR), and complete blood count (CBC) with 
differential must be drawn at baseline (Day -7 to Day 1).  Raw data will be 
reported.  
o CBC with differential must include hemoglobin, hematocrit, platelet 
count, total white blood cell count and automated white blood cell 
differential (manual differential if automated not available) (Procedure 
Manual).   
• 
Medical history and physical exam for the purpose of establishing baseline 
conditions (Section 6.2.1) 
• 
Audiogram on Day -7 to Day 1 for subjects receiving platinum-based 
chemotherapy 
• 
Use of the following concomitant medications in the 28 days prior to the 
anticipated Cycle 1 Day 1: G-CSF, antimicrobials, blood product transfusions, 
anti-neoplastic agents, and soy-based products.  See Sections 4.8, 6.3, and the 
Procedure Manual for additional details on concomitant medications. 


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In addition, the following target AEs must be assessed during the Pre-treatment Period.  
Use assessment closest to Cycle 1 Day 1 if more than one assessment is done during 
the Pre-treatment period. 
• 
Neutropenia 
• 
Febrile neutropenia, with temperature  
• 
Fever for temperatures > 101.5° F, or > 100° F more than once in a 24-hour 
period  
• 
Infections and Infestations: Maximum grade for any AE listed in this CTCAE 
category.  Infections meeting the AE reporting threshold must be listed in the 
medical history.  
• 
Oral mucositis 
• 
Tinnitus (subjects receiving platinum-based chemotherapy only) 
• 
Hearing impairment (subjects receiving platinum-based chemotherapy only) 
• 
Peripheral motor neuropathy (subjects receiving vincristine only) 
6.2.1 Medical History and Physical Examination 
A medical history must be obtained and physical exam performed during the Pre-
treatment Assessment to establish baseline medical condition(s) (Section 6.2). Medical 
history includes clinically significant diseases, history of cancer (including date of 
diagnosis, location of disease, stage, grade, biopsies, resections, prior cancer therapies 
and procedures), and selected medications (anti-neoplastic agents, blood products, soy 
products, antimicrobials, and G-CSF) used by the patient within 28 days prior to protocol 
therapy (genistein/placebo). 
A full physical examination will be performed at the Pre-treatment Assessment and Day 
1 of each cycle (Sections 6.2 and 6.3). Physical examinations will include examination of 
the following body systems: general appearance/constitution (including height and body 
weight), skin, neck, HEENT (head, ears, eyes, nose and throat), cardiovascular system 
(auscultation of heart sounds), lungs/chest (auscultation of lung fields), abdomen 
palpation, genitourinary system (auscultation of bowel sounds), lymph nodes, 
extremities, and nervous system.  
An abbreviated, symptom-directed physical exam will be performed at all other visits 
(Section 6.3). This must also be conducted in such a way to assess for incidence of 
secondary conditions listed as endpoints (i.e., infection, mucositis, etc.)  In addition, any 
clinically significant abnormal finding which was not noted at the baseline assessment 
must be reported as an AE, provided it also meets the reporting criteria in Section 9.  
Baseline conditions and AEs must be reported as diagnoses, when possible.  Laboratory 
value abnormalities present at the time of enrollment must be reported as baseline 
conditions according to their CTCAE classifications.  The baseline onset and severity of 
all grades of all target AEs defined in Section 6.2 must be reported, as well as any other 


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non-target baseline condition if its severity is greater than or equal to grade 3 (Section 
9.1.8).  The outcome of baseline conditions and resolution dates, when applicable, must 
be reported at the end of the follow-up period. 
6.3 Treatment Phase Assessments (Cycles 1 – 4) 
Investigators should maintain good clinical practice and perform standard of care 
assessments and procedures per local institutional guidelines.  In addition, the following 
list of study-specific assessments must be performed once a patient enters the 
Treatment Phase.  All visits and assessments must be completed within ± 72 hours of 
the milestone date unless otherwise specified. 
• 
The following will be performed for the purposes of assessing clinically significant 
AEs.  AEs found prior to the first study supplement dose must be reported as 
baseline conditions.  See Section 9 and the Procedure Manual for more 
information about AE reporting. 
o Chemistry/metabolic liver function labs on Day 1 of each cycle: must 
include serum creatinine, total bilirubin, AST, and ALT (Procedure 
Manual) 
o CBC with differential on Day 1 of Cycles 2, 3, and 4, and at weekly visits: 
must include hemoglobin, hematocrit, platelet count, total white blood cell 
count and automated white blood cell differential (manual differential if 
automated not available) (Procedure Manual).  See below for additional 
requirements for ANC reporting. 
o Full physical exam on Day 1 of each cycle and a symptom-directed 
physical exam at each of the weekly visits (Section 6.2.1) 
▪ 
The Pre-treatment and Cycle 1 Day 1 physical exams may be 
combined performed ≤ 72 hrs. prior to Cycle 1 Day 1. 
▪ 
Subjects receiving vincristine must be assessed for vincristine 
toxicity in the form of peripheral motor neuropathy.   
o Audiograms for subjects receiving a platinum-based chemotherapy agent 
at 0 - 4 days prior to Day 1 of Cycles 2, 3, 4, and 0 - 4 days prior to the 
last day of Cycle 4.  Assess hearing impairment and tinnitus. 
• 
ANCs must be obtained as follows: 
o The ANC must include both neutrophils and bands.  The following 
equation is recommended:  
ANC = WBC x 1000 (% Neutrophils + % Bands) 
o Obtain on Day 1 of Cycles 2, 3, 4 and at weekly visits 


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o Once ANC levels begin to decrease, ANC must be determined at least 
twice weekly (≤ 96 hours between blood collection) until ANC recovers to 
≥ 500 cells/µL, then switch to weekly testing in the following situations: 
▪ 
If nadir is < 500 cells/µl, begin once ANC ≥ 500 cells/µl, OR 
▪ 
If nadir is ≥ 500 cells/µl, begin once ANC has increased by 50% 
above nadir 
o If ANC is < 500 cells/µl at any point after beginning weekly testing, 
resume twice weekly testing until ANC ≥ 500 cells/µl.   
o ANC will be obtained daily during any admission for febrile neutropenia.  
o All ANC values will be reported. 
• 
Serum CRP, homocysteine, and ESR: Report raw data collected on Day 1 of 
Cycles 2, 3, 4, and the last day of Cycle 4 
• 
Cytokine Panel and Isoflavone Panels: Draw and process specimen per the 
Procedure Manual on Day 1 of Cycles 1, 2, 3, 4, and the last day of Cycle 4 
• 
Weight and height on Day 1 of each cycle 
• 
The following target AEs must be assessed and the maximum grade reported 
for each cycle in addition to standard AE/SAE reporting (Section 9): 
o Neutropenia 
o Febrile neutropenia, with maximum associated temperature per cycle 
o Fever, including number of days per cycle, for temperatures > 101.5° F, 
or > 100° F more than once in a 24-hour period (report maximum 
temperature) 
o Infections and Infestations: Maximum grade for any AE listed in this 
CTCAE category.  Infections meeting the AE reporting threshold must be 
listed individually.  
o Oral mucositis 
o Tinnitus (subjects receiving platinum-based chemotherapy only) 
o Hearing impairment (subjects receiving platinum-based chemotherapy 
only) 
o Peripheral motor neuropathy (subjects receiving vincristine only) 
• 
Report per cycle: 
o Study supplement:  
▪ 
Total number of tablets taken  


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▪ 
Subject compliance with study medication dosing as determined 
by 
self-reported 
administration 
reports 
and 
supplement 
reconciliation 
▪ 
Reason for dose change, if applicable.  Any AE(s) precipitating a 
dose reduction must be reported even the minimum AE reporting 
threshold is not otherwise met (Section 9.2). 
o Anti-neoplastic treatment delay(s):  
▪ 
Total number of days delayed from planned schedule  
▪ 
Cause for delay: AE, or reason other than AE 
o Anti-neoplastic agent dose reduction(s):  
▪ 
Delayed agent(s) 
▪ 
Planned dose(s)  
▪ 
Actual dose(s) 
▪ 
Cause for dose change: AE, or reason other than AE 
o All unplanned or prolonged hospitalizations due to (an) AE(s) (Section 
9.1.9):  
▪ 
Date of admission or start of prolongation and discharge date  
▪ 
Causes/diagnoses precipitating hospitalization or prolonged 
hospitalization 
• 
Concomitant medication review at each scheduled visit for the following:  
o Soy-based products: Product, dates of use.  Reporting is limited to the 
soy-containing products described in Section 4.8.1 and the patient 
handout in the Procedure Manual.   
o Antimicrobials: type (antibiotic, antifungal, antiviral, other); route of 
administration (IV, oral, other); dates of use; AE(s) precipitating use, 
prophylactic use, or the treatment of a presumed/known infection  
o Blood product transfusions: dates of use, blood product type (platelets, 
red blood cells, other), and indication (Section 4.8.2) 
o G-CSF: Number of days per cycle that G-CSF was administered,  primary 
or secondary use (planned before the cycle began or in response to 
prolonged neutropenia, respectively)  
• 
Date 
of 
disease 
recurrence 
or 
progression, 
description 
of 
recurrence/progression, and site(s) of disease  
• 
Date of secondary malignancy diagnosis, description of secondary malignancy, 
and site(s) of disease 


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• 
Date of death due to any cause, and description of clinical scenario surrounding 
the subject’s death.   
The procedures and assessments schedule is summarized on the Roadmaps in the 
Procedure Manual appendices.   
Day 8 assessments must be repeated at intervening/additional weekly visits resulting 
from an anti-neoplastic therapy treatment delay or any other factors that causes the 
prolongation of a course. 
6.4 Post-Treatment/Follow-up Assessments 
All subjects will be followed for a minimum of 30 days after the last dose of protocol 
therapy (genistein/placebo) to assess for AEs. If subjects complete all four cycles of anti-
neoplastic therapy, this visit will occur at 35 ± 5 days following the last day of Cycle 4. If 
subjects are withdrawn or discontinued prior to completion of the anti-neoplastic therapy, 
this will occur at 35 ± 5 days following the last day the study supplement is administered.  
All serious adverse events (SAEs), other grade 3 – 4 AEs that are believed to be related 
to the investigational intervention, cancer progressions and relapses (including date, 
description, and sites), secondary malignancies (including date, description, and sites), 
and deaths (with date and clinical narrative) must be reported until 6 months after the 
end of the study intervention.  See Section 9.2 for additional information on AE and SAE 
reporting during this period.  


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7 EVALUATION CRITERIA 
7.1 Primary Endpoint 
The primary endpoint of this clinical trial is the average day of neutrophil count recovery 
following myelosuppressive chemotherapy.  Neutropenia will be defined as ANC < 500 
cells/µl (grade 4 neutropenia per CTCAE), and the “day of recovery” for each subject 
during each cycle of chemotherapy will be defined as the first post-nadir day of each 
cycle that the ANC is ≥ 500 cells/µl (i.e. ≤ grade 3).  For example, if the ANC is 400 
cells/µl on Day 12 and 600 cells/µl on Day 14, then the day of recovery will be Day 14.  
For subjects whose ANC nadir is ≥ 500 cells/µl, the day of recovery will be the day of the 
first ANC after their lowest ANC is obtained.  
7.2 Secondary Endpoints (per cycle) 
“Incidence” refers to both the frequency of an event per subject and the number of 
affected subjects in this study. 
• 
Severity of neutropenia 
• 
Duration of grade 4 neutropenia during hospital admissions for febrile 
neutropenia 
• 
Frequency and duration of unplanned or prolonged hospitalizations due to (an) 
AE(s) (Section 9.1.9) 
• 
Days with fever (temperature > 101.5° F, or > 100° F more than once in a 24-
hour period) 
• 
Incidence and severity of infections 
• 
Duration of antimicrobial use 
• 
Duration and severity of oral mucositis  
• 
Duration and severity of peripheral motor neuropathy (in subjects treated with 
vincristine) 
• 
Incidence and severity of hearing impairment and tinnitus (in subjects treated 
with a platinum-based chemotherapy agent)  
• 
Number of days  of delays and percent reduction of full planned doses of 
anti-neoplastic agents due to (an) AE(s)  
• 
Incidence of primary and secondary G-CSF use  
• 
Number and cause of required blood product transfusions  
• 
Serum cytokine levels: 
o G-CSF, granulocyte-macrophage colony stimulating factor (GM-CSF), 
interferon-α (IFN-α), IFN-γ, IL-1β, IL-1 receptor antagonist (IL-1RA), IL-2 
receptor (IL-2R), IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-
17, TNF-α.  


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o Chemokines: eotaxin, IFN-γ induced protein 10 (IP-10), monocyte 
chemotactic protein 1 (MCP-1), monokine induced by IFN-γ (MIG), 
macrophage inflammatory protein 1-α (MIP-1α), MIP-1β, Regulated upon 
Activation Normal T cell Expressed and presumably Secreted (RANTES). 
• 
Serum growth factor levels: epidermal growth factor (EGF), fibroblast growth 
factor-basic (FGF-basic), hepatocyte growth factor (HGF), vascular endothelial 
growth factor (VEGF)  
• 
Serum CRP levels, homocysteine levels, and ESRs  
7.3 Toxicity and Safety 
Toxicity will be assessed in subjects randomized to both groups for 30 days following the 
last dose of protocol therapy (genistein/placebo), as indicated in Section 6.4. AEs will be 
graded using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.  See also Section 9. 


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8 STATISTICAL CONSIDERATIONS 
8.1 Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, stratified, two-arm 
trial with a cross-over component which results in both a between-group comparison (A 
vs B for Cycles 1 and 2 data) and a crossover within group difference comparison 
(genistein cycles minus placebo cycles data). Patterns of ANCs over time will be 
estimated and average day of recovery over the two cycles will be the primary 
comparison. Neutropenia is defined in Section 7.1.  For each subject, two co-primary 
endpoints will be estimated; a) the average day to recovery during Cycles 1 and 2, and 
b) the difference in the average days during genistein cycles and the average days 
during placebo cycles.   
In addition, the study is designed to capture other clinically-relevant short-term side 
effects of therapy that appear to be reduced by genistein supplementation. Secondary 
endpoints are listed in Section 7.2. 
8.2 Sample Size and Accrual 
This pilot study is designed to obtain preliminary data to describe the overall pattern of 
ANC over time during myelosuppressive chemotherapy, assess neutropenia, and to 
determine whether the data support a decrease in time to recovery of 3 days for the 
genistein group compared to placebo. Target sample size for this pilot study was based 
upon results from a chart review performed at UVa which found that the mean day of 
recovery for pediatric cancer patients receiving myelosuppressive chemotherapy was 
day 16.25.  Group sample sizes of 22 eligible subjects per group achieves approximately 
80% power to detect a difference of 3 days with a 5% one-sided Mann-Whitney-
Wilcoxon Test. These results were based on 3000 Monte Carlo samples assuming a null 
Poisson (mean 16.25) distribution and an alternative Poisson (mean 13.25) distribution.  
ANC determination and neutropenia are defined in Sections 6.3 and 7.1. Adjusting for a 
10% ineligibility/drop-out rate, approximately 49 - 50 subjects may need to be accrued to 
the study. 
8.3 Stratification Factors/ Randomization 
Stratification will be based on the length of chemotherapy cycles, between 14-day (i.e. 
Ewing sarcoma patients receiving interval compressed chemotherapy) and 21-day 
cycles (most others). Site will not be a stratification factor. Subjects will be randomized 
with equal allocation to each arm using a stratified block randomization scheme with 
varying block sizes (of size 2 - 4). 
8.4 Data Analyses Plans 
Graphical and repeated measure models will be used to describe the complete pattern 
of ANC over all four cycles. Between-group (Cycles 1 & 2) and crossover differences 
(Cycles 1 - 4) form the structure for treatment comparisons. Repeated measure models 


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will be used to assess differences in raw ANC, daily ANC, days with fever, duration of 
hospitalization, and duration of antimicrobial use for subjects admitted with febrile 
neutropenia. The Cochran–Mantel–Haenszel test statistics will be used in the analysis of 
stratified categorical data such as neutropenia grades (severe: ≤ 100 cells/µl; moderate: 
≤ 500 cells/µl; mild: ≤ 1000 cells/µl) and filgrastim (G-CSF) usage. For duration and 
severity of mucositis and peripheral motor neuropathy, detailed physical examinations 
will be documented at each weekly physical exam.  Grading (grade 1 - 5) will be 
performed according to the CTCAE guidelines, version 4.0.  The Cochran–Mantel–
Haenszel test will be used to compare grade and repeated measure models for duration 
of mucositis between cycles containing genistein versus placebo.   
Number of subjects who experience hearing impairment and tinnitus will be summarized 
by treatment for each cycle. The number of required blood product transfusions, both 
packed red blood cells and platelets, will be documented and compared during genistein 
and placebo cycles using repeated measure models.  Reporting will be in the form of 
total ml/kg body weight infused of red blood cells and platelets.  Criteria for transfusion 
are listed in Section 4.8.2. 


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9 ADVERSE EVENTS AND REPORTING 
After informed consent has been obtained but prior to initiation of investigational 
intervention, only SAEs caused by a protocol-mandated intervention must be reported 
(e.g. SAEs related to invasive procedures). 
After initiation of the investigational study supplement dosing, all AEs must be 
collected as described in the following sections through 30 days after the last study 
supplement dose (Section 6). In addition, investigators must report any deaths, SAEs, 
other AEs of concern that are believed to be related to the investigational intervention, 
cancer progression, cancer relapse, and secondary malignancies through six months 
after the end of the study intervention. See the Procedure Manual for additional 
information on and resources for AE reporting. 
All AEs, whether reported by the subject or noted by study personnel, must be recorded 
in the subject’s medical and study records. AEs must be assessed for seriousness, 
severity, attribution and expectedness by the investigator. The following sections provide 
definitions for AE characteristics and reporting requirements.   
AEs must be followed to resolution or stabilization, and reported as SAEs if they are or 
become serious. This also applies to subjects experiencing AEs that cause interruption 
or discontinuation of study intervention, or those experiencing AEs that are present at 
the end of their participation in the study. Such subjects should receive post-treatment 
follow-up as appropriate.  
If an ongoing AE changes in its severity or in its perceived relationship to study 
intervention, a new AE entry for the event must be completed. 
9.1 Definitions 
9.1.1 Adverse Event [72] 
An adverse event is any untoward medical occurrence in a subject who has received an 
investigational intervention, whether or not related to the investigational intervention(s). 
Medical conditions present before starting the investigational intervention (pre-existing 
conditions) will be considered AEs only if they worsen after starting the study 
supplement (Sections 6.3 and 9.1.6). AEs include unfavorable, harmful or pathological 
changes in the general condition of a subject; subjective or objective symptoms 
(spontaneously offered by the subject and/or observed by the Investigator or the study 
nurse); intercurrent events or exacerbation of pre-existing diseases which occurred after 
the administration of the study supplement; clinically significant changes in laboratory 
abnormalities; or any undesirable and unintended effect of research occurring in human 
subjects as a result of the collection of identifiable, private information for research 
purposes. 


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Only clinically significant AEs will be reported on this study.  Reporting will include, at 
minimum, the dates of onset and resolution, severity, attribution to study intervention, 
expectedness, seriousness, and treatment (medication, transfusion, procedure, other, or 
none).  AEs should be reported as diagnoses, when possible.   
9.1.2 Persistent or Recurrent Adverse Events 
A persistent AE is an event which extends continuously, without resolution, between 
assessments. This event must only be recorded once with the initial severity grade. If the 
severity of the event worsens, then the original event ends and a separate event is 
recorded at the greater grade or with an altered relationship to the study supplement.  
A recurrent AE is an event which resolves between assessments and subsequently 
recurs. This must be recorded as a separate event for each recurrence. 
9.1.3 Secondary Adverse Events 
In general, events occurring secondary to other events (e.g., cascade events or clinical 
sequelae) must be considered a single event identified by the primary cause. However, 
a secondary event must be listed as an independent event if it meets one of the 
following criteria: 
• 
Severe  
• 
Serious  
• 
Separated in time from the primary event 
If it is not clear as to whether events are dependent, then record as separate AEs. 
9.1.4 Abnormal Laboratory Values/Clinical Assessments 
It is the responsibility of the investigator to review and document all laboratory findings 
and clinical assessments, which may include vital signs, physical exams and 
electrocardiograms (ECGs). Medical and scientific judgment must be exercised in 
deciding whether a laboratory abnormality or clinical finding must be classified as an AE. 
An abnormal laboratory test result or clinical finding must be considered as an AE if it 
meets at least one of the following criteria: 
• 
Is associated with clinical symptoms 
• 
Results in a change in study treatment (e.g., treatment modification, interruption 
or discontinuation) 
• 
Requires a medical intervention or change in concomitant therapy  
• 
Clinically significant in the investigator’s judgment  
9.1.5 Death 
Death must be considered an outcome of an AE and not an independent AE. The event 
or condition that caused the death must be recorded as the AE with the outcome of 


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death. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, then the event must be reported as a “death NOS”. If the cause of death later 
becomes available (e.g., after autopsy), “death NOS” must be updated by the 
established cause of death.  
9.1.6 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present during the pre-treatment screening 
assessments. These conditions must be noted as medical history as described in 
Section 6.2.1. Pre-existing medical conditions are not considered AEs unless any of the 
following characteristics worsen following initiation of any study-related procedure: 
• 
Frequency 
• 
Severity 
• 
Character  
If any of the above conditions apply, then this must be recorded as an AE. Convey that 
this is a change in a preexisting condition when describing the event. 
9.1.7 Expectedness 
The expectedness of the AE will be determined by the investigator based on current 
literature and the investigator’s experience. The most common AE associated with 
genistein supplementation is grade 2 abdominal pain (Section 5.1.7).   
SAEs will also take into consideration the expectedness of an AE within the study 
population, due to the underlying anti-neoplastic treatment regimen and/or underlying 
disease.  
See Sections 9.2.1 and 9.2.2 for information on expectedness as it relates to required 
reporting. 
9.1.8 Severity 
The descriptions and grading scales found in the revised CTCAE version 4.0, dated 
28May2009, will be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov, Appendix A). 
To assess severity of AEs not included in the CTCAE version 4.0, use Table 2 below.  
Table 4. AE Grading Scale for AEs Not Specifically Listed in the NCI CTCAE 
Grade   Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLa 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 


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prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
aInstrumental activities of daily living (ADL) refers to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
bSelf-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
9.1.9 Serious Adverse Event [72] 
A serious adverse event or experience (SAE) or serious adverse drug reaction (ADR) is 
any AE temporally associated with the subject’s participation in research that meets any 
of the following criteria: 
• 
Fatal 
• 
Life-threatening (places the subject at immediate risk of death from the event as 
it occurred) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization* 
• 
Results in a congenital anomaly/birth defect 
• 
Results in a persistent or significant disability/incapacity 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
subject safety and may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition.   
For reporting purposes, also consider the occurrences of pregnancy as an event which 
must be reported as an important medical event. 
*Hospitalization or prolonged hospitalization must be documented and reported as a 
SAE, except if the hospitalization meets at least one of the following criteria: 
• 
The hospitalization is less than 24 hours and without an admission 
• 
Hospitalization for respite care 
• 
Planned hospitalization required for or related to anti-neoplastic treatment (e.g. 
for anticipated procedures such as administration of chemotherapy, central line 
insertion, metastasis interventional therapy, resection of primary tumor, or 
elective surgery) 
• 
Hospitalization for a pre-existing condition, provided that all of the following 
criteria are met: 
o The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease.  
o The subject has not suffered a causative AE. 


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If the hospitalization meets any of these criteria, then it is not considered a SAE. 
SAEs are subject to both expedited and routine reporting.  See Section 9.2.3.2 and the 
Procedure Manual for additional information on expedited reporting requirements for 
SAEs.  
 


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9.1.10 Attribution Assessment 
The investigator will evaluate all AEs and to assess the attribution, if any, to study 
supplement.  The following criteria will define the attribution [72]: 
Definite:   
The AE is clearly related to the investigational intervention 
Probable:  
The AE is likely related to the investigational intervention 
Possible:  
The AE may be related to the investigational intervention 
Unlikely:  
The AE is doubtfully related to the investigational intervention 
Unrelated:  
The AE is clearly NOT related to the investigational intervention 
9.2 Required Reporting  
9.2.1 UVa Cancer Center DSMC Reporting Requirements 
All AEs must be reported into UVa Cancer Center OnCore database within the time 
frame specified below.  All timeframes are expressed in (calendar) days from the first 
point at which any member of the study team learned of the event.  
For the purposes of reporting AEs for DSMC review, expectedness is defined in 
relationship to treatment with the investigational agent.  I.e. Is the AE in question 
expected when undergoing genistein treatment?  See Sections 5.1.7 and 5.2.4 for the 
expected AE.  AEs meeting the thresholds below require additional reporting in OnCore 
beyond the routine data capture associated with a reporting period.  
Target AEs do not need to be reported apart from routine data capture unless they meet 
the criteria below.  Progressions, recurrences, and secondary malignancies must be 
reported within 30 days of the end of the reporting period during which they occurred, or 
the next quarterly deadline, whichever comes last.  See the Procedure Manual for 
additional information pertaining to data capture. 
Table 5. DSMC reporting requirements for AEs that occur during Cycles 1 – 4 
Attribution 
to Study 
Supplement 
Grades 1 & 2 
Grade 3 
Grade 4 
Grade 5 
Expected & Unexpected Expected & Unexpected 
 Unexpected 
Unexpected 
Target 
AEs1 
All other:  
Target 
AEs1 
All other:  
 
 
Unrelated 
Unlikely 
OnCore: 
30 days/ 
quarterly3 
Not 
required 
OnCore: 
30 days/ 
quarterly3 
Not required 
OnCore: 
30 days/quarterly3 
See SAE 
Possible 
Probable 
Definite 
OnCore: 
30 days from 
end of Cycle 
OnCore: 
15 days from 
end of Cycle 
SAE4 
OnCore: (24-hrs), 7 days2 
1 Target AEs: Neutrophil count decreased, infection (any), mucositis oral, febrile neutropenia, 
fever, tinnitus & hearing impaired (subjects on platinum-based chemotherapy only), peripheral 


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motor neuropathy (subjects on vincristine only). 
2 Enter into Cancer Center database within 24 hours and submit supporting documentation within 
7 days.  
3 Data to be entered within 30 days of the end of the reporting period or the next quarterly 
deadline, whichever comes last.  Deadlines are Jan. 31, Apr. 31, July 31, and Oct. 31. 
4 Any AE that is an SAE must be reported using the SAE timeline regardless of grade or 
attribution.   
 
Less stringent reporting is required during the follow-up period. 
Table 6. DSMC reporting requirements for AEs that occur after the subject’s last 
cycle taking the study supplement until 6 months post-treatment (i.e. follow-up) 
Attribution 
to Study 
Supplement 
Grades 1 & 2 
Grade 3 
Grade 4 
Grade 5 
Expected & 
Unexpected 
Expected & Unexpected 
Unexpected 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
OnCore: 
30 days/quarterly2 
See SAE 
Possible 
Probable 
Definite 
OnCore: 
30 days from end of 
Reporting Period3 
OnCore: 
15 days from end of 
Reporting Period3 
SAE4 
OnCore: (24-hrs), 7 days1 
1 Enter into Cancer Center database within 24 hours and submit supporting documentation within 
7 days.  
2 Data to be entered within 30 days of the end of the reporting period or the next quarterly 
deadline, whichever comes last.  Deadlines are Jan. 31, Apr. 31, July 31, and Oct. 31. 
3 Reporting is not required if AE onset is > 30 days after the last dose of study supplement 
4 Any AE that is an SAE must be reported using the SAE timeline regardless of grade or 
attribution.   
 
9.2.2 IRB Reporting Requirements 
Serious and unexpected AEs must be submitted to the site IRB according to the 
participating site institutional policies. 
For the UVa clinical site, the PI or designee is responsible for reporting AEs and 
unanticipated problems to the UVa Institutional Review Board for Health Sciences 
Research (UVa IRB-HSR) according to the following guidelines. 
For the purposes of reporting to UVa IRB-HSR, expectedness is defined in 
relationship to the patient population.  I.e.  Is the AE in question expected given the 
characteristics of the population being studied or in terms of the nature, severity or 
frequency given the research procedures described in the protocol? 
 
 


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Table 7. IRB Reporting Requirements for UVa 
Type of Event 
To whom will it be 
reported: 
Time Frame for Reporting 
How reported? 
Any internal event resulting in 
death that is deemed 
DEFINITELY related to 
(caused by) study participation 
An internal event is one that 
occurs in a subject enrolled in 
a UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
AE  
See also OnCore reporting 
requirement (Section 9.2.3.2, 
Procedure Manual).  
IRB-HSR 
Within 7 calendar days from 
the time the study team 
received knowledge of the 
event.  Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
www.irb.virginia.edu/ 
 
External, Serious, Unexpected 
AE that results in a change to 
the risk section of the consent 
and/or modification to the 
protocol 
IRB-HSR 
 
 
 
IRB Online 
www.irb.virginia.edu/ 
 
Unanticipated Problems that 
are not AEs or protocol 
violations  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar days from 
the time the study team 
received knowledge of the 
event.  
Unanticipated Problem report 
form.  
http://www.virginia.edu/vprgs/
irb/HSR_docs/Forms/Reporti
ng_Requirements-
Unanticipated_Problems.doc  
Protocol Violations 
(The IRB-HSR only requires 
that MAJOR violation be 
reported, unless otherwise 
required by your sponsor, if 
applicable.) 
IRB-HSR 
 
 
Within 7 calendar days from 
the time the study team 
received knowledge of the 
event.  
 
Protocol Violation and 
Enrollment Exception 
Reporting Form 
http://www.virginia.edu/vprgs/
irb/hsr_forms.html 
Data Breach  
The UVa Corporate 
Compliance and 
Privacy Office 
 
 
ITC:  if breach 
involves  electronic 
data 
 
 
UVa Police if breach 
includes such things 
as stolen computers.  
As soon as possible and no 
later than 24 hours from the 
time the incident is 
identified. 
 
As soon as possible but no 
later than 24 hours from the 
time the incident is 
identified. 
 
IMMEDIATELY.  
 
 
UVa Corporate Compliance 
and Privacy Office: (434) 
924-9741 
 
 
ITC:  Information Security 
Incident Reporting 
procedure,  
http://www.itc.virginia.edu/se
curity/reporting.html 
 
Phone: (434) 924-7166 
 
Table 8. DSMC Reporting Requirements 
INDEPENDENT DSMB/DSMC 
DSMB/DSMC 
Reports 
IRB 
15 calendar days of the study team receiving the report 
Copy of DSMB/ 
DSMC report 
 
 
 


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9.2.3 Additional reporting Requirements 
9.2.3.1 
Target Adverse Events 
Target AEs are AEs of special interest and will be collected throughout the treatment 
phase, regardless of expectedness, severity, or attribution.  They are listed in Section 
6.3.  Target AEs will not be collected during the follow-up reporting periods unless the 
AEs otherwise meet the DSMC or IRB reporting requirements outlined in Sections 9.2.1 
and 9.2.2. 
9.2.3.2 
Additional Reporting Requirements for Affiliate Sites 
In addition to reporting in OnCore, all SAEs must be reported by facsimile within 24 
hours of the event to the Sponsor (UVa) as outlined in the Procedure Manual. Any SAEs 
that occur in the 30 days following the last dose of protocol therapy must be reported. 
After that time, only SAEs that are related to protocol therapy are required to be 
reported. For every SAE which occurs, affiliates must send an SAE report with the 
following information: 
• 
Safety reporting cover sheet (Procedure Manual appendices) 
• 
Relevant hospital case records and autopsy reports (where applicable) 
9.2.3.3 
Reporting to the FDA 
The Study Chair or designee is responsible for providing safety updates to the FDA per 
the following guidelines.  The reporting times refer to the time the study team received 
knowledge of the AE. 
Table 9. FDA Reporting Requirements 
UVa PI HELD IND 
Type of Event 
To whom will 
it be reported: 
Time Frame for Reporting 
How reported? 
Life-threatening 
and/or 
fatal unexpected events 
related or possibly related 
to 
the 
use 
of 
the 
investigational agent.* 
FDA 
Within 7 calendar days of 
the study team learning of 
the event 
Form FDA 3500A 
(MedWatch) 
or 
narrative 
 
Serious, unexpected and 
related or possibly related 
AEs* 
FDA 
Within 15 calendar days 
after the study team receives 
knowledge of the event 
Form FDA 3500A 
(MedWatch) 
or 
narrative 
All AEs 
FDA 
Annually 
IND annual report 
*Applies to AEs/SAEs not identified in Appendix C 
 
Certain anticipated SAEs will not be reported individually to the FDA in an expedited 
fashion due to their frequency in the study population independent of study supplement 
exposure.  The events listed in Appendix C are common in patients receiving the 
chemotherapeutic agents listed in Section 3.1 and so will instead be reported in 
aggregate to the FDA using an IND safety report should analysis indicate that the 
toxicities are occurring more frequently in patients taking genistein.   


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The Study Chair may also choose to refrain from single-event IND safety reporting 
should an AE/SAE be related to the subject’s underlying disease.  These events are not 
included in Appendix C due to the wide range of cancers that may participate in this 
study.  As above, such AE/SAEs will be reported using an IND safety report should 
aggregate analysis demonstrate increased toxicity associated with genistein treatment. 
Single-event IND safety reports submitted to the FDA will be blinded, per permission 
granted by the agency on 19May2017. 
Annual reports to the FDA will include AEs and SAEs collected as described in Section 
9.2.1, with the exception of target AEs collected solely for the purposes endpoint 
analysis.  Those target AEs are non-serious grades 1 and 2, any attribution to the study 
supplement, and non-serious grade 3 with an unrelated or unlikely relationship to the 
study supplement. 
9.2.3.4 
Reporting to Participating Sites 
The Study Chair or designee is responsible for providing safety updates to all 
participating sites per the following guidelines: 
 
Table 10. Required Reporting to Participating Sites 
UVa PI of MULTI-SITE TRIAL 
Type of Event 
To whom will it 
be reported: 
Time Frame for Reporting 
How reported? 
Serious, 
unexpected 
and related or possibly 
related AEs 
All Research Sites 
Within 15 calendar days 
after 
the 
Study 
Chair 
receives knowledge of the 
event 
IND Safety Report 
(Cover letter, copy of 
MedWatch 
or 
narrative) 
Unanticipated Problem All Research Sites 
Within 15 calendar days 
from the time the Study 
Chair receives knowledge 
of the event. 
Letter to Site PIs, 
Copy of MedWatch 
or narrative 
 


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10 DATA SAFETY MONITORING PLAN 
The Study Chair will provide continuous monitoring of subject safety in this trial with 
periodic reporting to the UVa Data Safety Monitoring Committee (DSMC). 
10.1 Data Collection/CRF Completion 
All data must be entered into OnCore in accordance the University of Virginia Cancer 
Center OnCore standard operating procedure (SOP), which can be found on the OnCore 
Resources page (see the OnCore Help tab).  AEs must be entered into OnCore as 
described in Section 9.2 and in the Procedure Manual. All other study specific data must 
be entered into OnCore in the timeframes specified in the SOP.  Sample CRFs are 
available in the Procedure Manual appendices. 
10.2 UVa Cancer Center Data Safety Monitoring Committee 
The UVa Cancer Center (CC) Data and Safety Monitoring Committee (DSMC) will 
provide oversight of the conduct of this study.  The CC DSMC will report to the UVa 
Protocol Review Committee (PRC). These reports will also be provided to participating 
sites for submission to their IRBs. 
The DSMC will review the following data in blinded format: 
• 
All AEs 
• 
Audit results 
• 
Application of study designed stopping/decision rules 
• 
Whether the study accrual pattern warrants continuation/action 
• 
Protocol violations 
The CC DSMC will meet every month for aggregate review of AE data.  Tracking reports 
of the meetings are available to the Study Chair for review.  Issues of immediate concern 
by the DSMC are brought to the attention of the Study Chair (and if appropriate to the 
PRC and IRB) and a formal response from the Study Chair is requested.   Per the CC 
NIH-approved institutional plan this study will be audited approximately every 6 or 12 
months.  
10.3 Review of Adverse Events by the Study Team 
Individual AEs will be reviewed by the treating physician and/or principal investigator, 
and the clinical research coordinator(s) (CRC).  Additional staff on the research team 
may also review AEs. 
SAEs will be reviewed by the Study Chair and Study Statistician at least once every six 
months after the first subject’s first dose with study supplement.  Those present at the 
meeting may include the Study Chair, PIs at other sites, sub-investigators, protocol 


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development staff, biostatisticians, research nurses, research coordinators, laboratory 
specialists, and laboratory research managers.  These meetings also include the review 
of individual participants to assess whether they are protocol candidates, whether AEs 
warrant discontinuation, and whether the existing protocol should be continued, 
amended, or closed. 


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11 STUDY MANAGEMENT 
11.1 IRB Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  Each site’s IRB must approve the 
consent form(s) and protocol.  All initial and amendment approvals, annual renewals, 
and IRB-stamped consent forms must be submitted to the Study Manager (Procedure 
Manual). 
Section 4.3 outlines expectations for properly obtaining and documenting informed 
consent. 
11.2 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  The UVa IRB-HSR will 
approve all aspects of this study, including the clinical trial protocol, informed consent 
documents, and subject materials.  Modifications to the protocol or consent form will be 
reviewed and approved by the UVa IRB-HSR prior to implementation, except when 
necessary to eliminate apparent immediate hazards to the study participants. The study 
will undergo continuing IRB review based on the level of risk as assessed by the IRB.  
This review will take place no less than annually. Participating sites will be responsible 
for ensuring their consent forms are written in accord with 21 CFR 50. 
Affiliate sites must submit this study for the review of their local site IRBs in accordance 
with local policies.  At a minimum, all consent forms, the protocol (all versions from the 
time of affiliate start-up), annual renewals, and study closure must be approved by the 
site IRB.  See the Procedure Manual for further details. 
11.2.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval/favorable opinion, if 
permitted by the site’s IRB.   
For any such emergency modification implemented at UVa, an IRB modification form 
must be completed by study personnel within five (5) business days of making the 
change.   
11.2.2 Protocol Deviations/Violations 
Protocol Deviations: A protocol deviation is any unplanned variance from an IRB 
approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 


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• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
Study personnel will record the deviation, and report to the Sponsor or DSMC in 
accordance with their policies.  Deviations must be summarized and reported to the site 
IRB at the time of continuing review or according to site IRB’s policy.  
Protocol Violations: An unplanned protocol variance is considered a violation if the 
variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or institutional policies. 
Violations must be reported by study personnel to the site IRB in accordance with the 
site IRB’s policy and to the Sponsor as outlined in the Procedure Manual. 
11.3 Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, 
Sponsor-Investigator 
correspondence, 
monitoring 
logs/letters, 
and 
regulatory documents (e.g. protocol and amendments, IRB correspondence and 
approvals/acknowledgements, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents must be kept on file until six years after the completion and final 
study report of this investigational study.  Completion is defined as study closure through 
the UVa IRB-HSR. 
11.4 Obligations of Investigators 
The PI is responsible for the conduct of the clinical trial at their site in accordance with 
Title 21 of the Code of Federal Regulations, all applicable local regulatory laws and 
regulations and/or the Declaration of Helsinki.  The PI is responsible for personally 


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overseeing the treatment of all study subjects at his or her site and must assure that all 
study site personnel, including sub-investigators and other study staff members, adhere 
to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical 
trials both during and after study completion. It is the responsibility of the PI to ensure 
that all study site personnel are aware that the study protocol and all data generated is 
confidential and not disclosed to third parties (with the exception of local and national 
regulatory bodies which require access for oversight purposes).  
The PI at each institution or site will be responsible for assuring that all the required data 
will be collected and entered onto the CRFs. Periodically, monitoring visits will be 
conducted and the PI will provide access to his or her original records to permit 
verification of proper entry of data. At the completion of the study, all CRFs will be 
reviewed by the PI and will require his or her final signature to verify the accuracy of the 
data. 
 


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66(9): p. 4816-25. 
27. 
Khoshyomn, S., et al., Synergistic action of genistein and cisplatin on growth inhibition 
and cytotoxicity of human medulloblastoma cells. Pediatr Neurosurg, 2000. 33(3): p. 
123-31. 
28. 
Ahmad, I.U., et al., Soy isoflavones in conjunction with radiation therapy in patients with 
prostate cancer. Nutr Cancer, 2010. 62(7): p. 996-1000. 
29. 
Adlercreutz, H., Phytoestrogens: epidemiology and a possible role in cancer protection. 
Environmental Health Perspectives, 1995. 103(Suppl 7): p. 103-12. 
30. 
Ruiz-Larrea, M.B., et al., Antioxidant activity of phytoestrogenic isoflavones. Free 
Radical Research, 1997. 26(1): p. 63-70. 
31. 
Stoll, B.A., Macronutrient supplements may reduce breast cancer risk: how, when and 
which? European Journal of Clinical Nutrition, 1997. 51(9): p. 573-7. 
32. 
Ryan-Borchers, T.A., et al., Soy isoflavones modulate immune function in healthy 
postmenopausal women. Am J Clin Nutr, 2006. 83(5): p. 1118-25. 
33. 
Mitchell, J.H. and A.R. Collins, Effects of a soy milk supplement on plasma cholesterol 
levels and oxidative DNA damage in men--a pilot study. Eur J Nutr, 1999. 38(3): p. 143-
8. 
34. 
Djuric, Z., et al., Effect of soy isoflavone supplementation on markers of oxidative stress 
in men and women. Cancer Lett, 2001. 172(1): p. 1-6. 
35. 
Ruiz-Larrea, M.B., et al., Antioxidant activity of phytoestrogenic isoflavones. Free Radic 
Res, 1997. 26(1): p. 63-70. 
36. 
Arora, A., M.G. Nair, and G.M. Strasburg, Antioxidant activities of isoflavones and their 
biological metabolites in a liposomal system. Arch Biochem Biophys, 1998. 356(2): p. 
133-41. 
37. 
Giles, D. and H. Wei, Effect of structurally related flavones/isoflavones on hydrogen 
peroxide production and oxidative DNA damage in phorbol ester-stimulated HL-60 cells. 
Nutr Cancer, 1997. 29(1): p. 77-82. 
38. 
Sierens, J., et al., In vitro isoflavone supplementation reduces hydrogen peroxide-
induced DNA damage in sperm. Teratog Carcinog Mutagen, 2002. 22(3): p. 227-34. 
39. 
Wei, H., et al., Inhibition of tumor promoter-induced hydrogen peroxide formation in vitro 
and in vivo by genistein. Nutr Cancer, 1993. 20(1): p. 1-12. 


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40. 
Sarkar, F.H. and Y. Li, The role of isoflavones in cancer chemoprevention. Front Biosci, 
2004. 9: p. 2714-24. 
41. 
Kameoka, S., et al., Expression of antioxidant proteins in human intestinal Caco-2 cells 
treated with dietary flavonoids. Cancer Lett, 1999. 146(2): p. 161-7. 
42. 
Chan, W.H. and J.S. Yu, Inhibition of UV irradiation-induced oxidative stress and 
apoptotic biochemical changes in human epidermal carcinoma A431 cells by genistein. J 
Cell Biochem, 2000. 78(1): p. 73-84. 
43. 
Kapiotis, S., et al., Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL 
oxidation and protects endothelial cells from damage by atherogenic LDL. Arterioscler 
Thromb Vasc Biol, 1997. 17(11): p. 2868-74. 
44. 
Kuzu, N., et al., Protective role of genistein in acute liver damage induced by carbon 
tetrachloride. Mediators Inflamm, 2007. 2007: p. 36381. 
45. 
Cai, Q. and H. Wei, Effect of dietary genistein on antioxidant enzyme activities in 
SENCAR mice. Nutr Cancer, 1996. 25(1): p. 1-7. 
46. 
Duan, W., et al., Antiinflammatory effects of genistein, a tyrosine kinase inhibitor, on a 
guinea pig model of asthma. Am J Respir Crit Care Med, 2003. 167(2): p. 185-92. 
47. 
Upadhyay, S., et al., Differential sensitivity of normal and malignant breast epithelial cells 
to genistein is partly mediated by p21(WAF1). Clin Cancer Res, 2001. 7(6): p. 1782-9. 
48. 
Das, A., N.L. Banik, and S.K. Ray, Flavonoids activated caspases for apoptosis in 
human glioblastoma T98G and U87MG cells but not in human normal astrocytes. 
Cancer, 2010. 116(1): p. 164-76. 
49. 
Seo, H.S., et al., Induction of apoptotic cell death by phytoestrogens by up-regulating the 
levels of phospho-p53 and p21 in normal and malignant estrogen receptor alpha-
negative breast cells. Nutr Res, 2011. 31(2): p. 139-46. 
50. 
Li, Y., et al., Epigenetic regulation of multiple tumor-related genes leads to suppression 
of breast tumorigenesis by dietary genistein. PLoS One, 2013. 8(1): p. e54369. 
51. 
Kingsley, K., et al., Soy protein extract (SPE) exhibits differential in vitro cell proliferation 
effects in oral cancer and normal cell lines. J Diet Suppl, 2011. 8(2): p. 169-88. 
52. 
Chen, F.P. and M.H. Chien, Phytoestrogens induce differential effects on both normal 
and malignant human breast cells in vitro. Climacteric, 2014. 17(6): p. 682-91. 
53. 
Bai, Y.P., et al., Rosiglitazone attenuates NF-kappaB-dependent ICAM-1 and TNF-alpha 
production caused by homocysteine via inhibiting ERK1/2/p38MAPK activation. Biochem 
Biophys Res Commun, 2007. 360(1): p. 20-6. 
54. 
Pang, X., et al., Homocysteine induces the expression of C-reactive protein via NMDAr-
ROS-MAPK-NF-kappaB signal pathway in rat vascular smooth muscle cells. 
Atherosclerosis, 2014. 236(1): p. 73-81. 
55. 
Thaler, R., et al., Homocysteine suppresses the expression of the collagen cross-linker 
lysyl oxidase involving IL-6, Fli1, and epigenetic DNA methylation. J Biol Chem, 2011. 
286(7): p. 5578-88. 
56. 
Wenzel, U., D. Fuchs, and H. Daniel, Protective effects of soy-isoflavones in 
cardiovascular disease. Identification of molecular targets. Hamostaseologie, 2008. 
28(1-2): p. 85-8. 
57. 
Castro, S.B., et al., Immunomodulatory effects and improved prognosis of experimental 
autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment. Int 
Immunopharmacol, 2012. 12(2): p. 465-70. 
58. 
Hsu, A., et al., Dietary soy and tea mitigate chronic inflammation and prostate cancer via 
NFkappaB pathway in the Noble rat model. J Nutr Biochem, 2011. 22(5): p. 502-10. 
59. 
Wu, S.H., et al., Soy food intake and circulating levels of inflammatory markers in 
Chinese women. J Acad Nutr Diet, 2012. 112(7): p. 996-1004, 1004 e1-4. 


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60. 
Chun, O.K., et al., Serum C-reactive protein concentrations are inversely associated with 
dietary flavonoid intake in U.S. adults. J Nutr, 2008. 138(4): p. 753-60. 
61. 
Floegel, A., et al., Antioxidant intake from diet and supplements and elevated serum C-
reactive protein and plasma homocysteine concentrations in US adults: a cross-sectional 
study. Public Health Nutr, 2011. 14(11): p. 2055-64. 
62. 
Mansour, A., et al., Genistein induces G2 arrest in malignant B cells by decreasing IL-10 
secretion. Cell Cycle, 2004. 3(12): p. 1597-605. 
63. 
Ghaemi, A., et al., Genistein induces a protective immunomodulatory effect in a mouse 
model of cervical cancer. Iran J Immunol, 2012. 9(2): p. 119-27. 
64. 
Guo, T.L., et al., Genistein modulates immune responses and increases host resistance 
to B16F10 tumor in adult female B6C3F1 mice. J Nutr, 2001. 131(12): p. 3251-8. 
65. 
Tacyildiz, N., et al., Soy isoflavones ameliorate the adverse effects of chemotherapy in 
children. Nutr Cancer, 2010. 62(7): p. 1001-5. 
66. 
Fischer, L., et al., Clinical characteristics and pharmacokinetics of purified soy 
isoflavones: multiple-dose administration to men with prostate neoplasia. Nutr Cancer, 
2004. 48(2): p. 160-70. 
67. 
Takimoto, C.H., et al., Phase I pharmacokinetic and pharmacodynamic analysis of 
unconjugated soy isoflavones administered to individuals with cancer. Cancer Epidemiol 
Biomarkers Prev, 2003. 12(11 Pt 1): p. 1213-21. 
68. 
de Ruijter, J., et al., Genistein in Sanfilippo disease: a randomized controlled crossover 
trial. Ann Neurol, 2012. 71(1): p. 110-20. 
69. 
Lazarevic, B., et al., 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. Nutr Cancer, 2011. 63(6): p. 889-98. 
70. 
Lazarevic, B., et al., The effects of short-term genistein intervention on prostate 
biomarker expression in patients with localised prostate cancer before radical 
prostatectomy. Br J Nutr, 2012. 108(12): p. 2138-47. 
71. 
Strom, B.L., et al., Exposure to soy-based formula in infancy and endocrinological and 
reproductive outcomes in young adulthood. JAMA, 2001. 286(7): p. 807-14. 
72. 
NCI Guidelines: Adverse Event Reporting Requirements for NCI Investigational Agents. 
2012, National Cancer Institute: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df. 
 
 


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13 APPENDICES 
 
A. CTCAE Grading Criteria 
B. Genistein Product Information 
C. Toxicities Excluded from Single-event IND Safety Reporting to the FDA 
 
 


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APPENDIX A: CTCAE 
 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4 
 
An electronic pdf copy of the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
may be obtained from the CTEP website.  The web address is:  
http://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf  
 
An online version of the current version of the CTCAE may be accessed at: https://safetyprofiler-
ctep.nci.nih.gov/.  Please note that searches in the online Safety Profiler must utilize the “literal” button rather 
than keyword” or enter. 
 
 
 


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APPENDIX B: STUDY MEDICATION INFORMATION 
 
 
 
 
 
 
 
 


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GenVida™ TG Product Data Sheet 
 


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GenVida™ TG Product Safety Sheet 


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Genistein Fact Sheet 
 
Protocol Title:  A Randomized, Placebo-Controlled Pilot Study of Genistein Supplementation in 
Pediatric Cancer Patients Receiving Myelosuppressive Chemotherapy (UVa-Gen001) 
 
NOTE:  THIS INFORMATION IS FOR CONFIDENTIAL REVIEW BY HOUSESTAFF AND 
NURSES ADMINISTERING INVESTIGATIONAL MEDICATION 
 
NAME AND SYNONYMS:  
Chemical Name: 5, 7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one 
Other Names: i-cool tablets containing 30 mg geniVida™ TG (Product code 5011590)   
 
FORM(S) AND STRENGTH(S): 
30 mg/tablet 
 
USUAL DOSE RANGE, SCHEDULE AND ROUTES OF ADMINISTRATION: 
  
Genistein is the main isoflavone component in dietary soy1.  The genistein concentration of 30 
mg is roughly the equivalent of two cups of soy milk.  See protocol section 1.3 for more 
information regarding genistein as a component of dietary soy intake, including safety data.  
 
Concentrations of purified genistein used in adult clinical trials have ranged from 30 – 600 
mg/day.  Data on the use of purified genistein in pediatric populations is limited.  A recent study 
on children with Sanfilippo disease administered a genistein-rich soy isoflavone extract 
containing 10 mg/kg/day genistein2 and a trial on children and adults with lymphoid 
malignancies used 0.1 – 0.18 mg/kg of an immunoconjugated genistein3. 
 
1. 
Sarkar, F.H. and Y. Li, The role of isoflavones in cancer chemoprevention. Front Biosci, 2004. 9: p. 2714-24. 
2. 
de Ruijter J, Valstar MJ, Narajczyk M, Wegrzyn G, Kulik W, Ijlst L, Wagemans T, van der Wal WM, Wijburg FA. 
Genistein in Sanfilippo disease: a randomized controlled crossover trial. Ann Neurol. 2012 Jan;71(1):110-20. doi: 
10.1002/ana.22643. 
3. 
Chen CL, Levine A, Rao A, O'Neill K, Messinger Y, Myers DE, Goldman F, Hurvitz C, Casper JT, Uckun FM. 
Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with 
B-lineage lymphoid malignancies. J Clin Pharmacol. 1999 Dec;39(12):1248-55. 
 
OBJECTIVE:  
See Protocol Section 2 
 
PROTOCOL DESIGN:   
See Protocol Sections 1.1, 4.7.2 
 
PROTOCOL DOSAGE RANGE:  
See Protocol Sections 4.7.2 and 5.1.6 
  
 
PHARMACOLOGY:  
Genistein is an isoflavonoid that preferentially binds to estrogen receptor-β, but uses both 
estrogen receptors α and β to modulate gene expression1,2.  It inhibits protein-tyrosine kinase 
and topoisomerase-II.  It has been shown to cause G2 phase arrest in human and murine cell 
lines and displays antineoplastic and antitumorigenic activity3.   
 


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Genistein has a low oral bioavailability due to its extensive metabolism in the intestine and liver4.  
Acid hydrolysis or intestinal microflora-mediated hydrolysis releases ingested genistein from the 
glucoside genistein.  It can then be absorbed or further metabolized to dihydrogenistein or 5-
hydroxy-equol5.  A 50 mg/kg purified genistein dose given to six human subjects resulted in a 
plasma concentration of 1.26 ± 0.27 m, a Tmax of 5.2 hr., and an elimination half-life of 6.8 hr4. 
 
Genistein’s predominate distribution site is controversial.  Rat studies have shown higher 
concentrations of the compound in the intestines, stomach, kidney, liver, lung, heart, brain, 
plasma, reproductive organs, and brain.  The excretion pathways for genistein and its 
metabolites are intestinal, biliary, and renal4. 
 
In vivo animal studies have shown that the pharmacokinetics for this compound may be gender-
dependent4. 
 
1. 
Henley DV, Korach KS. Physiological effects and mechanisms of action of endocrine disrupting chemicals that 
alter estrogen signaling. Hormones (Athens). 2010 Jul-Sep;9(3):191-205. 
2. 
Rietjens IM1, Sotoca AM, Vervoort J, Louisse J. Mechanisms underlying the dualistic mode of action of major 
soy isoflavones in relation to cell proliferation and cancer risks. Mol Nutr Food Res. 2013 Jan;57(1):100-13.  
3. 
NIH U.S. National Library of Medicine TOXNET Toxicology Data Network ChemIDplus. “Genistein.” Accessed 
September 22, 2014. http://chem.sis.nlm.nih.gov/chemidplus/rn/446-72-0 
4. 
Yang Z1, Kulkarni K, Zhu W, Hu M. Bioavailability and pharmacokinetics of genistein: mechanistic studies on its 
ADME. Anticancer Agents Med Chem. 2012 Dec;12(10):1264-80. 
5. 
Behloul N1, Wu G. Genistein: a promising therapeutic agent for obesity and diabetes treatment. Eur J 
Pharmacol. 2013 Jan 5;698(1-3):31-8. 
 
ADVERSE EFFECTS:  
See Protocol Sections 4.7.4, 5.1.7, and genistein safety data sheet section 11.1 
 
By way of comparison, the safety profiles of two commercially-available genistein-containing 
supplements are listed below. 
 
Fosteum PLUS1 
 
“FOSTEUM® PLUS Capsules 
calcium compounds (dicalcium malate and pentacalcium hydroxide triphosphate) (500 mg) 
phosphate (70 mg) 
genistein aglycone (27 mg)  
citrated zinc bisglycinate (20 mg)  
trans-menaquinone-7 (90 µg) 
cholecalciferol (400 IU) 
 
“Recommended dosage:  1 capsule q12 hours (54 mg genistein/day) 
 
“Toxicity: 
Genistein showed no toxicity in rats following acute dosing up to 2000 mg/kg. Long-term toxicity 
studies up to 52 weeks duration using oral administration of 0-500 mg/kg/day in rats and dogs 
showed minimal adverse effects. From these studies, the no observed adverse effect level 
(NOAEL) for genistein in rats was determined to be 50 mg/kg/day and in dogs >500 mg/kg/day. 
These intake levels are at least 50-fold greater than the recommended human dose of the 
genistein in FOSTEUM PLUS on a mg/kg basis. 
 
“Adverse Events from Fosteum Plus: 


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In a three-year clinical trial2, 389 subjects were randomized to either genistein plus calcium and 
vitamin D3 (n = 198) or calcium and vitamin D3 alone (n=191). A total of 52 subjects in both 
groups discontinued due to adverse events. Study discontinuation in these subjects was due to 
gastrointestinal symptoms, including abdominal and epigastric pain, dyspepsia, vomiting and 
constipation. Discontinuation was reported in both groups. The incidence of adverse events was 
statistically higher in the genistein group throughout the study. The major adverse events are 
shown in the table below without attribution of causality. 
 
Adverse 
Events 
Year 1 
Year 2 
Year 3 
Genistein 
+Ca/D3  
(n=178) 
Ca/D3  
(n=172) 
Genistein 
+Ca/D3  
(n=150) 
Ca/D3  
(n=154) 
Genistein 
+Ca/D3  
(n=71) 
Ca/D3  
(n=67) 
Abdominal Pain 
4 (2.2%) 
2 (1.1%) 
2 (1.3%) 
1 (0.6%) 
1(1.4%) 
1(1.5%) 
Dyspepsia 
2 (1.1%) 
1 (0.6%) 
7 (4.7%) 
2 (1.3%) 
2(2.8%) 
1(1.5%) 
Constipation 
5 (2.8%) 
3 (1.7%) 
8 (5.3%) 
3 (1.9%) 
2(2.8%) 
1(1.5%) 
 
“Some of these adverse event occurrences may be attributable to the intake of 1,000 mg per 
day of calcium carbonate by subjects in both groups. Taking FOSTEUM PLUS with food may 
reduce or eliminate some gastrointestinal symptoms.” 
 
Citracal Plus3 
Contents per serving: 
Vitamin D  
400 IU  
Calcium  
600 mg  
Magnesium  
50 mg  
Zinc  
7.5 mg  
Copper  
1 mg  
Manganese  
2 mg  
Molybdenum  
75 mcg  
Genistein  
27 mg  
 
 
1. 
FosteumPLUS.  “Package insert.” Accessed September 22, 2014. 
http://www.fosteumplus.com/professionals/package-insert.php 
2. 
Herbert Marini, MD; Letteria Minutoli, MD; Francesca Polito, PhD; Alessandra Bitto, MD; Domenica Altavilla, 
PhD; Marco Atteritano, MD; Agostino Gaudio, MD; Susanna Mazzaferro, MD; Alessia Frisina, MD; Nicola Frisina, 
MD; Carla Lubrano, MD; Michele Bonaiuto, MD; Rosario D’Anna, MD; Maria Letizia Cannata, MD; Francesco 
Corrado, MD; Elena Bianca Adamo, MD; Steven Wilson, PhD; and Francesco Squadrito, MD. Effects of the 
Phytoestrogen Genistein on Bone Metabolism in Osteopenic Postmenopausal Women. Ann Intern Med. 
2007;146:839-847. 
3. 
CITRACAL® Plus Bone Density Builder. “Supplement facts.” Accessed September 22, 2014. 
http://labeling.bayercare.com/omr/online/citracal-plus-bone-density-builder.pdf 
 
CONTRAINDICATIONS:   
Soy allergy 
 
ADMINISTRATION AS PER STUDY:   
See Protocol Section 5.1.6 
 
STORAGE AND STABILITY (in vial and infusion form): 


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See Protocol Section 5.4 
 
PREPARED PER GMP GUIDELINES  (suitable for human use):  Yes 
 
 


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APPENDIX C: TOXICITIES EXCLUDED FROM SINGLE-EVENT IND SAFETY 
REPORTING TO THE FDA 
 
See Section 9.2.3.3 for additional information about the submission of these toxicities to the 
FDA. 
 
Adverse Events 
Actinomycin 
Carboplatin 
Cisplatin 
Cyclophosphamide 
Daunorubicin 
Doxorubicin 
Etoposide 
Ifosfamide 
Topotecan 
Vincristine 
Myelosuppression 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Anemia 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Leukopenia 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neutropenia 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Thrombocytopenia 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Febrile Neutropenia 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Infection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nausea 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vomiting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diarrhea 
X 
X 
  
X 
X 
X 
X 
  
X 
X 
Abdominal Pain 
X 
  
  
X 
X 
X 
X 
  
X 
X 
Anorexia 
X 
  
  
X 
  
  
X 
  
X 
  
Mucositis 
  
X 
  
  
X 
X 
  
  
  
  
Hypersensitivity Reaction 
  
X 
  
  
  
  
  
  
  
  
Cardiotoxicity 
  
  
  
X 
X 
X 
  
  
  
  
Ototoxicity 
  
X 
X 
  
  
  
  
  
  
  
Nephrotoxicity 
  
X 
X 
  
  
  
  
X 
  
  
Hepatotoxicity 
X 
  
  
  
  
  
X 
  
  
  
Hypomagnesmia 
  
X 
X 
X 
  
  
  
  
  
  
Hypokalemia 
  
X 
X 
  
  
  
  
  
  
  
Hypocalcemia 
  
X 
X 
  
  
  
  
  
  
  
Hyponatremia 
  
X 
X 
  
  
  
  
  
  
  
Neurotoxicity 
  
X 
X 
  
  
  
  
X 
  
X 
Neuropathy 
  
X 
X 
  
  
  
  
  
  
X 
Alopecia 
X 
  
  
X 
X 
X 
X 
X 
X 
X