Vitamin D, Leptin, Vitamin D Receptor Polymorphism, and Treatment-Related Morbidity in Ovarian Cancer
Phase: EARLY_PHASE1
Conditions: Ovarian Cancer
Sponsor: University of Oklahoma

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Vitamin D, Leptin, Vitamin D Receptor Polymorphism, and Treatment-Related Morbidity 
in Ovarian, Primary Peritoneal and Fallopian Tube Cancer 
Version: 2.0  
Date: 9/9/2021 
NCT# 03028519 
 
Sponsor: 
Stephenson Cancer Center 
                        800 NE 10th Street 
                        Oklahoma City, OK, 73104 
Phone 405-271-8001 x48151 
 
 
 
Study Chair: Laura L. Holman, MD, MS 
Stephenson  Cancer Center 
800 NE 10th Street 
Oklahoma City, OK, 73104 
Phone: 405-271-8001 x54816 
Laura-L-Holman@ouhsc.edu 
 
Co-Investigators: 
Lauren E. Dockery, MD 
The University of North 
Carolina at Chapel Hill 
101 Manning Dr.    
Chapel Hill, NC, 27514  
Phone: (919) 843-2077 
lauren_dockery@med.unc.edu 
 
 
 
Translational Study Chair: 
Doris Benbrook, PhD 
Stephenson  Cancer Center 
975 NE 10th Street, BRC-1270 
Oklahoma City, OK 73104 
 
 
Kathleen N. Moore, MD, MS 
Stephenson  Cancer Center 
800 NE 10th Street 
Oklahoma City, OK 73104 
IRB NUMBER: 7488
IRB APPROVAL DATE: 11/23/2021

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Statistician: 
Sara K. Vesely, PhD 
The University of Oklahoma Health Sciences Center 
801 NE 13th Street 
Post Office Box 26901 
Oklahoma City, OK, 73104 
Phone: 405-271-2229 x48069 
Sara-Vesely@ouhsc.edu 
 
Investigational Product: Cholecalciferol (Vitamin D3, a fat soluble vitamin involved 
in many biologic processes). 
Protocol Number: OU201612LH- Vitamin D Ovarian 
 
This clinical trial will be conducted in compliance with the protocol, International 
Conference on Harmonization Good clinical Practice Guidelines E6 (ICH-GCP), other 
applicable regulatory requirements and with the Declaration of Helsinki and its 
amendments. 
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Table of Contents 
 
 
 
1.0 Objectives ..............................................................................................................4 
2.0 Background Information. Rationale for selected approach and trial design ................ 4 
3.0 Study Design ..........................................................................................................7 
4.0 Study Population ....................................................................................................8 
5.0 Study Modalities .....................................................................................................9 
6.0 Study Procedures and Treatment Plan ...................................................................11 
7.0 Dose Limiting Toxicities .......................................................................................12 
8.0 Study Parameters .................................................................................................12 
 
9.0 Evaluation Criteria .................................................................................................13 
10.0 Duration of Study ...............................................................................................13 
11.0 Study Monitoring and Reporting Procedures........................................................14 
12.0 Statistical Methods .............................................................................................17 
13.0 Data Handing and Recordkeeping .......................................................................18 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0 Hypothesis and Objectives 
 
1.1 Specific hypotheses: 
 
1.1.1 Low serum 25(OH)D will be associated with increased treatment-related 
morbidity. 
1.1.2 
Repletion of 25(OH)D will be associated with an increase towards normal of 
serum leptin levels.  
1.1.3 
VDR FokI SNP polymorphism will be associated with lower circulating levels 
of 25(OH)D. 
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1.2 
Objective(s)  
 
1.2.1 
Primary objective: 
 
1.2.1.1 To assess treatment-related morbidity (including 30-day 
postoperative surgical morbidity and chemotherapy-related morbidity) and 1- 
year disease-free survival in patients with deficient serum 25(OH)D levels at 
the time of ovarian, primary peritoneal, or fallopian tube cancer diagnosis who 
did and did not receive vitamin D repletion. 
1. 2.2 
Secondary objectives: 
 
1.2.2.1 To describe serum 25(OH)D levels, serum leptin levels, and VDR FokI 
SNP status among newly diagnosed ovarian, primary peritoneal, or fallopian 
tube cancer patients.  
1.2.2.2 To determine the proportion of patients with ovarian, primary 
peritoneal, or fallopian tube cancer that have deficient vitamin D at diagnosis 
and have normal serum 25(OH)D after oral vitamin D supplementation during 
primary therapy.  
1.2.2.3 To identify potential relationships between serum 25(OH)D and 
serum 
  
leptin levels when controlling for BMI. 
1.2.2.4 To evaluate change of serum leptin levels with repletion of 25(OH)D  
in   
patients with low levels at the time of ovarian primary peritoneal, or fallopian 
tube cancer diagnosis. 
 
 
 
 
1.3 
Translational Research Objectives: 
 
1.3.1 To evaluate VDR FokI SNP status relationship with serum 25(OH)D 
levels and treatment-related morbidity and cancer outcomes.  
 
 
2.0 Background Information. Rationale for selected approach and  
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trial design.  
2.1 Overview of Ovarian Cancer 
Ovarian cancer (including primary peritoneal and fallopian tube cancer) is the fifth 
leading cause of cancer-related deaths in women in the United States and the most 
lethal gynecologic cancer [1]. It was estimated that in 2016, more than 22,000 women 
will be diagnosed with ovarian cancer leading to more than 14,000 deaths [2]. The 
median age of diagnosis of women with ovarian cancer is 63, with increased 
comorbidities leading to treatment-related toxicities in older women [3]. The inability to 
receive adjuvant chemotherapy negatively impacts overall survival (OS). Number of 
cycles of chemotherapy also appears to be important. For example, elderly women who 
receive more than three chemotherapy cycles have been found to have improved OS [3]. 
Further study to identify factors to improve treatment tolerability and reduce treatment- 
related morbidity in ovarian cancer patients are warranted. 
 
2.2 Vitamin D Deficiency in Cancer 
Vitamin D has been well-studied due to its role in many important cellular pathways. 
Laboratory and observational studies suggest that it plays a role in many diseases such 
as autoimmune diseases, cardiovascular disease, diabetes, cancer risk and cancer 
survival. The correlation of low serum 25(OH)D with elevated risk for malignancy has 
been best studied in colorectal cancer [4]. Decreased levels of serum 25(OH)D have 
been correlated with increased risk of breast cancer in postmenopausal women. [5]. 
Women receiving chemotherapy and anti-hormonal therapy for breast cancer experience 
treatment-induced bone loss due to premature ovarian failure or direct cytotoxic effects 
of chemotherapy. This causes an increase in the osteoporosis and skeletal morbidity 
risk[6]. Similar effects can be estimated in ovarian cancer patients given that standard 
treatment requires surgical menopause as well as cytotoxic therapy in the majority of 
patients.   
The majority of studies pertaining to vitamin D and ovarian cancer concern the 
association of low serum 25(OH)D with increased cancer risk. Limited study has been 
performed investigating the correlation of serum vitamin D and ovarian cancer prognosis 
or treatment-related morbidity. A study performed in Australia investigated serum 
25(OH)D levels at the time of diagnosis of ovarian cancer in 670 women. They noted a 
significant association between higher circulating 25(OH)D concentrations and longer 
survival in women with ovarian cancer when adjusting for other clinical predictors of  
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survival [7]. Similarly, Walentowicz-Sadlecka et al. reported low serum 25(OH)D 
concentrations in women with ovarian cancer undergoing primary cytoreductive surgery 
to be associated with lower overall survival[8]. The impact of repletion of vitamin D in 
ovarian, primary peritoneal, or fallopian tube cancer patients has yet to be determined. 
 
Findings from an unpublished study performed at the University of Oklahoma have 
shown an inverse correlation between low levels of serum vitamin D and treatment- 
related morbidity in women aged 65 years and older with ovarian cancer. More 
specifically, when comparing median serum 25(OH)D levels between patients who 
experienced chemotherapy delay >7days versus those who did not, lower mean 
25(OH)D levels were significantly associated with chemotherapy delays (23.6 ng/dL, 
n=28 no delay versus 14.6 ng/dL, n=30 delay, p=.0112). (Figure 1)[9]. 
 
Figure 1. Serum 25(OH)D levels by chemotherapy delay status.  
Delay (>7 days) n=30, median 25(OH)D 14.6 ng/dL. No delay n=28, median 25(OH)D 23.6 ng/dL 
(p=0.0112). 
 
 To date, there have been no prospective or randomized controlled trials evaluating 
serum 25(OH)D and treatment-related risks in cancer patients. No data exists regarding 
the effect of repletion of vitamin D and prevention of ovarian cancer treatment-related 
morbidity. As previously mentioned, number of cycles of chemotherapy received appears 
to correlate with improved OS in women with ovarian cancer [3]. Given the findings of 
the above-mentioned study correlating low serum 25(OH)D levels and chemotherapy  
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delay, vitamin D represents a potentially modifiable factor that could improve treatment 
tolerance among women with ovarian cancer.  
 
2.3 Leptin and Ovarian Cancer 
Leptin is an adipokine that appears to stimulate growth of cancer cells while decreasing 
apoptosis [10]. Serum leptin levels have also been linked to elevated levels of pro- 
inflammatory cytokines in malignancy [11]. Retrospective analysis of data from NHANES 
III revealed an inverse relationship between serum leptin levels and cancer death in 
women[12]. In ovarian cancer, there is some data to show that lower leptin levels may 
be associated with increased initial tumor burden and subsequent increases in leptin 
may correlate with complete cytoreduction [13]. Further study is needed to better 
understand the role of leptin in ovarian cancer. Vitamin D receptors are involved in 
production of adipokines such as leptin; however, the response of serum leptin levels to 
repletion of vitamin D remains unclear [1]. Conflicting data exists between meta- 
analyses investigating changes in leptin following correction of vitamin D levels in 
humans [1]. This study aims to assess for potential relationships between serum 
25(OH)D levels and leptin levels, including any changes that may occur during repletion 
of 25(OH)D.   
 
Women with treatment-related morbidity often experience delays in treatment, changes 
in chemotherapeutic regimens and surgical or chemotherapy-related complications 
requiring hospitalization. Identifying modifiable risk factors among patients with ovarian 
cancer (including fallopian tube and primary peritoneal cancer) that can prevent 
treatment-related morbidity represents an important goal in the care of these women. 
Safety: 
 
Cholecalciferol is a generally safe and well-tolerated medication. Repletion of vitamin D is 
considered standard of care and will be undertaken utilizing current available 
guidelines[14].  
 
 
 
Translational Research Background:  
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Vitamin D receptors (VDR) are extensively expressed in epithelial cells of both normal 
and tumor ovarian tissue. VDR functions as a transcriptional regulatory factor involved in 
decreasing cell proliferation and inhibition of apoptosis [15]. As such, this may carry 
implications for ovarian cancer tumorigenesis. The VDR rs2228570 (FokI) single 
nucleotide polymorphism (SNP) represents the most common and best studied SNP in 
the VDR gene leading to an alteration of VDR protein structure and decreased 
transcriptional activity as compared to the wild type [15, 16]. Meta-analyses of several 
small studies have associated FokI SNP with increased risk of ovarian cancer, [15, 16]. 
One such study performed a meta-analysis with pooled odds ratios and 95% confidence 
intervals to assess the associations between VDR polymorphisms (Cdx-2, FokI, BsmI, 
ApaI, and TaqI) and risk for breast and ovarian cancer. Only the FokI SNP was found to 
be associated with increased risk of breast and ovarian cancers[17]. Currently, no data 
exists to correlate VDR SNP polymorphisms to circulating 25(OH)D levels at the time of 
diagnosis of ovarian cancer. There is limited data to suggest that in both prostate cancer 
and colorectal cancer, the homozygous VDR FokI SNP (prostate) and homozygous VDR 
TaqI SNP (colorectal) are associated both with increased risk of the respective 
malignancy and lower circulating 25(OH)D levels [18, 19]. 
 
 
3.0 Study Design 
 
This study will contain 2 cohorts, those with normal serum 25(OH)D and those with low 
serum 25(OH)D at enrollment. The study will take place in women with ovarian, primary 
peritoneal, and fallopian tube cancer, subsequently referred to as ovarian cancer in this 
document due to the overlap in disease and treatment. 
Patients who have given written consent to enroll in the study will have a serum 25(OH)D 
drawn in a gold-topped tube (1 to 5mL volume) at time of enrollment and prior to initiation 
of treatment for their cancer. Serum 25(OH)D levels will be analyzed per laboratory protocol 
in our University CLIA certified lab. Blood will also be drawn for analysis of serum leptin 
levels and VDR FokI SNP genotype. A purple-topped tube (7 to 10mL volume) and red- 
topped tube will be collected from prospective patients. The Stephenson Cancer Center 
Biospecimen Bank will process the red and purple-topped tube into plasma and Buffycoats, 
label them with a de-identified code and transfer them to Dr. Benbrook’s lab. The plasma  
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will be used to evaluate leptin by ELISA and the Buffycoats used to evaluate the FokI SNP 
using PCR. Retrospective serum specimens will be used to measure leptin.  
 
Patients with low serum vitamin D levels, defined as <20 ng/mL, will be provided a supply 
of cholecalciferol (vitamin D3), 50,000 IU weekly for 8 weeks that will be dispensed in the 
Stephenson Cancer Center outpatient pharmacy in order to standardize therapy. They will 
then be provided with a prescription for 2,000 IU of cholecalciferol (vitamin D3) daily 
following completion of 8 weeks of therapy based on current Endocrine Society guidelines in 
agreement with U.S. Preventive Services Task Force recommendations [14]. Treatment with 
cholecalciferol will not impact initiation of treatment for ovarian cancer. Compliance with 
cholecalciferol repletion will be assessed with medication reconciliation at every 
gynecologic oncology visit.  
Vitamin D therapy will be stopped in any patient developing the above exclusion criteria of 
GFR <30, inability to tolerate oral medications, malabsorption syndrome, or primary 
hyperparathyroidism. In the unlikely event of evidence of vitamin D toxicity, treatment with 
vitamin D will be stopped. The Stephenson Cancer Center laboratory defines vitamin D 
toxicity as levels >100 ng/mL. Based on IOM literature, it would highly unlikely for 
individuals to experience vitamin D toxicity at the prescribed doses. Symptoms of vitamin D 
intoxication are caused by the resultant hypercalcemia and include anorexia, weight loss, 
polyuria, arrhythmias, fatigue, and soft tissue calcifications [20]. Patients experiencing 
these symptoms would receive testing for serum calcium and vitamin D. Vitamin D 
treatment would be stopped for any value indicative of toxicity.  
 
Demographic, clinical, and disease characteristics and outcomes will be collected from all 
patients prospectively. The patient’s treatment course information will also be collected 
prospectively, but will not be dictated by this study. Serum 25(OH)D and leptin levels will 
be collected again at the completion of primary therapy, 6 months after the completion of 
primary therapy, and at the time of disease recurrence. If disease recurrence occurs prior to 
6 months after completion of primary therapy, this time point will be omitted. If disease 
recurrence does not occur prior to 1 year, serum 25(OH)D and leptin levels will be drawn at 
the time of the 1-year surveillance visit. If patients remain vitamin D deficient at any of 
these follow-up time points, they will be referred to an endocrinologist or primary care 
physician for further work-up and treatment of their vitamin D deficiency. Patients who are 
vitamin D deficient at completion of therapy but were not previously on supplement will be  
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referred to a primary care physician for further management. Data collection will continue 
for 1 year or until the time of disease recurrence. Patient’s will no longer have data 
collected after obtaining serum 25(OH)D and leptin levels at the time of recurrence.  
A retrospective cohort of women with low serum 25(OH)D that did not receive repletion of 
vitamin D will be used as a control group for comparison. This control group will be 
identified from available tumor bank serum samples including those previously identified in 
the above-mentioned unpublished study at the University of Oklahoma. These samples will 
be used to evaluate serum levels of 25(OH)D, leptin, and evaluate Buffycoats VDR SNP 
polymorphism for FokI.  
 
 
 
 
 
Cohort  
Therapy 
1 (Normal 25(OH)D) 
None 
2 (Low 25(OH)D)  
50,000 IU  
(<20ng/mL) 
cholecalciferol  
weekly for 8 weeks  
followed by 2,000 IU  
daily thereafter 
 
 
4.0 Study Population 
 
4.1 Eligible Patients 
 
4.1.1 The study population will consist of women with newly diagnosed ovarian, 
fallopian tube, or primary peritoneal cancer and no previous treatment. 
4.1.2 A retrospective cohort of women with ovarian, fallopian tube, or primary 
peritoneal cancer and low serum 25(OH)D that did not receive repletion identified 
from available tumor bank serum samples. 
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4.2 
Inclusion Criteria (Prospective patients) 
 
4.2.1 Patients must have a histologic diagnosis of ovarian, fallopian tube, or primary 
peritoneal carcinoma per pre-treatment biopsies by laparoscopy, or interventional 
radiology, paracentesis, or CT guided core biopsy. Histologic documentation of the 
original primary tumor is required via the pathology report. 
4.2.2 Patients must have adequate: 
 
4.2.2.1 Renal function: Glomerular Filtration Rate (GFR) > 30. 
 
4.2.2.2 Gastrointestinal absorption: No underlying malabsorption syndrome 
(i.e. inflammatory bowel disease, celiac disease). 
4.2.2.3 Ability to tolerate oral medication. 
 
4.2.3 Patients taking vitamin D at the time of enrollment without a diagnosis of 
vitamin D deficiency. 
4.2.4 Patients of childbearing potential must have a negative pregnancy test prior to 
the study entry and be practicing an effective form of contraception. If applicable, 
patients must discontinue breastfeeding prior to study entry. 
4.2.5 Patients must have signed an IRB-approved informed consent  and 
authorization permitting release of personal health information. 
4.2.6 Patients must be at least 18 years old. 
 
4.3 
Ineligible Patients 
 
4.3.1 Patients with a known pre-existing diagnosis of vitamin D deficiency. 
4.3.2 Patients with renal disease and a GFR <30. 
4.3.3 Patients with primary hyperparathyroidism. 
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4.3.4 Patients with other invasive malignancies, with the exception of nonmelanoma 
skin cancer. Patients with concomitant endometrial cancer diagnosed at the time of 
their ovarian cancer are allowed to participate if the endometrial cancer is FIGO 
stage IB or less. 
4.3.10 Patients of childbearing potential, not practicing adequate contraception, 
patients who are pregnant, or patients who are breastfeeding are not eligible for this 
trial. 
4.4 
Inclusion of Minorities 
 
Potential subjects shall not be excluded from participating in this or any study solely on the 
basis of ethnic origin or socioeconomic status. Every attempt shall be made to enter all 
eligible patients into this protocol and therefore address the study objectives in a patient 
population representative of the entire ovarian, fallopian tube and peritoneal primary cancer 
population treated by participating institutions. 
 
5.0 Study Modalities 
 
5.1 
Cholecalciferol (vitamin D3) 
 
Refer to the pharmacologic information for cholecalciferol. See 
http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6606#pro for the most 
complete and current information on the following: 
5.1.1 Formulations 
 
- Cholecalciferol (Vitamin D3) 50,000 IU is supplied as an oral capsule. It is a vitamin 
D analog. Cholecalciferol is a provitamin (25(OH)D) with an active metabolite 1,25- 
dihydroxyvitamin D (calcitriol). The drug is initiatlly hydroxylated hepatically and then 
converted into the active metabolite renally.  
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5.1.2 Storage 
 
Unopened vials of cholecalciferol are stable for the life indicated on the package 
stored at 15oC to 30oC (59oF to 86oF).  
Adverse Effects: Consult the package inserts for the most current and complete 
information. No adverse reactions currently listed in manufacturer’s labeling. 
According to the IOM, vitamin D toxicosis is highly unlikely at the prescribed doses. 
Symptoms of vitamin D toxicosis are caused by the resultant hypercalcemia and 
include: anorexia, weight loss, polyuria, arrhythmias, fatigue, and soft tissue 
calcifications [15].  
Consult the American Hospital Formulary Service Drug Information guide, 
Facts and Comparisons, or the package insert for additional information. 
5.1.3 Preparation and dosing 
The dosage of cholecalciferol is based on current Endocrine Society guidelines in 
agreement with U.S. Preventive Services Task Force recommendations [14]. 
5.1.4 Drug ordering and distribution 
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Cholecalciferol will be ordered by and distributed from the outpatient pharmacy at 
the Stephenson Cancer Center. Study drugs will be kept in a locked space, physically 
separated from standard clinic or office drug supplies.  
5.1.5 Drug Accountability: 
 
All study drug received, dispensed and returned must be accounted for in a Drug 
Accountability log, including patient number and initials, date study drug dispensed, 
amount dispensed, amount returned (if applicable) and amount remaining in stock. 
The institution must maintain an accurate inventory log of all study drug received 
and used. Pill counts at each patient visit will be utilized to document compliance 
with oral medication.  
 
6.0 Study Procedures and Treatment Plan 
 
All necessary site-specific regulatory documents, including the PI biographical 
sketch, IRB approval, and IRB approved informed consent, must have been 
submitted to the IRB and the Stephenson Cancer Center CTO prior to beginning 
patient enrollment. The University of Oklahoma will submit the necessary documents 
to obtain national clinical trial listing  
6.1 
Patient Enrollment 
 
When a suitable candidate has been obtained for protocol entry, the following 
steps should be taken: 
6.1.1 An IRB-approved informed consent form and authorization 
permitting the release of personal health information must be signed 
by the patient or guardian. Current FDA, NCI and institutional 
regulations concerning informed consent will be followed. 
6.1.2 All eligibility requirements indicated in Section 4.0 must be 
satisfied. 
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6.1.3 A completed, signed and dated, Patient Registration form should 
be filled out by the clinical study site (OU) and placed in the regulatory 
binder 
6.1.4 Upon receipt of the signed and dated form from the clinical trials 
office at OU SCC, the clinical study site will enter the patient's name 
and study number in their Enrollment Log to verify the patient's entry 
into the study and additional study procedures may commence. 
6.2 
Treatment Plan 
 
6.2.1 Screening visits will be conducted within 21 days prior to study 
drug administration. 
Patients 
will undergo baseline evaluations prior to dosing. 
 
6.2.2 This study will evaluate the administration of cholecaciferol to 
vitamin D deficient patients with ovarian cancer in relation to ability to 
replete 25(OH)D levels, treatment-related morbidity, and serum leptin 
levels. 
6.3 
Sequence and timing of drug administration 
 
Vitamin D deficient patients will receive oral cholecalciferol 50,000 IU weekly 
starting at the time of diagnosis of vitamin D deficiency. Initiation of 
cholecalciferol therapy will not delay initiation of standard treatment for 
ovarian cancer, nor will it preclude enrollment in other clinical trials. 
Therapeutic dosing at 50,000 IU will continue weekly for a total of 8 weeks. 
Patients will then be given a prescription for maintenance dosing 2,000 IU 
cholecalciferol thereafter.  
 
 
 
7.0 Dose Limiting Toxicities 
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As described above, vitamin D toxicosis is extremely rare at the prescribed doses. In 
the unlikely event of evidence of vitamin D toxicity, treatment with vitamin D will be 
stopped. The Stephenson Cancer Center laboratory defines vitamin D toxicity as 
levels >100 ng/mL.  
 
8.0 Study Parameters 
 
8.1 
Observations and Tests 
 
The following observations and tests are to be performed and recorded on the 
appropriate form(s).  
 
Observation 
and Tests 
Screening At each 
treatment 
visit 
Completion 
of primary 
therapy 
6 months 
after 
therapy 
completion 
Time of 
recurrence 
or 1 year 
surveillance 
(if no 
recurrence) 
History & 
Physical 
1 
X  
X 
X 
X 
Vital Signs 
and Weight 
1 
Toxicity 
assessment 
1 
X 
X 
X 
Serum 
25(OH)D 
1 
X 
X 
X 
Serum 
Leptin 
1 
X 
X 
X 
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Serum Cr 
(and GFR) 
1 
Red top 
and Purple 
topped 
blood tubes 
(for VDR 
SNP  
analysis) 
1 
Serum 
pregnancy 
test (if 
potential 
exists) 
1 
 
 
1. Must be obtained within 21 days prior to initiating protocol therapy. 
All other blood draws (end of treatment, 6 months after therapy completion, Time of recurrence 
or 1 year surveillance) must occur within 8 weeks of expected date.  
 
 
 
8.2 
Translational Research 
Requirements 8.2.1 Specimen 
Requirements  
A red topped and a purple topped tube of blood will be drawn from the patient 
at the time of screening.  
The patient must give permission for her specimens to be used for this 
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mandatory translational research component. The participating institution is 
required to submit the patient’s specimens as outlined below.  
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9.0 Evaluation Criteria 
 
9.1.1 Response Criteria 
 
9.1.1.1 Evaluation of Biomarkers 
Clinical Response 
If serum 25(OH)D is initially below the lower normal limit, it must 
normalize (>20ng/mL) for a patient to be considered experiencing a 
complete response to repletion.  
9.1.2 Progression-Free Survival: 
 
Progression-Free Survival (PFS) is defined as the duration of time from start 
of treatment to time of progression or death, whichever occurs first. 
9.1.3 Survival: 
 
Survival is defined as the duration of time from start of treatment to time of 
death or the date of last contact. 
 
10.0 Duration of Study 
 
10.1 
Patients with serum 25(OH)D <20ng/mL will receive 
cholecalciferol 50,000 IU weekly for 8 weeks.  
10.2 
Following repletion, patients will receive a prescription for 
2,000 IU cholecalciferol as maintenance. Per Endocrine Society 
guidelines, patients should continue maintenance cholecalciferol 
indefinitely. 
 
11.0 Study Monitoring and Safety Reporting Procedures 
 
11.1 
Adverse Event Reporting 
 
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11.1.1 Definitions (per 21 CFR 312.32(a)): 
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IRB NUMBER: 7488 
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Adverse event: “Any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related.” Life- 
threatening adverse event or life-threatening suspected adverse reaction: “An 
adverse event or suspected adverse reaction is considered “lifethreatening” 
if, in the view of either the investigator or sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an adverse 
event or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death.” Serious adverse event or serious suspected 
adverse reaction: “An adverse event or suspected adverse reaction is 
considered “serious” if, in the view of the investigator, it results in any of the 
following outcomes: 
Death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity 
or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.” 
Suspected adverse reaction: “Suspected adverse reaction means any adverse 
event for which there is a reasonable possibility that the drug caused the 
adverse event. For the purposes of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between 
the drug and the adverse event. Suspected adverse reaction implies a lesser  
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degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug.” 
Unexpected adverse event or unexpected suspected adverse reaction. “An 
adverse event or suspected adverse reaction is considered “unexpected” if it 
is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required 
or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure referred 
only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. “Unexpected,” as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation.” 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 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 CTCA version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
Furthermore, this study will fall under the purview of the Stephenson Cancer 
Center Data Safety Monitoring Committee (DSMC).  
11.1.2 Reporting Expedited Adverse Events 
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In compliance with FDA regulations, as contained in 21 CFR 312.64, AEs must 
be reported to the Stephenson Cancer Center Data Safety Monitoring 
Committee by the investigator.  
All serious and unexpected suspected adverse reactions must be reported 
directly to the Stephenson Cancer Center Data Safety Monitoring Committee 
either by telephone or by e-mail by the Investigator, study coordinator, clinical 
research associate, or other designated study personnel, within 24 hours of 
becoming aware of such an event. The Investigator also must report all such 
events promptly to the appropriate IRB/EC per their requirements. 
11.1.3 Documenting Adverse Events 
 
All AE information must be documented on the forms provided and approved 
by OU IRB. Additional follow-up information (e.g., test results, autopsy, and 
discharge summary) may be obtained to supplement AE reports. A copy of all 
initial and follow-up reports will be included with the patient’s study files. 
11.1.4 Causality Assessment of Adverse Events 
 
The relationship between an AE and the study drug will be determined by the 
Investigator on the basis of his or her clinical judgment and the following 
definitions. 
An AE will be considered associated with the use of study drug if there is a 
reasonable possibility that the AE may have been caused by the study drug. 
This definition applies to those AEs that are considered definitely, probably, 
and possibly related to the use of the study drug: 
Definitely Related: An AE that follows a temporal sequence from 
administration of the study drug; follows a known response pattern to 
the study drug; improves after stopping the study drug (positive 
dechallenge) and reappears after repeat exposure (positive  
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rechallenge); and cannot be reasonably explained by known 
characteristics of the patient's clinical state or by other therapies 
Probably Related: An AE that follows a reasonable temporal sequence 
from administration of the study drug; follows a known response 
pattern to the study drug; improves after dechallenge; and cannot be 
reasonably explained by the known characteristics of the patient's 
clinical state or by other therapies. 
Possibly Related: An AE that follows a reasonable temporal 
sequence from administration of the study drug and follows a known 
response pattern to the study drug but could have been produced by 
the patient's clinical state or by other therapies. An AE may be 
considered not associated with the use of study drug if there is not a 
reasonable possibility that the AE may have been caused by the study 
drug. This definition applies to those AEs that are considered unlikely 
or not related to the use of the study drug: 
Unlikely to be Related: An AE assessed as unlikely to be related to 
study drug is defined as an AE for which sufficient information exists 
to indicate a high improbability that the event is related to the study 
drug. 
 Not Related: An AE assessed as not related to study drug is defined 
as an AE for which sufficient information exists to indicate that the etiology is 
unrelated to the study drug. Two or more of the following variables apply: 
- The AE does not follow a reasonable temporal sequence after 
administration of the study drug. 
- The AE is readily explained by the patient’s clinical state or other 
therapies. 
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- Negative dechallenge—the AE does not abate upon dose reduction 
or cessation of therapy (assuming that it is reasonable to expect 
abatement of the AE within the observed interval). 
 
 
 
11.1.5 Severity Assessment of Adverse Events 
 
Severity of AEs will be graded according to the CTCAE Version 4.0. 
 
Adverse events not included in the CTCAE, Version 4.0 must be graded as follows: 
Mild, Moderate, Severe, Life-threatening, and Fatal according to the following 
definitions: 
 Mild: The AE is noticeable to the patient but does not interfere with routine 
activity. 
Moderate: The AE interferes with routine activity but responds to 
symptomatic therapy or rest. 
Severe: The AE significantly limits the patient's ability to perform routine 
activities despite symptomatic therapy. 
 
 Life-threatening: The AE places the patient at risk of death at the time of the  
event. 
 
 Fatal: The AE results in the death of the patient. 
 
11.2 Study Monitoring 
 
Safety oversight will be performed by Stephenson Cancer Center’s (SCC) internal 
Data and Safety Monitoring Committee (DSMC). The DSMC is composed of 
individuals with the appropriate expertise in adult and pediatric hematology and 
medical oncology, radiation oncology, translational and correlative science, 
pharmacy, nursing and biostatistics. The DSMC operates under the rules of an 
approved data safety monitoring plan which complies with the National Cancer 
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Institute (NCI) guidelines published as Essential Elements of a Data and Safety 
Monitoring Plan for Clinical Trials Funded by NCI as of January 2005 and the 
“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and Contracts, 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 
 
The Data Safety Monitoring Committee is charged with oversight of participant 
safety, study conduct and the validity and integrity of data for clinical trials at 
SCC. While the focus of the DSMC is to monitor interventional investigator 
initiated trials (IITs) that are not subject to external monitoring, it has the 
authority to monitor any SCC protocol when potential concerns are identified. 
The DSMC also has the authority to suspend or close a study until the principal 
investigator addresses any issues that may cause harm or increase risks to 
subjects.  The DSMC reports all findings to the Institutional Review Board (IRB). 
 
Under the direction of the DSMC chair, a full board meeting is convened on a 
biannual basis to review the accumulated safety data, accrual information, and 
additional information as stated in the DSMC plan. 
 
DSMC Auditing 
In addition to monitoring, the DSMC oversees an internal auditing process to 
ensure subject safety and data quality. All cancer-related clinical trials active at 
the SCC are eligible for audit; however, priority is placed on those clinical trials 
that are not monitored or audited by an outside entity. If an external entity 
conducts an audit of a clinical trial at the SCC, then the findings of that audit are 
reported to the DSMC, either through the formal audit report provided by the 
external auditing entity, if available, or from the PI, who will report any findings 
communicated during the audit process.  
 
 
. 
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11.3 Data Disclosure and Patient Confidentiality 
 
Patient medical information obtained as a result of this study is considered 
confidential. Disclosure to third parties other than those noted below is prohibited. 
All reports and communications relating to patients in this study will identify each 
patient only by their initials and number. Medical information resulting from a 
patient’s participation in this study may be given to the patient’s personal physician 
or to the appropriate medical personnel responsible for the patient’s welfare. Data 
generated as a result of this study are to be available for inspection on request by 
Stephenson Cancer Center Data Safety Monitoring Committee, the clinical trial office 
auditors and monitors, the Investigational Review Board (IRB)/Ethics Committee 
(EC) and the Institutional Biosafety Review Committee (or equivalent). De-identified 
data generated by participation in this study will be securely shared with co-
investigator (Dr. Dockery) at the University of North Carolina at Chapel Hill for 
the purposes of data analysis and manuscript preparation.  
All laboratory specimens, evaluation forms, reports, and other records that leave the 
site will be identified by a coded number to maintain patient confidentiality. All study 
records will be kept in a locked file cabinet or other secured area. All computer entry 
and networking programs will be identifiable only by coded numbers. Patient 
personal medical information may be reviewed by representatives of the Stephenson 
Cancer Center Data Safety Monitoring Committee, of the IRB, or of regulatory 
authorities in the course of monitoring the progress of the clinical trial. Every 
reasonable effort will be made to maintain such information as confidential. 
 
12.0 Statistical Methods 
 
Upon analysis, patients will be divided into two groups: Vitamin D Deficient Women 
and Vitamin D Normal Women.   
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Outcomes to be analyzed include differences in demographics, clinical, and tumor 
characteristics between groups, and differences in treatment-related morbidity or 
mortality between groups, including completion of treatment and treatment delays, 
and survival. Both 30-day postoperative surgical morbidity and chemotherapy-related 
morbidity will be assessed. The ability to normalize 25(OH)D levels with oral 
supplementation in the vitamin D deficient group will be evaluated.   
 
Descriptive statistics will be used to summarize the demographic and clinical 
characteristics of patients. Chi-square and t-tests will be used to make comparisons 
between groups. Survival will be estimated with Kaplan-Meier curves and Cox 
proportional hazards regression. The anticipated enrollment is 100 patients based on 
estimated new diagnoses of ovarian cancer treated in the Division of Gynecologic 
Oncology annually at the Stephenson Cancer Center. Based on the previously 
mentioned unpublished data, we presume that at least 25 of the prospectively 
enrolled patients will be vitamin D deficient. All of the vitamin D deficient women will 
be repleted with oral vitamin D. We will compare outcomes between these patients 
and 75 vitamin D deficient ovarian cancer patients from previous years (these will 
include patients from the above-mentioned previous retrospective review as well as 
other patients with banked blood samples) using logistic regression. We will control 
for age, stage, and histology. With 25 prospective patients and 75 retrospective 
patients we will have 80% power to detect differences of 32% in chemotherapy delay 
between ovarian patients who were not vitamin D deficient (33%) and who were 
vitamin D deficient (65%). 
 
Additionally, the association between serum leptin and 25(OH)D levels will be 
compared among groups, including any change in leptin levels observed in the 
vitamin D supplementation group. Because there is a positive linear association 
between BMI and serum leptin levels, BMI will be corrected for during analysis for 
potential relationships between serum leptin and 25(OH)D. 
 
The proportion of patients with VDR FokI SNP will be assessed. We will also 
compare levels of vitamin D at diagnosis, differences in treatment-related morbidity 
or mortality including completion of treatment, treatment delays, survival and  
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response to vitamin D supplementation across 3 SNP allele groups (homozygous 
mutated, heterozygous mutated, homozygous wild type).   
 
13.0 Data Handling and Recordkeeping 
 
13.1 
Data Collection 
 
The Investigator will utilize an electronic CRF for each subject. Entries made in eCRF 
must be verifiable against source documents; any discrepancies should be explained 
and documented. The Investigator will be responsible for reviewing all data and CRF 
entries and will sign and date the designated pages in each subject’s CRF, verifying 
that the information is true and correct. The Investigator is responsible for the review 
and approval of all responses. 
13.2 
Data Management 
 
All CRF data will be entered into a validated database maintained by the OU Clinical 
Trials Office (REDCap). REDCap (Research Electronic Data Capture) is a secure, 
web-based application designed to support data capture for research studies, 
providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking 
data manipulation and export procedures; 3) automated export procedures for 
seamless data downloads to common statistical packages; and 4) procedures for 
importing data from external sources [21] All data entry, verification and validation 
will be performed in accordance with written standard operating procedures of the 
OU Clinical Trials Office. The database will be authorized for lock once all defined 
procedures are completed. 
13.3 
Data Privacy 
 
The investigator must adhere to applicable data privacy laws and regulations. The 
investigator is responsible for ensuring that sensitive information is handled in  
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accordance with local requirements (e.g., Health Insurance Portability and 
Accountability Act of 1996 [HIPAA]). Appropriate consent and authorizations for use 
and disclosure and/or transfer (if applicable) of protected information must be 
obtained. Only the subject number and subject initials will be recorded in the CRF, 
and if the subject name appears on any other document (e.g., laboratory report), it 
must be obliterated on copies of the documents. The subjects will be informed that 
representatives of the Stephenson Cancer Center Data Safety Monitoring 
Committee, IRB, or regulatory authorities may inspect their medical records to verify 
the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
13.4 
Retention of Records 
 
The Principal investigator must maintain all documentation relating to the study for a 
period of 2 years after marketing application approval, or if not approved, 2 years 
following the formal termination of clinical development of the investigational 
product. Whenever possible, an original recording of an observation must be retained 
as the source document. However, a photocopy of a record is acceptable, provided it 
is legible and is a verified copy of the original document. The investigator must not 
destroy any records associated with the study without receiving approval from the 
Stephenson Cancer Center Data Safety Monitoring Committee. The investigator 
must notify the Stephenson Cancer Center Data Safety Monitoring Committee in the 
event of accidental loss or destruction of any study records. If the investigator leaves 
the institution where the study was conducted, the Stephenson Cancer Center Data 
Safety Monitoring Committee must be contacted to arrange alternative record 
storage options. 
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