A Pilot Study of the Effects of High-Dose Oral Calcitriol in Breast Cancer Patients Prior to Surgery
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: University of Rochester

 Amended 20 AUG 14 
UNIVERSITY OF ROCHESTER CANCER CENTER 
A Pilot Study of the Effects of High-Dose Oral Calcitriol 
on Bone Health in Breast Cancer Patients 
STUDY CHAIR:  
Luke J. Peppone, Ph.D. 
STUDY CO-CHAIRS: 
Gary R. Morrow, Ph.D., M.S. 
Joseph A. Roscoe, Ph.D. 
David G. Hicks, M.D. 
Kristin A. Skinner, M.D. 
Mary E. Reid, Ph.D. 
NCT01293682

2 
 
Study Schema ................................................................................................................. 3 
1.0  Background .............................................................................................................. 4 
2.0  Objectives ................................................................................................................ 9 
3.0  Subject Eligibility .................................................................................................... 10 
4.0  Treatment Assignment ........................................................................................... 11 
5.0  Treatment Protocol ................................................................................................. 13 
6.0  Treatment Evaluation ............................................................................................. 20 
7.0  Statistical Considerations ....................................................................................... 23 
8.0  Records to be Kept ................................................................................................. 25 
9.0   Patient Consent and Peer Judgment ..................................................................... 26 
10.0  References ........................................................................................................... 26 
 
 
 

3 
 
Study Schema 
 
 
The calcitriol intervention is aimed at reducing fracture risk by maintaining proper bone 
density.  Calcitriol is efficacious in maintaining proper bone health and muscle mass 
among the general population, but little research has been done on breast cancer patients.  
In addition, calcitriol may be effective in reducing tumor proliferation and angiogenesis, 
while increasing tumor apoptosis.  Each of those factors could have beneficial effects on 
breast cancer outcomes. 
 
Hypothesis: A weekly oral dose of calcitriol 45 μg will be efficacious in preventing 
bone loss among invasive breast cancer patients. 
 
Primary Objectives 
 
To collect data on the efficacy and feasibility of Calcitriol 45 μg for maintaining 
proper bone health among invasive breast cancer patients for a period of 12 
weeks. 
 
To collect preliminary data on the effect of Calcitriol 45 μg on bone resorption, as 
measured by Cross-Linked N-Telopeptide of Type I collagen (NTx) in invasive 
breast cancer patients over the course of 12 weeks. 
 
To collect preliminary data on the effect of Calcitriol 45 μg on markers of bone 
formation, as measured by bone-specific alkaline phosphatase (BAP) in invasive 
breast cancer patients over the course of 12 weeks. 
Secondary Objective 
 
Screen new patients
•Positive biopsy
-Will be used in later 
comparisons
•Invasive breast cancer
•No history of 
hypercalcemia
At surgical consult
•Consent patients who 
will have surgical 
resection and probable 
chemotherapy
•Demographics and
on-study information 
•Baseline Brief  
Symptom Inventory
•Blood sample to 
assess serum vitamin 
D levels and bone 
resorption and bone 
formation markers. 
Intervention
Calcitriol
45 μg/week
Baseline 
Measures
Blood Draw
-Bone resorption 
(NTX)
-Bone formation 
(BAP)
-1α,25(OH)2D3
Baseline 
Symptom 
Inventory
Historical 
Controls
- Matched on 
age and stage 
of breast cancer
At surgical 
resection
(2-4 Weeks 
later)
-Collect tissue 
sample for 
comparison of 
pathological 
markers with 
initial biopsy.
Safety check
Follow-Up
(Weeks 6 and 12)
Final Outcome
●Changes in 
NTx (a marker of 
bone resorption) 
between baseline 
and end of trial
●Changes in 
Bone Alkaline 
Phosphatase
(BAP, a bone 
formation marker) 
between baseline 
and end of trial
●Changes in 
serum 1, 25 OH2
D Levels
●Safety Checks
Safety 
Check
Day 5
-Serum 
Calcium 
Levels
-Serum
Phosphate 
Levels

4 
 
To collect preliminary data on the effect of pre-surgical Calcitriol 45 μg therapy 
on tumor cell apoptosis (caspase 3 and survivin), tumor cell proliferation (Ki-67), 
tumor invasiveness (ER α, PgR, VDR, EGFR, HER2, VEGF, and IGFR), 
1α,25(OH)2D3, and Mammostrat Recurrence Score in invasive breast cancer 
patients. 
 
 
1.0  Background 
 
1.1  Incidence and Survival Rate for Invasive Breast Cancer 
Breast cancer is, by far, the leading type of cancer among women in the United 
States, with an estimated 182,460 new cases in 2008 alone.1  In addition to the 
incident cases of invasive breast cancer, an additional 62,000 cases of cancer in 
situ will be diagnosed.2  In this year, breast cancer will claim the lives of 40,480 
women in the United States, which represents 15% of the total cancer deaths.1  In 
the United States, approximately 17% of breast cancer patients are under the age 
of 50 (premenopausal) at time of diagnosis, while the remaining 83% of patients 
are 50 years of age or older at the time of diagnosis.3  The incidence rate for 
estrogen receptor positive (ER+) breast cancer is approximately 190 per 100,000 
women, while the incidence rate for estrogen receptor negative (ER-) breast 
cancer is about 4 times less at 47 cases per 100,000 women.  Overall, over 70% of 
total breast cancers display some sort of estrogen activity.4  The mortality rate for 
breast cancer is lower compared to other cancer sites, with an overall 5-year 
survival of 89% for all stages of breast cancer and 98% for localized breast 
cancer.2  Due to the decreasing mortality rate of cancer, there are more than 10 
million cancer survivors in the United States alone, with more than 2 million 
breast cancer survivors.5, 6  Because many of these survivors do not succumb to 
cancer, other health problems, such as bone loss, have become a concern. 
 
1.2  Bone Health Complications in Breast Cancer Patients 
We propose to conduct an efficacy and feasibility pilot of breast cancer patients 
studied over 12 successive weeks to identify the ability to safely participate in a 
high-dose oral calcitriol (a vitamin D analog) intervention.  Additionally, the 
influence of the intervention on bone health and pathological tumor markers will 
be evaluated.  Numerous studies have demonstrated that proper supplementation 
with vitamin D and its main analog (calcitriol) can improve bone health in a wide 
variety of populations.  The majority of trials have focused on post-menopausal 
women, who are generally at higher risk for bone loss.  Peri-menopausal women 
lose 3%-5% of their bone mass annually, while postmenopausal women lose 
approximately 2% of their bone mass annually, compared with just 0.5% in men.7, 
8  Progressive bone loss can lead to a condition called osteoporosis, a skeletal 
disorder characterized by diminished bone strength.  Women with this condition 
are predisposed to increased risk of fracture, and this disorder can result in 
suffering and functional decline for the individual and drain health care 
resources.9  In 2004, there were an estimated 10 million women with osteoporosis 

5 
 
and an addition 34 million women with its precursor, osteopenia.9  The effects of 
osteoporosis can be devastating.  Every year, hip fractures are responsible for 
300,000 hospitalizations.10  Studies have shown that up to 25% of the elderly who 
fracture a hip die within one year.10  Other research has found that over 30% of 
survivors will be permanently disabled and approximately 20% of survivors will 
need long-term care in a nursing home.11-14  The cost attributed to hip fractures 
can exceed $80,000 per person and costs the United States over $25 billion 
annually, along with 550,000 years of lost life.10 
  
 
1.3  Calcitriol and Bone Health 
Calcitriol could prove to be a safe, low-cost treatment for preserving bone health 
in breast cancer patients.  Humans obtain Vitamin D from sunlight, food, and 
supplementation.15  Vitamin D plays a vital role in maintaining proper bone health 
and works in conjunction with calcium.  Greater levels of vitamin D have been 
shown to increase the intestinal absorption of calcium.16  One study demonstrated 
that an increase in serum vitamin D produced a 45%-65% increase in intestinal 
absorption of calcium.17  Although no consensus exists on optimal vitamin D 
levels, most experts agree a 25-hydroxyvitamin D level of less than 20 ng per 
milliliter is deficient.18  Based on these guidelines, it is estimated more than 1 
billion people worldwide and between 40%-100% of elderly U.S. residents are 
vitamin D deficient.19-22  Further research has shown that more than 50% of 
postmenopausal women already being treated for osteoporosis had deficient 
vitamin D levels.23, 24   
 
Bone health is a major concern in women undergoing treatment and who have 
completed treatment for breast cancer.  Cancer-treatment-induced bone loss 
(CTIBL) is a long-term side-effect of various breast cancer treatments.25  
Chemotherapy, hormone therapy, and radiation treatment frequently lead to, 
either directly or indirectly, to bone mass depletion in breast cancer patients.26  
Studies have documented accelerated bone loss in breast cancer patients, and this 
bone loss frequently goes undiagnosed.6, 27, 28  Research shows that breast cancer 
survivors have greater bone loss than women of similar age who were not 
diagnosed with cancer.29-31  Researchers believe that risk factors for bone loss are 
already present in many women preceding a breast cancer diagnosis.29  Treating 
bone loss in a prophylactic manner leads to greater success than delayed 
treatment.32, 33  The accelerated bone loss seen in these patients in all likelihood 
will lead to a higher rate of falls and fractures.34, 35   

6 
 
 
 
However, the American Society of Clinical Oncology (ASCO) recommends 
pharmaceutical interventions (e.g. bisphosphonates) only after a severe amount of 
bone loss in patients considered osteoporotic.36  A host of side effects exist for 
patients taking bisphosphonates.  For those taking the oral medication, poor GI 
absorption, nausea, and diarrhea are all common effects.37  Those on IV 
bisphosphonates commonly experience fever, flu-like symptoms, and myalgia.38  
Among the most serious side-effects is osteonecrosis of the jaw, which can 
require surgical intervention.39, 40  All of these side-effects tend to lead to poor 
compliance.41  A review of bisphosphonate compliance found that patients were 
between 18% and 78% compliant with the medication. 42   
 
While bone loss is a significant problem for breast cancer patients and 
pharmaceutical interventions result in less than ideal compliance, vitamin D and 
calcitriol supplementation could be an effective intervention for bone health.  A 
review of clinical trials found vitamin D supplementation had a positive effect on 
bone mineral density.43  Trials that used a low-dose vitamin D intervention (≤ 400 
IU/d) failed to find significant prevention of fractures.20, 44  In contrast, 
interventions that used a higher dose of vitamin D (≥ 700 IU/d) found significant 
positive effects on fracture prevention.45-49  A pooled analysis of those trials found 
vitamin D significantly reduced the risk of hip fracture by 26% and any 
nonvertebral fracture by 23%.50  Other interventions used the active vitamin D 
analog, calcitriol, because of its higher efficiency and quicker absorption in 
humans.  These trials demonstrated calcitriol is effective in maintaining bone 
mineral density and reducing fractures.51-57  A pooled analysis revealed calcitriol 
interventions significantly reduced the rate for nonvertebral fractures by 48% and 
all fractures by 48%.  A comparative analysis found that calcitriol was 
significantly more effective at reducing bone loss and fractures than native 
vitamin D.58   
 
In addition to regulating bone health, vitamin D also protects against falls and 
helps maintain muscular strength.59, 60  A meta-analysis of 5 randomized clinical 
trials reported a 22% reduction in falls by those receiving vitamin D 

7 
 
supplementation.61  Similarly, calcitriol has been shown to protect against falls.  
One trial found those supplemented with calcitriol, in addition to having adequate 
calcium intake, had a 55% reduction in falls.62  A 2001 intervention trial reported 
a significant reduction in the number of falls for those treated with calcitriol 
compared to placebo.54  A recent comparative meta-analysis concluded that 
calcitriol was more effective at preventing falls than native vitamin D.63 
 
1.4  Other Effects of Calcitriol 
Research during the past 10 years has demonstrated that appropriate intakes may 
provide greater benefits than previously known.64  Vitamin D exerts numerous 
effects on cellular growth and regulation through both genomic and non-genomic 
mechanisms.65  The effects are mediated through the vitamin D receptor (VDR), 
which has been found in both neoplastic and non-neoplastic tissues of the breast, 
pancreas, colon, brain, lymph nodes, among other sites.66-68  Tumor regression or 
growth reveals the balance between cellular proliferation and cellular death.69  
Reducing tumor cellular proliferation drives towards tumor regression, as 
apoptosis outpaces proliferation.70  Both in vitro and in vivo studies have 
demonstrated calcitriol is extremely effective at reducing breast cancer cell 
proliferation.71-75  Additional research has found that calcitriol is also extremely 
efficient at inducing apoptosis in breast cancer cells.76-79  Angiogenesis is the 
formation of new blood vessels and is usually a hallmark in tumor metastasis.80  
High-dose calcitriol has exhibited the ability to significantly limit the angiogenic 
potential of breast tumors.81-83   
 
1.5  Calcitriol Dosing 
To date, the maximum tolerated dosage of 
vitamin D has not been clearly established.  
Many clinical trials have failed to produce 
protective bone health effects from vitamin D 
because the supplementation level was too 
low.20, 44  Some researchers have suggested 
that interventions should use high, intermittent 
doses of vitamin D to increase serum levels 
and overcome low adherence.84  Trials that 
supplemented participants with ≥ 700 IU/d of 
vitamin D were able to show protection 
against bone loss.45-49  In both North America 
and Europe, the upper limit for vitamin D 
intake is considered to be 2,000 IU/d.85, 86  
However, many researchers, even government 
committees, believe numerous individuals are 
vitamin D deficient and the upper limit is too 
low.43, 87, 88  These recommendations were 
formulated out of concern for safety and to 
prevent toxicity, such as hypercalcemia.64  
However, a growing number of clinical trials 

8 
 
have given vitamin D doses many times the upper limit.  One trial administered 
100,000 IU of vitamin D every four months for five years without reports of 
toxicity.49  Another intervention administered 50,000 IU/d of vitamin D for a 
period of 8 weeks without a change in serum calcium.89  A long-term trial was 
able to administer 18,000 IU/d (9 times higher than the upper limit) of vitamin D 
for a period of 5 years without evidence of adverse events.90  A review of these 
trials shows that vitamin D is not toxic at intakes much greater than previously 
considered unsafe.64 
84 
 
The pattern is similar in terms of dosing for calcitriol.  Higher doses of calcitriol 
were typically not possible when given on a daily dosing schedule because of the 
development of hypercalcemia and hypercalcuria.91, 92  In recent years, 
researchers discovered that a less frequent dosing schedule allowed them to 
circumvent potential dose-limiting toxicities.93, 94  A weekly administration of 
high-dose oral calcitriol was shown to be safe in cancer patients.95, 96  The dosage 
was not limited by toxicities, but rather by nonlinear pharmacokinetics.97  
Subsequent studies have shown substantial dose escalation was possible when 
calcitriol was administered once a week.98-105  Trump et al. were able to 
administer 12 μg of calcitriol three consecutive days (36 μg/week) without any 
dose-limiting toxicities.106  A trial of prostate cancer patients found that 60 

9 
 
μg/week of calcitriol was well tolerated with docetaxel, as the patients did not 
show signs of hypercalcemia.107  Recently, 7 separate clinical trials were able to 
successfully administer 45 μg/week (or 0.5 μg/kg/week) of calcitriol to patients 
undergoing adjuvant cancer therapy.108-114  In the larger trials, participants were 
able to remain on calcitriol for one year or longer.115, 116  These studies 
demonstrated this dose was well tolerated and adverse events were extremely rare.  
In fact, a number of studies have shown that doses much greater than can be 
safely administered.  A phase I study in patients with cancer found calcitriol was 
well tolerated at a dose of 165 μg/week.117  Another phase I trial administered 
calcitriol at doses up to 38 μg/d for three consecutive days (114 μg/week) without 
dose-limiting toxicity.118  It is these trials which that established intermittent oral 
dosing of calcitriol as a method of significant dose escalation and produced 
potentially therapeutic levels.119  Additionally, calcitriol enhances the effects of 
radiation, chemotherapy, hormone therapy, and other antineoplastic treatments.120-
123  Based on previous trials, the 45 μg/week of calcitriol is an ideal dose to elicit 
positive effects and should pose only a minimal risk to the subject enrolled in this 
study.  Nonetheless, potential toxicities related to calcitriol will be closely 
monitored.  
 
1.6  Summary 
We propose to conduct a feasibility and efficacy pilot in breast cancer patients 
studied over 12 weeks to identify the ability to safely participate in a high-dose 
oral calcitriol intervention and to investigate the subsequent effects on bone 
health.  The study will accrue 25 patients and is intended to provide pilot data for 
a later grant submission.  The anticipated results could serve as important 
information with clinical and methodological applications.  Acquiring a better 
understanding of treatments capable of preserving bone health in breast cancer 
patients could lead to a higher quality of life and functional independence for 
these survivors. 
2.0  Objectives 
The calcitriol intervention is aimed at reducing fracture risk by maintaining proper bone 
density.  Calcitriol is efficacious in maintaining proper bone health and muscle mass 
among the general population, but little research has been done on breast cancer patients.  
In addition, calcitriol may be effective in reducing tumor proliferation and angiogenesis, 
while increasing tumor apoptosis.  Each of those factors could have beneficial effects on 
breast cancer outcomes. 
 
Hypothesis: A weekly oral dose of calcitriol 45 μg will be efficacious in preventing 
bone loss among invasive breast cancer patients. 
 
2.1 Primary Objectives 
 
2.1.1  To collect data on the efficacy and feasibility of Calcitriol 45 μg for maintaining 
proper bone health among invasive breast cancer patients for a period of 12 

10 
 
weeks. 
 
2.1.2  To collect preliminary data on the effect of Calcitriol 45 μg on bone resorption, as 
measured by Cross-Linked N-Telopeptide of Type I collagen (NTx) in invasive 
breast cancer patients over the course of 12 weeks. 
 
2.1.3 To collect preliminary data on the effect of Calcitriol 45 μg on markers of bone 
formation, as measured by bone-specific alkaline phosphatase (BAP) in invasive 
breast cancer patients over the course of 12 weeks. 
 
2.2 Secondary Objective 
 
2.2.1 To collect preliminary data on the effect of pre-surgical Calcitriol 45 μg therapy 
on tumor cell apoptosis (caspase 3 and survivin), tumor cell proliferation (Ki-67), 
tumor invasiveness (ER α, PgR, VDR, EGFR, HER2, VEGF, and IGFR), 
1α,25(OH)2D3, and Mammostrat Recurrence Score in invasive breast cancer 
patients. 
 
 
3.0  Subject Eligibility 
Inclusion Criteria: 
 
3.1 
Must be female. 
 
3.2 
Must have pathologically confirmed incident, primary invasive breast cancer. 
 
3.3 
Must be awaiting surgical resection. 
 
3.4 
Women of child-bearing potential (i.e. women who are pre-menopausal or not 
surgically sterile) must use acceptable contraceptive methods (abstinence, 
intrauterine device (IUD), or double barrier device) and must have a negative 
serum or urine pregnancy test within 1 week prior to beginning treatment on this 
trial.  Contraceptive use needs to be continued at least 1 month after the trial has 
ended. 
 
3.5 
Must provide informed consent.  
 
3.6  
Must be willing to discontinue use of calcium and/or vitamin D supplements other 
than multivitamin supplementation. 
 
3.7  
Participants must have an ionized serum calcium level within normal limits (1.19-
1.29mmol/L) and a total corrected serum calcium of < 10.2mg/dl. 
 
Exclusion Criteria: 
 

11 
 
3.8 
Subjects with life-threatening conditions that would preclude them from breast 
cancer treatment including: chronic cardiac failure, which is unstable despite 
medication use; uncontrolled hypertension; uncontrolled diabetes mellitus; or 
unstable coronary artery disease. 
 
3.9 
Patients with severe metabolic disorders, which includes phenylketonuria (PKU), 
homocystinuria, and Fabry's disease, that would preclude them from taking 
calcitriol. 
 
3.10 
Patients with a previous history of any other cancer except non-melanomous skin 
cancer within the past 5 years. 
 
3.11 
Patients with impaired renal function (CRCL < 60 mL/min) or who had kidney 
stones (calcium salt) within the past 5 years. 
 
3.12 
Patients with hypercalcemia (corrected serum CA > 10.2 mg/dl) or a history of 
hypercalcemia or vitamin D toxicity. 
 
3.13 
Patients currently taking calcium supplements or aluminum-based antacids must 
immediately discontinue their use if they are to enroll in the study.   
 
3.14 
Patients currently taking vitamin D supplements must immediately discontinue 
their use if they are to enroll in the study.   
 
3.15 
Patients with a known sensitivity to calcitriol. 
 
3.16 
Women who are pregnant or lactating. 
 
3.17 
Women on antiresorptive drugs (e.g. bisphosphonates) within the past year. 
 
3.18 
Women currently using oral contraception. 
 
3.19 
Women with malabsorptive syndromes (i.e. cystic fibrosis, chronic pancreatitis) 
or taking medications that decrease the absorption of fat soluble vitamins (i.e. 
Orlistat, Questran). 
 
3.20 
Participants assigned to calcitriol who are routinely taking a multivitamin 
supplement may continue the supplement as long as the amount of vitamin D in 
the supplement is not in excess of the RDA (recommended daily allowance) of 
400 IU or 10 μg.  If they are not taking a multivitamin supplement, they will be 
asked to not start supplementation while on study. 
 
 
4.0  Treatment Assignment 
4.1 
All patients who meet the eligibility criteria, sign the patient informed consent 

12 
 
form, and complete baseline assessments will immediately be assigned to the 
treatment Arm. 
 
4.1.1 This is a single sequence study with one trial arm, and patients will be 
assigned to the intervention arm as follows: 
 
Treatment Arm  
 
Condition 
1 
Calcitriol 45 μg:  Patients will be given 45 μg/week of 
calcitriol beginning prior to surgical resection for a period 
of 12 weeks.   

13 
 
5.0  Treatment Protocol 
 
5.1 
This will be a one-arm clinical trial examining the feasibility and efficacy of a 
Calcitriol 45 μg regimen for the maintenance of bone health among invasive 
breast cancer patients.   
 
5.2 
Consent Process and Initial Assessments 
 
5.2.1 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.1.1 Patients will be evaluated by their treating physician approximately 
once a month while enrolled in this study. 
 
5.2.2 Upon consent, the patient will complete an On-Study Data Form providing 
demographic data.  Questions concerning the patients’ sun exposure 
history, medical history, supplement usage history, along with baseline 
brief symptom inventory are also included.  Additionally, patients will be 
evaluated on vitals (Resting Heart Rate, Height, Weight & Blood 
Pressure).  Patients will proceed to phlebotomy to give a blood sample.  
They will then proceed to the University of Rochester Medical Center 
pharmacy to receive their study medication. 
 
5.2.3 Any woman of childbearing potential will have a pregnancy test.  If the 
woman is not pregnant, she may proceed with the study.  The women must 
also agree to practice barrier methods of contraception for the duration of 
the study. 
 

14 
 
5.2.4 All patients will receive a 12 week supply of calcitriol, which consists of 
twelve 45μg pills of calcitriol to be taken once a week (QW). 
 
5.3 
Bone Health Biomarkers and Pathological Markers 
 
5.3.1 Measures of bone pathology will be performed through ARUP Medical 
Laboratories.  Pre and post-intervention tests for Cross-linked N-
teleopeptide of type I collagen (NTx), a specific indicator of bone 
resorption will be performed.  In addition, pre and post-intervention test 
for bone-specific alkaline phosphatase (BAP), an indication of bone 
formation will be performed. 
 
5.3.2 
 
 
 
 
  
 
 
 
 
 
 
 
5.4 
Calcitriol 45 μg Intervention 
 
5.4.1 The Calcitriol 45 μg intervention will be monitored and directed by a team 
of professionals including: Dr. Luke J. Peppone, Research Assistant 
Professor of Radiation Oncology at the University of Rochester Medical 
Center, Dr. Gary R. Morrow, Professor of Radiation Oncology at the 
University of Rochester Medical Center; Dr. Kristen Skinner, Chief of 
Surgical Oncology at the University of Rochester Medical Center; Dr. 
Mary Reid, Research Scientist at Roswell Park Cancer Institute; and Dr. 
David G. Hicks, Director of Surgical Pathology at the University of 
Rochester Medical Center. 
 
5.4.2 The Calcitriol 45 μg intervention will follow the guidelines listed below: 
 
5.4.2.1 The Calcitriol 45 μg intervention is based on previous trials of 
Calcitriol 45 μg conducted among cancer patients.125-133 
 
5.4.2.2 
 
 

15 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

16 
 
 
 
5.4.3 Toxicity Monitoring: 
 
After the first dose of calcitriol is administered on day 0, the patients will 
return for blood collection on day 5.  On day 5, any patient displaying any 
grade ≥ 3 toxicity related to the study drug will be removed from the 
study.  Toxicities resulting from the study drug or removal from the 
study will not result in a delay of surgical resection.  Patients will also 
have a safety check during their pre-surgical workup.  The patients will 
return at 6 weeks and 12 weeks for blood collection.  These visits will be 
coordinated with surgical oncology visits, medical oncology visits, or 
radiation oncology visits to reduce patient burden.  Following her 
appointment, the patient will proceed directly to phlebotomy. 
 
Removal from study:  Patients will be removed from the study for any of 
the following reasons: 
 
1. Any grade ≥ 3 toxicity related to the study drug. 
2. A grade 2 toxicity that persists for more than 2 weeks. 
3. Withdrawal of consent. 
 
For any clinically adverse event, the toxicity grading scale established by 
the FDA will be used.  It is as follows: 
 
Grade 1 toxicity (Mild): No interference with activity 
Grade 2 toxicity (Moderate): Some interference with activity not requiring 
medical intervention. 
Grade 3 toxicity (Severe): Prevents daily activity and requires medical 
intervention. 
Grade 4 toxicity (Potentially Life Threatening): ER visit or hospitalization. 
 
For hypercalcemia, the FDA toxicity grading scale specific to serum 
calcium will be used: 
 
Grade 1 toxicity (Mild): 10.3-11.0 mg/dL 
Grade 2 toxicity (Moderate): 11.1-11.5 mg/dL 
Grade 3 toxicity (Severe): 11.6-12.0 mg/dL 
Grade 4 toxicity (Potentially Life Threatening): > 12.0 mg/dL 
 
The FDA toxicity grading scale will be used for determining all adverse 
events. 
 
In addition to blood safety checks throughout the study, a research 
coordinator will call each patient at on the day of the week she is 
scheduled to take Calcitriol 45 μg to ensure compliance and assess side 
effects.  The nurse will record any adverse events (AE) and/or serious 

17 
 
adverse events (SAE).  Any patient who reports an AE or SAE will be 
scheduled for a clinical visit.  In addition, the research coordinator will 
inquire as to any change in over the counter supplement usage.  Reports 
regarding potential toxicities, patient safety, and outcomes will be 
submitted to the University of Rochester Medical Center Research 
Subjects Review Board (RSRB).  The potential risks and side effects of 
calcitriol include:134 
 
Because calcitriol is the active analog of vitamin D, adverse effects are 
similar to those found with excessive vitamin D intake.  Because of the 
short biological half-life of calcitriol, elevated serum calcium levels 
normalize within a few days, much quicker than with native vitamin D 
supplementation. 
 
Early signs and symptoms of vitamin D intoxication: Weakness, headache, 
somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone 
pain, metallic taste, anorexia, abdominal pain, or stomach ache. 
 
Late signs and symptoms of vitamin D intoxication:  Polyuria, polydipsia, 
anorexia, weight loss, nocturia, conjunctivitis, pancreatitis, photophobia, 
rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, 
albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic 
calcification, nephrocalcinosis, hypertension, cardiac arrhythmias, 
dystrophy, sensory disturbances, dehydration, apathy, arrested growth, 
urinary tract infections, and, rarely, overt psychosis. 
 
This protocol requests a Comprehensive Metabolic Profile (Panel 14).  Of 
main concern is serum calcium, specifically hypercalcemia.  A serum 
calcium level between 8.4 and 10.2 mg/dL is considered normal.  Any 
level > 10.2 mg/dL or < 8.4 mg/dL is considered outside the safety range 
and the investigators should be notified. 
 
 
5.4.4 Adverse Events 
 
5.4.4.1 An adverse event (AE) is any untoward medical occurrence in a 
patient administered a pharmaceutical product, which does not 
necessarily have a causal relationship with the treatment.  An 
adverse event can be any unfavorable and unintended sign (eg, 
including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the drug, whether or not it is 
considered to be drug related.  This includes any newly occurring 
event or previous condition that has increased in severity or 
frequency since the administration of drug. 
 
5.4.4.2 A serious adverse event (SAE) is any adverse event, occurring at 
any dose and regardless of causality that: 

18 
 
• Results in death. 
• Is life-threatening.  Life-threatening means that the patient was at 
immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction which hypothetically might have 
caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization.  Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned 
prior to study entry are not considered AEs if the illness or disease 
existed before the patient was enrolled in the trial, provided that it 
did not deteriorate in an unexpected manner during the trial (eg, 
surgery performed earlier than planned). 
• Results in persistent or significant 
disability/incapacity.  Disability is defined as a substantial 
disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an 
event that may not result in death, be life-threatening, or require 
hospitalization but may be considered an SAE when, based upon 
appropriate medical judgment, it may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions for SAEs.  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.   
 
5.4.4.3 An unexpected adverse event is any drug experience, the 
specificity or severity of which is not consistent with the risk 
information described in the investigators brochure or general 
investigational plan (see section 5.91). Unexpected as used in this 
definition refers to an adverse drug event that has not been 
previously observed rather than from the perspective of such 
experience not having been anticipated from the pharmacological 
properties of the drug.  
 
 
5.4.5 Adverse Event Reporting 
 
 
University of Rochester Medical Center Reporting - Serious adverse 
events that are associated with the study and occur while a subject is on 
study until 14 days after the date the subject goes off study must be 
reported in writing to the Strong Memorial Hospital IRB within 10 
working days. They are also reported to the Data Safety Monitoring 
Committee within the same time frame. Adverse events that are both 

19 
 
unexpected fatal or life-threatening events must be reported 
immediately to the IRB. 
 
 
5.4.6 Data Safety Monitoring Plan 
 
 
Investigators will conduct continuous review of data and patient safety.  
The review will include for each treatment arm level:  the number of 
patients, significant toxicities as described in the protocol, dose 
adjustments, and responses observed.  The Investigator will submit twice 
yearly summaries of this data to the Clinical Trials Monitoring Committee 
for review.   
 
Clinical Trials Data Safety Monitoring Committee:  The Director of the 
Cancer Center delegates responsibility for continued review and 
monitoring of all clinical trials conducted by the URCC to the Clinical 
Trials Data Safety Monitoring Committee.  This committee provides 
oversight of study progress and safety by review of accrual and adverse 
events at annual meetings. Any adverse event requiring expedited review 
per protocol will be submitted to the Data Safety Monitoring Committee 
(DSMC) for determination as to whether further action is required.  The 
study PI and the study medical monitor determine if the adverse event 
requires expedited review.  Interim meetings are scheduled, as needed, to 
address specific issues that require immediate attention to assure patient 
safety.   
 
 
 
The Committee:   
 
a) 
Reviews assigned clinical trials conducted at the URCC for progress and 
safety. 
 
b) 
Reviews all adverse events requiring expedited reporting as defined in the 
protocol. 
 
c) 
Reviews reports generated by the URCC data quality control review 
process. 
 
d) 
Submits recommendations for corrective actions to the Protocol Review 
Committee and the PI 
 
e) 
In general, outcome data is not made available to individuals outside of 
the DSMC until accrual has been completed and all patients have 
completed their treatment.  At this time, the DSMC may approve the 
release of outcome data on a confidential basis to the trial PI for planning 
the preparation of manuscripts and/or to a small number of other 
investigators for purposes of planning future trials.  Any release of 
outcome data prior to the DSMC’s recommendation for general 

20 
 
dissemination of results must be reviewed and approved by the DSMC. 
 
 
 
 
Safety Coordinator:  The Medical Director of the Cancer Center Clinical Trials 
Office appoints the Safety Coordinator.  The Safety Coordinator monitors adverse 
event rates utilizing the URCC Clinical Trials database.  If any assigned study has 
had two or more of the same SAEs reported in a month or more than six of the 
same SAEs in six months, the DSMC will review the summary of SAEs, discuss 
events with the Study Chair, and conduct a more detailed review with the Study 
Chair.  The Data Safety Monitoring Chair will determine if further action is 
required. 
 
5.4.7 All study drugs will be dispensed and all biological specimens will be 
collected at the University of Rochester Medical Center. 
 
5.4.8 The principal investigator and/or the study coordinator will be present at 
all participant study visits.  Checklists for study procedure elements will 
be used to ensure compliance. 
 
5.4.9 The data is collected by either the study coordinator or the principal 
investigator.  The paper files that may contain identifying information are 
kept in a locked file within the locked study coordinators office.  When the 
data is entered into the computer, no identifying information is used and 
only available to staff within the Behavioral Medicine Unit of Radiation 
Oncology.  Computer records with identifying information are kept in 
locked files only accessible by the data manager, the PI, and study 
coordinator, and will be password protected. 
 
Numerous mechanisms are in place to ensure the data integrity and 
validity.  The study uses the exact same procedures as the University of 
Rochester Community Clinical Oncology Program (CCOP) uses.  The 
University of Rochester serves as a research base for CCOP, which is an 
NCI sponsored collection of clinical centers for the conduct of multi-
center clinical trials, which has been sponsored for more than 25 years.  
All the methods of data collection and the instruments have been 
previously validated and have been used in numerous trials conducted at 
the University of Rochester.  
 
5.4.10 There will be no cost to the patient for the study medication, the 
pathological tests, blood tests, or bone health tests.  All costs will be paid 
from funds controlled by Dr. Gary R. Morrow within the James P. Wilmot 
Cancer Center. 
6.0  Treatment Evaluation 
6.1 
Measures 

21 
 
 
 
6.1.1 Bone health biomarkers 
 
 
 
6.1.1.1 Levels of bone resorption will be measured by Cross-linked N-
teleopeptide of type I collagen (NTx).  NTx is a specific indicator 
of bone resorption.  It is generated from bone by osteoclasts as a 
degradation product of type I collagen, and it can easily be 
measured in urine or serum.  NTx has been shown to be a valid and 
reliable measure of bone resorption.135  Researchers believe that 
markers of bone resorption are superior to markers of bone 
formation and more accurately predict changes in bone mass.136  
Bone resorption markers are also able to predict failing bone health 
in advance of BMD. 
 
6.1.1.2 Levels of bone formation will be measured by bone-specific 
alkaline phosphatase (BAP).  Bone formation markers, 
specificially (BAP), are also considered a valid measure of bone 
health.137, 138  Although BAP is a valid measure of bone health, 
measures of bone resorption tend to be better predictors of bone 
health. 
 
6.1.2 Breast tumor prognostic markers will be assessed using a number of 
markers specific to malignancies. 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
  
 
  
 

22 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2.2 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 

23 
 
 
6.1.3 Cancer symptoms 
 
 
6.1.3.1 The effects of breast cancer will be measured by the Symptom 
Inventory.  The Symptom Inventory is a list of 13 symptoms 
modified from measures created at MD Anderson and Memorial-
Sloan Kettering Cancer Centers.  Patients are asked to rate the 
severity of several symptoms, such as pain, nausea and fatigue.  
Responses are anchored using an 11 point scale ranging from 0 to 
10 (Not Present At All to As Bad As You Can Imagine).   
 
7.0  Statistical Considerations 
 
7.0 
Primary measures and analyses:  
 
 
7.0.1 Bone Resorption: NTX 
 
7.0.2 Bone Formation: BAP 
 
Since the primary objective of this pilot study is to gather preliminary efficacy 
and feasibility data for the development of a planned career development grant 
application, the primary analyses will consist of calculating mean change scores 
(i.e., baseline assessment minus final assessment) and standard deviations for the 
two variables above.  In addition, a paired-sample t-test will be used to calculate 
the differences between the baseline and end of trial value for both BAP and 
NTX.  An independent t-test will be used to calculate the difference between the 
baseline and end of trial value for both BAP and NTx between the trial arms.  
Lastly, ANCOVA models will be used for BAP and NTx with the addition of 
relevant covariates collected during the study.  Results of these two analyses will 
be interpreted cautiously because of the limited sample size.  
 
7.1 
Secondary measures and analyses: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.7 
 
 
  
 

24 
 
 
7.1.8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 
Sample Size 
 
7.2.1 Twenty-five women will constitute an adequate size to provide pilot data 
for subsequent studies. 
 
7.2.2 Based on a discussion with breast cancer clinicians at the University of 
Rochester Medical Center about patient volume and projecting an accrual 
rate of 25%, it will take approximately one year to enroll 26 women. 

25 
 
8.0  Records to be Kept  
 
 
8.1 
All hardcopy research records will be stored onsite in the University of Rochester 
Medical Center, in the Behavioral Medicine Unit of the James P. Wilmot Cancer 
Center.  The Cancer Center is secured by electronic key cards.  Offices within the 
Cancer Center are again secured by key and data is kept in locked file cabinets.  
Electronic research records are stored on the University of Rochester Medical 
Center’s password secured and firewall protected networks.  These are the same 
methods of security used for patient medical records.  Human serum samples and 
biopsy samples are stored in locked freezers, within locked and alarmed 
laboratories that are accessible by key codes and electronic card swipes.  All study 
data will be kept for a period of 10 years after the study and all reports and 
publications are complete.   
 
8.2 
All data (information, human blood samples, and human tissue samples) collected 
for the current study will be used in post hoc analyses as appropriate.  No blood 
samples or biopsy samples will be banked and data will not be used for future 
studies without prior consent of the patient.  The patient is provided the 
opportunity to be contacted for future research studies in the informed consent.  
The patient’s individual research record will not be shared with their treating 
physician, unless they provide consent or the patient’s treating physician is a 
study physician, in which case they will have access to study data as a study co-
investigator.  Overall study results will be presented to participants, faculty and 
staff at the University of Rochester Medical Center after completion of the study.  
Schedule of Clinical Visits, Data and Specimen Collection 
Procedure
0
5 Days
2-4 weeks 6 Weeks 12 Weeks
Eligibility Interview
+
Informed Consent
+
Medical History
+
+
+
Assess Supplement Use
+
+
+
+
Blood CBC Levels
+
+
+
+
+
Plasma Vitamin D Levels
+
+
+
+
+
Bone Biomarkers
+
+
+
Symptom Inventory
+
+
Phone call reminders
Weekly Weekly
Weekly
Weekly
Weekly
Toxicity monitoring
+
+
+
+
+
Surgical Resection
+
Time Since Randomization

26 
 
Study results will be presented at professional meetings and published.   
 
8.3 
The study coordinator will assign a numerical Study ID to each participant once 
they have signed the consent form.  All study forms and questionnaires will use 
this number and the participant’s first, middle, and last initials as identifiers, to 
ensure data integrity.  Other identifying information will not exist on these forms.  
A complete list of study participants with study ID, name, and contact information 
will be maintained separately. This linkage information will only be accessible to 
the study coordinator, study investigators, and the individual responsible for 
maintaining the database. 
9.0   Patient Consent and Peer Judgment 
 
9.1 
Current, state, federal, and institutional regulations concerning informed consent 
will be followed.   
10.0  References 
 
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