Clinical trial NCT01588522
Conditions: Chemotherapy-Induced Alopecia
Keywords: alopecia
Sponsor: BPGbio
Start date: 2012-09-17; Completion date: 2017-02-16
Enrollment: 28 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The goal of this clinical trial is to learn if Compound 31543 (topical calcitriol) for treatment of hair-loss in patients with a diagnosis of breast cancer, gynecologic cancer or sarcomas receiving a taxane-based chemotherapy is safe. The main questions it aims to answer are:

* What medical problems do participants have when using compound 31543?
* How much Compound 31543 is in blood after treatment?
* How much hair is lost during treatment?

Participants will:

* Apply Compound 31543 to their scalp twice a day, starting at least 5 days before starting chemotherapy for at least 3 months or until chemotherapy treatment is completed.
* Have blood drawn on weeks 1, 5, 9, 13, and 54.
* Have photographs taken of their hair before starting and at weeks 7, 15, 27, and 54.
* Keep a diary of the condition of their hair.

Detailed description:
This was a multi-center, single arm, dose-escalation Phase 1 study to determine the maximum tolerated dose (MTD), PK, and the overall safety and tolerability of Compound 31543 in patients with a diagnosis of early-stage or locally advanced, unresectable and/or metastatic cancer, or patients with operable cancer, who were scheduled to receive follow up treatment with a taxane-based chemotherapy regimen, as per the physician's discretion. A standard 3+3 dose escalation design was employed, over 6 dose levels, with 3 to 6 patients at each dose level. Eligible patients in each cohort, \>18 years of age and scheduled to receive a taxane-based regimen with treatment breaks as per physician's discretion, initially received or applied the topical formulation of Compound 31543 to the scalp twice daily either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).To determine the MTD for Compound 31543, dose escalation was conducted in stepwise increments, in the absence of dose-limiting toxicity (DLT) defined as clinically significant Grade 3 or 4 non-hematologic toxicity assessed as possibly, probably, or definitely related to Compound 31543 and not to the taxane-based chemotherapy, as best determined by investigator; assessment of DLTs was made weekly during the first 28 days of Compound 31543 treatment and subsequently thereafter every 4 weeks.

Pharmacokinetic (PK) data were evaluated for each dose level before escalation of Compound 31543 to the next dose level in all patients. PK blood samples were collected on Day 1 prior (pre-dose) to the first-morning dose of topical Compound 31543 and at 2, 4, and 8 hours post-dose after the first application of Compound 31543 on Day 1. PK samples were also collected 12 hours after the last, evening dose of Compound 31543 (i.e., before the first Day 1 of the next 28-day treatment) on Weeks 5, 9, 13, and 54.

Potential efficacy of the Compound 31543 was evaluated by photographic assessments and self-assessment diaries performed at baseline and Weeks 7, 15, 27, and 54. Photographic assessments were performed using a Canon digital camera system on views of the front of head/face, bilateral sides of head, and back and top of head/scalp view, as well as close-up photographs of a superior view and a vertex view with hair parted in the center and combed away from the part. Photographs were standardized for lighting, camera angle, and position to the participant's head.

Additionally, patients maintained a medication application diary and a self-assessment diary. The patient completed diary collected patient-reported assessments of hair thickness, fullness, volume, breakage, and cosmetic qualities (ease of styling, etc.) based on a 10-point analog scale for each parameter/question during the first 15 weeks after initiating calcitriol Compound 31543 and at Weeks 19, 23, and 27.

Arms: arm 1: Compound 31543 Calcitriol (5 μg/mL), Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks). arm 2: Compound 31543 Calcitriol (10 μg/mL), Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks). arm 3: Compound 31543 Calcitriol (20 μg/mL), Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks). arm 4: Compound 31543 Calcitriol (40 ug/mL), Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks). arm 5: Compound 31543 Calcitriol (60 μg/mL), Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks). arm 6: Compound 31543 Calcitriol (80 μg/mL), Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).
Interventions: intervention 1: Compound 31543 Calcitriol 5 μg/mL intervention 2: Compound 31543 Calcitriol 10 μg/mL intervention 3: Compound 31543 Calcitriol 20 μg/mL intervention 4: Compound 31543 Calcitriol 40 μg/mL intervention 5: Compound 31543 Calcitriol 60 ug/mL intervention 6: Compound 31543 Calcitriol 80 μg/mL
Intervention descriptions: intervention 1: 5 μg/mL Topical Solution intervention 2: 10 μg/mL Topical Solution intervention 3: 20 μg/mL Topical Solution intervention 4: 40 μg/mL Topical Solution intervention 5: 60 ug/mL Topical Solution intervention 6: 80 μg/mL Topical Solution

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
A Multi-Center, Phase 1 Dose-Escalation Study, to 
Evaluate the Safety, Tolerability and Pharmacokinetics 
of a Topical Compound 31543 (Calcitriol, USP) in Adult 
Cancer Patients Receiving Taxane-based 
Chemotherapy Regimens for the Treatment of 
Advanced or Recurrent Disease
Protocol Number:
CTL0211
Amendment Number:
9
Study Drug:
Compound 31543
Sponsor:
Berg, LLC
1845 Elm Hill Pike
Nashville, TN37210
USA
Medical Monitor:
Brian Berman, MD, PhD
Date Final:
November 02, 2015
CONFIDENTIAL: This document (and all copies thereof) is the property of Berg, LLC and contains valuable trade secrets 
and confidential information, including proprietary technical and business information (hereafter ‘Confidential 
Information”). By accepting this document, you agree that the Confidential Information contained herein will not be 
disclosed to others without prior written authorization from Berg, LLC and shall only be used for the purpose intended by 
the document only.


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
1 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................ 5 
1.1 
Berg Protocol CTL0211 .............................................................................. 5 
2 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................... 7 
2.1 
Primary Objective ....................................................................................... 7 
2.2 
Secondary Objectives.................................................................................. 7 
3 
BACKGROUND AND RATIONALE ................................................................ 8 
3.1 
Chemotherapy-Induced Alopecia ............................................................... 8 
3.2 
Calcitriol, 1,25-dihydroxyvitamin D3......................................................... 8 
3.3 
Pre-clinical Studies ..................................................................................... 9 
3.3.1 
Animal Studies .............................................................................. 9 
3.3.2 
Summary of Pre-clinical Skin Penetration Studies ..................... 11 
3.4 
Clinical Studies ......................................................................................... 12 
4 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................. 16 
4.1 
Design 16 
4.2 
Intervention ............................................................................................... 16 
5 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................... 18 
5.1 
Investigational Product ............................................................................. 18 
6 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................... 20 
6.1 
Subject Inclusion Criteria ......................................................................... 20 
6.2 
Subject Exclusion Criteria ........................................................................ 20 
7 
PRETREATMENT EVALUATION ................................................................. 22 
8 
TREATMENT/INTERVENTION PLAN ........................................................ 23 
8.1 
Taxane-Based Chemotherapy Administration .......................................... 23 
8.2 
Dose Escalation ......................................................................................... 23 
8.3 
Pharmacokinetics (All Patients) ................................................................ 25 
8.4 
Definition of Dose-Limiting Toxicity (DLT) and Treatment Modifications26 
8.4.1 
Dose-Limiting Toxicity Related to Calcitriol .............................. 26 
8.4.2 
Dose-Limiting Toxicity ................................................................ 27 
9 
EVALUATION DURING TREATMENT/INTERVENTION ....................... 28 
9.1 
Clinical ...................................................................................................... 28 
9.2 
Laboratory ................................................................................................. 28 
9.3 
Dermatology Evaluation. .......................................................................... 28 
9.4 
Photographic Record of Hair and Scalp .................................................... 28 
9.5 
Subjective Record of Hair and Scalp ........................................................ 29 
10 
POST-TREATMENT EVALUATION ............................................................. 36 


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11 
TOXICITIES/SIDE EFFECTS ......................................................................... 37 
12 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT38 
13 
CRITERIA FOR REMOVAL FROM STUDY ............................................... 39 
14 
BIOSTATISTICS ................................................................................................ 40 
14.1 
Safety Analyses ......................................................................................... 41 
14.2 
Significance Level .................................................................................... 41 
14.3 
Exploratory Analyses ................................................................................ 41 
14.4 
Interim Analyses ....................................................................................... 41 
14.5 
Sample Size/Accrual Rate ......................................................................... 41 
15 
RESEARCH PARTICIPANT REGISTRATION ........................................... 43 
16 
ADVERSE EVENTS .......................................................................................... 44 
16.1 
Clinical Adverse Events ............................................................................ 44 
16.2 
Relationship Between the Adverse Event and the Study Drug ................. 44 
16.3 
Treatment and Follow-Up of Adverse Events .......................................... 44 
16.4 
Laboratory Test Abnormalities ................................................................. 45 
16.4.1 Follow-Up of Abnormal Laboratory Test Values ....................... 45 
17 
SERIOUS ADVERSE EVENTS (SAE) ............................................................ 46 
17.1 
SAE Reporting .......................................................................................... 46 
17.2 
Berg SAE Reporting Requirements .......................................................... 47 
18 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ...... 48 
18.1 
Informed Consent Procedures ................................................................... 48 
18.2 
IRB Approval ............................................................................................ 48 
18.3 
Confidentiality .......................................................................................... 48 
18.3.1 Patient Confidentiality ................................................................ 48 
18.3.2 Investigator and Staff Information .............................................. 49 
19 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ....... 50 
19.1 
Amendments to Protocol........................................................................... 50 
19.2 
Trial Documentation and Storage ............................................................. 50 
19.3 
Data Collection ......................................................................................... 50 
19.4 
Trial Monitoring, Auditing, and Inspecting .............................................. 51 
19.5 
Disclosure and Publication Policy ............................................................ 51 
20 
APPENDICES ..................................................................................................... 52 
21 
REFERENCES .................................................................................................... 53 
 


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LIST OF TABLES 
Table 1: 
Average Results across Donors for Calcitriol Content in Epidermis, Dermis,  
and Total Absorption ............................................................................................ 12 
Table 2: 
Storage Conditions for Clinical Phase 1 ............................................................... 19 
Table 3: 
Dose Escalation ..................................................................................................... 25 
Table 4: 
Evaluation Scale for Photographic Review of Hair Loss/Gain ............................ 29 
Table 5: 
Study Evaluation Schedule Part A – The Basic Information ................................ 30 
Table 6: 
Study Evaluation Schedule Part B – The Tests and the Study  
Drug Application .................................................................................................. 33 
 
LIST OF FIGURES 
Figure 1. 
Total Absorption and Mass Balance Results across Skin Donors ........................ 11 
 
 


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1 
PROTOCOL SUMMARY AND/OR SCHEMA 
1.1 
Berg Protocol CTL0211 
Study Title: A multi-center, Phase 1, dose-escalation study to evaluate the safety, tolerability 
and pharmacokinetics of a topical compound31543 (Calcitriol, USP) in adult cancer patients 
receiving taxane-based chemotherapy regimens for the treatment of advanced or recurrent 
disease. 
This will be a dose escalation study to determine the maximum tolerated dose (MTD) and the 
overall safety and tolerability of a topical compound 31543 (Calcitriol) in  patients with a 
diagnosis of early stage or locally advanced, unresectable and/or metastatic cancer, or patients 
with operable cancer, who are scheduled to receive follow up treatment with a taxane-based 
chemotherapy regimen (either pre-operatively or post-operatively), as per physician’s 
discretion.A standard 3+3 dose escalation design will be employed with 3-6 patients at each dose 
level. Eligible patients ≥18 years of age and scheduled to receive a taxane-based regimen with 
treatment breaks as per physician’s discretion, will start applying the topical solution twice a day 
at each cohort dose level two weeks or 7 days ± 2 days prior to initiation of chemotherapy and 
then continue twice daily for 3 months or until termination of chemotherapy treatment. If topical 
calcitriol is found to be effective in preventing and/or diminishing taxane chemotherapy-induced 
alopecia as determined by the photographic assessments and patient self-assessments, patients 
will be allowed to continue topical application for the duration of their chemotherapy treatment, 
assuming no dose limiting toxicities (DLTs) related to the topical agent or intolerable side effects 
are observed. Toxicity to the topical compound 31543 (calcitriol) will be assessed on a weekly 
basis during the first 28 days of topical treatment and subsequently every four weeks by a study 
clinician, either a physician or a nurse. For the purpose of pharmacokinetic studies (PKs), blood 
samples will be collected on Day 1 of topical treatment at the following time points: pre-dose, at 
2 hrs (±30 minutes), 4 hrs (±30 minutes), and 8 hrs (±1 hr post dose) after a single application on 
the morning of Day 1. The second application of drug product will be applied 10-14 hrs after the 
initial application and after the 8 hr PK sample. Thereafter, topical application frequency will be 
twice daily, morning and night. Subsequently, a PK sample will be taken 12 hrs (±2 hrs) after the 
last dose of each 28-day treatment, before the first application of Day 1 of the next 28-day 
treatment cycle. This schedule will continue for three consecutive 28-day topical treatment 
cycles. (PKs will be drawn at Weeks 1, 5, 9, and 13. In addition, if patients are still on study, a 
PK will also be drawn at Week 54.)  
As a secondary objective, potential efficacy of the topical calcitriol will be evaluated by 
photographic assessment. Photographic assessment will be performed using a Canon digital 
camera system to ensure standardization and uniformity among all enrolled patients. The 
following five views will be obtained at each photographic assessment: bilateral sides of 
head/scalp view, front of head/face view, back of head/scalp view, and top of head/scalp 
view.Additionally, close-up photographs will be taken at the same time points. They will include 
the mid-pattern of the scalp from a superior view and a vertex view with hair parted in the center 
and combed away from the center part. Photographs will be standardized for lighting, camera 
angle, and position to the participant’s head.These assessments will be performed at the 
following time points: at baseline, Weeks 7, 15, 27, and 54. Photographs for patients in each 
cohort representing baseline, and treatment Weeks 7 and 15 will be presented blind to the study 
PI and dermatologist, Mario Lacouture, after at least 3 patients have completed 15 weeks of 
treatment. Photographs will also be taken at Week 27 and Week 54 of the study but will be 


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included in the final photographic assessment as secondary information. In addition, all patients 
will be asked to maintain an application log throughout treatment to ensure compliance.  
Additionally patients will maintain a medication application diary and a self-assessment diary. 
The medication application diary will collect daily application details of the medication. This 
will include application dates and times, chemotherapy cycle, and whether the medication was 
applied (or reason if the medication was not applied). The self-assessment diary will require 
assessment of hair thickness, hair fullness, hair breakage, and hair cosmetic qualities (ease of 
styling, etc.) on an analog 10 point scale to assess patient-reported efficacy. The PI clinical 
assessment of baseline, Weeks 7 and 15 photographs will be used, together with the patient diary 
information, for the primary assessment of alopecia. The study is expected to take place over a 
period of approximately 12 months, including the screening period. 
 
 


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2 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary Objective 
• 
To determine the maximum tolerated dose (MTD) and the overall safety and 
tolerabilityof topical Compound 31543(Calcitriol, USP)in adult cancer patients receiving 
taxane-based chemotherapy regimens.  
2.2 
Secondary Objectives 
• 
To determine the single and multiple dose pharmacokinetics of Compound 31543 at 
different dose levels. 
• 
To evaluate preliminary efficacy of Compound 31543 Topical Solution for preventing 
chemotherapy-induced alopecia. 
 
 


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3 
BACKGROUND AND RATIONALE 
3.1 
Chemotherapy-Induced Alopecia 
Chemotherapy-Induced Alopecia or CIA is a non-cicatricial alopecia and represents one of the 
most common and distressing dermatological adverse events associated with the use of many 
different chemotherapeutic agents. Taxanes (paclitaxel/ docetaxel), doxorubicin, 
cyclophosphamide, and 5-fluorouracil can cause alopecia in >80%, 60%-100%, >60%, and 10%-
50% of patients, respectively.1 Among women undergoing therapy with paclitaxel monotherapy, 
alopecia can be observed in up to 82% of patients.2,3 CIA is believed to occur when hair follicles 
are in anagen phase and results in anagen effluvium due to toxicity of chemotherapy and its 
metabolites on the hair follicle.1 CIA typically begins at 1-3 weeks and is complete at 1-2 months 
after the initiation of chemotherapy. This type of hair loss is usually reversible after the 
completion of therapy, with regrowth that occurs after a delay of 3-6 months. Nevertheless, the 
new hair often demonstrates changes in its color, structure, and texture with growth rate that may 
be significantly reduced.1 This particular toxicity has significant psychosocial and quality-of-life 
consequences. It negatively affects patients’ perception of physical appearance, body image, 
sexuality, and self-esteem.5-7 More importantly, among women, 58% consider it the most 
disturbing reaction and 8% are at risk of avoiding therapy due to this toxicity.8 Despite such 
profound effects on patients, to date no effective preventative or treatment options are available. 
One approach, scalp-cooling, has been investigated since 1970s and has shown to diminish CIA. 
However, there is a lack of adequate clinical data with only 7 out of 53 conducted trials that were 
randomized, and further clinical and biochemical research is needed.9 Scalp cooling has been 
used to treat CIA.10 Topical minoxidil 2% topical solution has also been investigated in 
prevention of CIA and has been shown to diminish its duration but failed to prevent it.11 While 
multiple other experimental approaches are being investigated, no pharmacologic agent has been 
approved for prevention or treatment of CIA.1 
3.2 
Calcitriol, 1,25-dihydroxyvitamin D3 
Vitamin D plays a critical role in calcium and phosphate homeostasis through its actions in the 
intestine, kidney, and parathyroid glands. These actions are mediated by the activated, hormonal 
form, 1,25-dihydroxyvitamin D3 (calcitriol).12 Calcitriol is made by hydroxylation of calcidiol 
and represents the active form of Vitamin D and is the most potent steroid hormone derived from 
cholecalciferol. In addition to these critical functions, calcitriol also plays a role at other sites, 
including control of cell proliferation, differentiation, the synthesis and secretion of cytokines 
and other hormones. Calcipotriol is a Vitamin D analogue that has a similar activity in regard to 
Vitamin D receptor binding when compared with the active form of Vitamin D3, calcitriol. It 
inhibits epidermal proliferation, modulates keratinization and inflammation but is much less 
potent in regulating calcium metabolism. Because of these properties, numerous investigations 
have been conducted with Vitamin D and its analogs in their potential therapeutic application in 
cancer, immune modulation, and regulation of endocrine system.14 Interest in Vitamin D3 
derivatives for prevention of CIA has emerged based on the novel work by Joaquin Jimenez, MD 
at the University of Miami. A serendipitous experiment showed a topical solution of calcitriol to 
reduce alopecia that was attributed to its ability to arrest the cell cycle and reduce the sensitivity 
of the epithelium to chemotherapy. Unlike androgenetic alopecia, CIA occurs due to massive 
anagen effluvium attributed to toxicity of chemotherapy and their metabolites on the hair follicle 
cells. The rapid cell proliferation in hair follicles during anagen renders hair follicles susceptible 


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to the toxicity of chemotherapy. Therefore, one approach to prevent CIA is to inhibit cell 
proliferation in order to diminish the sensitivity of hair follicles to chemotherapy. 
3.3 
Pre-clinical Studies 
3.3.1 
Animal Studies 
Both CIA and alopecia areata (AA) have been extensively studied due to the availability of 
animal models which closely mimic the diseases in the human. In this regard, it was previously 
demonstrated that alopecic chemotherapies (cytarabine, cyclophosphamide, doxorubicin, 
doxorubicin/cyclophosphamide, etoposide) induce alopecia in the neonatal rat model (Sprague 
Dawley rats). In this model, rats of 8 to 11 days of age are injected intraperitoneally with 
chemotherapy. Alopecia ensues 5-7 days later, and is graded depending on the hair loss 
observed. The protective compounds are given on Day 5 after birth for 6 days. This model is 
useful to study CIA because the hair follicles at this stage are in 100% anagen, which renders 
them susceptible to chemotherapy toxicity and is comparable to the human setting.17-19 This is a 
very effective and a reproducible model and can be used to study protective formulations against 
CIA. Some of the drawbacks of this model is that the hair follicles are in the first hair growth 
cycle after birth and that the rats have white fur and lack pigmentation.1 In contrast, the use of 
neonatal Long Evans rats allows studying pigmented hairs. Another model that is widely used to 
study the effect of chemotherapy is an adult C57BL/6 mouse model. The hair follicles in this 
model have gone through several postnatal growth cycles and the hair shafts are pigmented, 
similar to the human scalp.1 The anagen cycle in this particular model is induced by depilation 
and is observed 8 to 9 days after the procedure. Using this model and cyclophosphamide, it has 
been demonstrated that as a response to cytotoxicity of chemotherapy, the hair follicle utilizes 
two pathways: dystrophic anagen or dystrophic catagen, which determines the onset of 
chemotherapy-induced alopecia and the pattern of hair re-growth.1 A new model that has been 
used to investigate CIA is an adult Long Evans rat model, which allows studying hair follicles 
that have gone through several cycles and rats possess both pigmented and non-pigmented hairs. 
Additionally, the induction of anagen phase is performed by shaving fur with clippers, the 
method that may avoid the trauma to the hair follicles that is induced by depilation. Another 
excellent model to study alopecia, more specifically, AA, has been the C3H/HeJ mouse model.20 
In this model, 20% of the animals spontaneously develop alopecia in clusters or throughout the 
entire body (alopecia universalis) by 18 months of age. Alopecia patterns and histopathological 
analysis has shown that the pathology in this animal is almost identical to that of the human.  
1,25-Dihydroxyvitamin D3 protects by modulating the differentiation of hair follicle 
keratinocytes, rendering them resistant to the toxic metabolites of chemotherapy. During the 
course of screening therapeutic compounds to treatAA, 1,25-Dihydroxyvitamin D3 was tested. 
The following study was conducted to characterize the effect of 1,25-Dihydroxyvitamin D3 
indifferent types of alopecia, namely, CIA, Post-Chemotherapy Alopecia (PCA) andAA. The 
overall goal of this project was to determine if 1,25-Dihydroxyvitamin D3could be used to treat 
alopecia in general. 
The results of pre-clinical studies strongly suggest that 1,25(OH)2D3 exerts a protectiveeffect 
against chemotherapy-induced alopecia, but it does not treat alopecia itself. The rationale behind 
the preventive effect of 1,25(OH)2D3 in CIA is that healthy hair follicles can be arrested and 
thereby rendered resistant to the chemotherapy. However, in hair follicles that are already 
apoptotic, treatment with 1,25(OH)2D3 does not offer any benefit.  


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Findings in another animal study demonstrated a potential mechanism by which application of 
topical calcitriol may diminish the incidence of CIA. Topical treatment with calcitriol was 
demonstrated to significantly diminish the degree of follicular apoptosis induced by 
cyclophosphamide in C57BL/6 mice.21 Another experiment conducted with BALB/c mice, the 
animal model which allows investigating the hair follicles in the first adult anagen phase and 
evaluate gender differences, demonstrated that topical application of calcitriol for 5 days prior to 
intraperitoneal administration of cyclophosphamide significantly reduced the degree of CIA in a 
dose-dependent manner in male mice.22 The protective effect of topical calcitriol was diminished 
in tumor-bearing male mice that were injected with EMT-6 murine breast tumor cells.22 In 
contrast, pre-treatment with topical calcitriol in tumor-bearing female mice injected with EMT-6 
murine breast tumor cells had a more efficient protective effect against cyclophosphamide 
induced alopecia as compared to female mice without tumor and their tumor-bearing male 
counterparts.22 Histopathologic examination of post-mortem skin demonstrated marked reduction 
in morphological alterations induced by cyclophosphamide in hair follicles and a protective 
effect from cyclophosphamide-induced follicular damage.22 However, in this model, no 
significant differences in apoptosis staining pattern were noted between mice treated with topical 
calcitriol and those without exposure to the solution. 
On the other hand, another animal study using the female C57BL/6 adolescent mice instead of a 
neonatal rat model, failed to demonstrate efficacy of topical calcitriol in prevention of 
cyclophosphamide-induced alopecia. Interestingly, however, the regrowth of pigmented hair 
shafts was significantly accelerated, enhanced, and quantitatively improved. Histopathologic 
investigations suggested that this may have been due to hair follicles favoring the “dystrophic 
catagen pathway” of response to chemical injury: follicular repair strategy allowing for the 
unusually fast reconstruction of a new, undamaged anagen hair bulb.23 
Multiple in vivo animal investigations failed to demonstrate the potential protective effect of 
calcitriol from cytotoxicity of chemotherapy on cancer cells. No statistically significant 
difference in the survival rate was seen between Sprague Dawley rats transplanted with 
chloroleukemia C51 cells pretreated with 0.2μg of 1,25(OH)2D3 and those pretreated with an 
ethanol vehicle prior to cyclophosphamide treatment.16 More importantly, pretreatment with 
topical calcitriol of EMT-6 murine breast tumor-bearing male mice prior to intraperitoneal 
administration of cyclophosphamide resulted in the greater reduction in the rate of tumor growth 
as compared to mice treated with either agent alone, suggesting potential anti-tumor effects of 
calcitriol. Similarly, pretreatment with 2.5 μg of calcitriol 3 doses daily for 3 days, followed by 
administration of varying doses of paclitaxel of squamous cell carcinoma and human prostate 
cell carcinoma bearing mice resulted in significant tumor regression.15 
 
 


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3.3.2 
Summary of Pre-clinical Skin Penetration Studies 
Prototype formulations of Berg Compound 31543 (calcitriol) Topical Solution containing either 
1 µg/mLor 3 µg/mL of active calcitriol and excipient control were tested and evaluated utilizing 
human cadaver skin in Franz cell percutaneous measurement chambers. Data from 3 donors with 
3 replicates/donor/formulation (1 replicate/blank) at a 48-hr dose exposure period were 
conducted (Figure 1).The purpose of this study was to determine the penetrability of both 
formulations in a human skin model. 
Figure 1. 
Total Absorption and Mass Balance Results across Skin Donors 
Distribution of Calcitriol from Intact Human Cadaver Skin over 48 hrs from a Single Application. (Mean 
± SE as Total Mass [ng/cm]). 
Reservoir
Dermis
Epidermis
Surface Wash
0.01
0.1
1
10
100
 CAR-03-027
 CAR-03-031
 CAR-03-035
 CAR-03-037
 CAR-03-039
 CAR-03-041
 Non-Dosed Blank Cells
Nanograms/cm
2 Recovered
Sample Source
ND
 
 
 
 


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Table 1: 
Average Results across Donors for Calcitriol Content in Epidermis, Dermis, and Total 
Absorption 
Percutaneous Absorption of Calcitriol using Human Cadaver Skin over 48 hrsfrom a Single Application. 
(Mean ± SE as Total Mass [ng]). 
Test Article 
Epidermis 
(ng/cm2) 
Dermis 
(ng/cm2) 
Total Absorption 
(ng/cm2) 
Calcitriol 1µg/mL  
Lot CAR-03-027 
1.95 ± 0.37 
0.22 ± 0.22 
19.71 ± 1.24 
Rogn 1 µg/mL 
Lot CAR-03-031 
3.26 ± 0.89 
0.39 ± 0.39 
19.69 ± 1.33 
Trans 1 µg/mL 
Lot CAR-03-035 
3.78 ± 1.09 
 0.00 ± 0.00* 
19.49 ± 0.86 
Trans 3 µg/mL 
Lot CAR-03-037 
12.88 ± 1.48 
0.00 ± 0.00 
21.02 ± 0.20 
Phospho 1 µg/mL 
Lot CAR-03-039 
4.38 ± 0.27 
0.00 ± 0.00 
19.92 ± 0.63 
Phospho 3 µg/mL 
Lot CAR-03-041 
9.66 ± 0.84 
0.00 ± 0.00 
17.60 ± 0.50 
Non-Dosed Blank Cells 
0.37 ± 0.37 
0.00 ± 0.00 
13.75 ± 0.59** 
* Zero values indicate results below the lower limit of detection. 
** Presumed to be endogenous calcitriol being released from the skin. 
 
The data suggests that the amount measured in the reservoir solution is slightly greater than the 
amount of endogenous calcitriol that may be present (which is being released from the skin into 
the reservoir solution) and does not differentiate the topical formulations. However, no 
endogenous calcitriol was measured in non-dosed chambers for the epidermis, dermis and 
surface wash samples, indicating that the amount that is measured in those compartments from 
the dosed skin sections is from the applied dose. This is further supported by the two 
formulations that contain 3 µg/mL calcitriol versus those with 1 µg/mL concentration. The 
formulations showed a range of approximately 10-20% of drug penetration into the epidermis, 
based on the applied dose, but little to no penetration into the dermis (1% or less of applied 
dose). 
Prototype formulation CAR-03-031 containing API # 31543 (calcitriol) in a vehicle of propylene 
glycol and dehydrated alcohol, 200 proof in a 40/60 ratio (W/W), has been identified as the 
prototype formulation for further development. 
3.4 
Clinical Studies 
One Phase 1 trial of topical topitriol (calcitriol) has been conducted. In this study, patients with 
stage II-IV breast cancer were scheduled to receive cyclophosphamide 500mg/m2, doxorubicin 
50mg/m2, and 5-fluorouracil 500mg/m2 on Day 1 every 21 days. Topical calcitriol was applied to 
the scalp twice a day. The drug was applied by a nurse during the first 5 days of treatment and by 
the patient or a family member thereafter. The cream was rubbed around the entire scalp and was 
maintained without washing for 8 hrs. Three different doses were evaluated: 500 μg per day for 7 


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days prior to chemotherapy, 1000μg per day for 7 days prior to chemotherapy, and 2000μg per 
Day 5 days prior and post-chemotherapy. Treatment was continued until the appearance of grade 
2 alopecia, as graded by the National Cancer Institute Common Terminology Criteria for 
Adverse Events NCI-CTCE. Patients’ serum and urine calcium excretion were monitored. 
Overall, there were 14 patients evaluated in this trial. All of the patients developed grade 2 
alopecia 20-30 days after the first course of chemotherapy. Plasma and urinary calcium levels 
remained within normal limits during the study period. All patients treated with the first dose 
level, 4 out of 6 treated with 1000μg per day, and 2 out of 4 patients treated with 2000μg per day 
developed mild pruritic maculopapular dermatitis on the scalp and surrounding skin exposed to 
topical topitriol.24 
One of the drawbacks of this pilot Phase 1 trial may be the inadequate dosing schedule, because 
topical application of the cream was only performed 1 week prior to chemotherapy 
administration. It is possible that the treatment duration was not sufficient to induce catagen 
stage in scalp hair follicles that subsequently made them more susceptible to cytotoxicity of 
chemotherapy. To compensate for this potential deficiency, in our trial topical calcitriol will be 
applied starting 2 weeks prior to the initiation of chemotherapy in an attempt to induce catagen 
stage that is anticipated to render protection against CIA. Patients unable or unwilling to wait the 
2 week pre-treatment period may elect to pre-treat for 7 days ± 2 days. Continued application on 
the daily basis will ensure the maintenance of catagen stage and extended protection throughout 
administration of multiple doses of a taxane-containing regimen.  
Additionally, the previously conducted Phase 1 trial used a water-based formula that was 
originally intended for use in psoriasis. The drug delivery mechanisms are likely to vary 
significantly between the scalp epidermis and hyperproliferative psoriasis plaques, which may 
explain higher penetration and increased incidence of maculopapular dermatitis. Secondly, 
higher doses utilized in the previous Phase 1 trial may have been also responsible for the high 
incidence of contact dermatitis in the majority of treated patients. The formulation of topical 
compound31543 (calcitriol) that will be employed in this proposed trial is an anhydrous alcohol 
and glycol based formulation with penetration characteristics that favors epidermal exposure of 
the active ingredient.  
Another trial investigated the potential of a topical Vitamin D analogue, calcipotriol, in 
preventing chemotherapy-induced alopecia. Patients with breast cancer undergoing therapy with 
cyclophosphamide 600mg/m2, methotrexate 40mg/m2, and 5-fluorouracil 600mg/m2 given on 
Days 1 and 8 in a 4-weekly cycle were randomized to receive either topical calcipotriol scalp 
solution 50 μg/mL or a vehicle. The solution was applied twice daily from 4 days prior to 
chemotherapy and continued for 14 days in each treatment cycle. However, there was no 
detectable effect of topical calcipotriol on the proportion of patients that experienced hair loss, 
hair shedding rates, and hair regrowth of hair density.25 
The lack of interference of calcitriol with the efficacy of chemotherapy and the ability to 
potentiate its cytotoxic effects, previously demonstrated in in vitro and in vivo animal models, 
has also been demonstrated by several clinical trials. This was demonstrated by a Phase 2 
randomized controlled trial of patients with advanced androgen-independent prostate cancer who 
received weekly docetaxel with DN-101(high-dose calcitriol, 45 μg) versus placebo. The primary 
objective of this study was to evaluate the proportion of patients achieving PSA response (≥ 50% 
PSA reduction, confirmed at least 4weeks later) in the two treatment arms. DN-101 (45μg) or 
placebo was administered orally on Day 1 followed by docetaxel 36mg/m2intravenously on Day2 


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along with dexamethasone (4mgorally 12 hrs before, 1 hr before, and 12 hrs after docetaxel 
administration).This regimen was administered weekly for 3 consecutive weeks of a 4-week 
cycle. For each patient, the ﬁrst dose of docetaxel (Week 1, Cycle 1 only) was attenuated (27 
mg/m2) to collect additional safety data for the combination of DN-101 with docetaxel. Two 
hundred-ﬁfty patients were randomly assigned (125 patients in each arm). PSA decline 
(≥50%conﬁrmed 4weeks later) within 6 months of enrollment was reached in 49% of placebo 
treated patients and 58%of DN-101-treated patients (P=0.16). At anytime while on study, this 
end point was achieved in 52% of placebo treated patients and 63% of DN-101-treated patients 
(P=0.07). Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST 
Version 1.0)was present in 59 of placebo-treated patients (47%) and 48 of DN-101 treated 
patients (38%). Tumor response was seen in 14 (24%) and 14 (29%) of placebo and DN-101-
treated patients, respectively (P=0.51). Overall survival showed a promising improvement in the 
DN-101 group over the placebogroup withaHRof 0.67 (95%CI, 0.45 to 0.97;P=0.04).The 
addition of calcitriol was associated with a reduction in the risk of death by approximately one 
third.26 Overall, no increase in toxicity was seen with the addition of DN-101 to docetaxel. 
Toxicities that might be expected with administration of supraphysiologic doses of calcitriol 
were uncommon with weekly administration ofDN-101 except for mild hypercalcemia. Six 
percent of placebo-treated patients and 7% of DN-101-treated patients had grade 1 to 2 creatinine 
elevation, 8% of placebo-treated patients and 33%of DN-101-treated patients had transient 
hypercalcemia. All the hypercalcemia episodes observed in theDN-101 arm were grade 1 and 
required no intervention, and did not result in dose reduction or delay in therapy. No patients on 
placebo and one patient on DN-101 experienced symptomatic renal calculi. Interestingly, the 
incidence of any grade 3 or 4 adverse events was 70% in placebo treated patients and 58% in 
DN-101 treated patients (P=0.065). Adverse effects leading to discontinuation of therapy were 
seen in 28% of placebo-treated patients and 22% of DN-101-treatedpatients. Serious adverse 
events, generally those requiring hospitalization, were observed in 41% of placebo-treated 
patients and 27% of DN-101-treated patients (P=0.023).26 The incidence of docetaxel-induced 
alopecia was comparable between the two arms. The incidence of all-grade alopecia was 41% 
and 45% in the docetaxel plus placebo arm and DN-101 plus docetaxel arm, respectively.26 
In contrast, the follow-up randomized Phase 3 trial of high-dose calcitriol in combination with 
weekly docetaxel as compared with placebo in combination with docetaxel administered every 
three weeks, showed that treatment with calcitriol was associated with significantly shorter 
survival.953 men with castration resistant prostate cancer were randomized to 45 µg DN-101, 36 
mg/m2docetaxel, and 24 mg dexamethasoneweekly (ASCENT arm, 477 patients) for 3 out of 
every 4 weeks or control arm (476 patients, 5 mg prednisone twice a day, and 75 
mg/m2docetaxel and 24 mg dexamethasone every 3 weeks). The primary endpoint was overall 
survival. At an interim analysis, more deaths were observed in the ASCENT arm, and the trial 
was halted early. Median overall survival was 16.8 months (95% CI, 15.8-19.3) for ASCENT 
subjects and 19.9 months (95% CI, 18.6-22.7) for controls. In multivariate analysis adjusting for 
baseline variables, ASCENT was associated with shorter survival (HR=1.33; p=0.019). The 
proportions of patients with adverse events (AEs) were similar, and consistent with the known 
side effects of docetaxel. Dose modification for docetaxel toxicity was more frequent in the 
ASCENT arm (229 ASCENT vs. 160 control subjects).The shorter survival in the ASCENT arm 
was potentially attributed to inferior efficacy of weekly docetaxel administration as compared to 
docetaxel administered every three weeks.27 
 


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14 patients have been enrolled in this current study, CTL0211 (2 patients were enrolled but did 
not receive study drug, therefore 12 patients have been treated with study drug.)  No DLT have 
been observed.  Amendment 8 will add additional patients to be enrolled at increasing dose 
levels to determine the MTD.   
 
 


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4 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a multi-center, single arm, dose-escalation Phase 1 study. Eligible patients will begin 
applying the topical formulation of Compound 31543 to the scalp twice daily 2 weeks prior to 
the first dose of chemotherapy and continue the application twice daily until termination of 
chemotherapy treatment. Patients unable or unwilling to wait the 2 week pre-treatment period 
may elect to pre-treat for 7 days ± 2 days. Dose escalation will occur in stepwise increments of 
the immediate prior dose group, in the absence of grade 3 or greater toxicities attributed to the 
topical calcitriol, in order to determine the MTD for this agent. Dose-limiting toxicity (DLT) will 
need to possibly, probably or definitely (defined in Section 8.4) be related to topical calcitriol 
and not taxane-based regimen as best determined by participating investigators. Similarly, 
appropriate dose modifications or treatment interruption of the chemotherapeutic regimen will be 
instituted according to the current standard of care. Determination of DLTs of the topical 
calcitriol formulation will be made during the first 28 days of topical agent application. Subjects 
will be managed with adequate safety monitoring and pharmacokinetic (PK) analysis in order to 
determine levels of exposure. PK analysis will be done before each new cohort moves forward. 
For the purpose of PK studies, blood samples will be collected on Day 1 of topical treatment at 
the following time points: pre-dose, at 2 hrs (± 30 minutes), 4 hrs (± 30 minutes), and 8 hrs (±1 
hr post-dose) after a single application on the morning of Day 1. The second application of drug 
product will be applied 10-14 hrs after the initial application and after the 8 hr PK sample. 
Thereafter, topical application frequency will be twice daily, morning and night. Subsequently, a 
PK sample will be taken 12 hrs (±2 hrs) after the last dose of each 28-day treatment, before the 
first application of Day 1 of the next 28-day treatment cycle. This schedule will continue for 
three consecutive 28-day topical treatment cycles (PKs will be drawn at Weeks 1, 5, 9, 13. In 
addition, if patients are still on study, a PK will also be drawn at Week 54). 
4.2 
Intervention 
Patients with a diagnosis of early stage or locally advanced, unresectable and/or metastatic 
cancer, or patients with operable cancer, who are scheduled to receive follow up treatment with a 
taxane-based chemotherapy regimen (either pre-operatively or post-operatively), as per 
physician’s discretion will be screened for eligibility to participate. All eligible patients will start 
applying 0.25mL of Compound 31543 (Calcitriol, USP) to each of the four quadrants of the 
scalp(front right, front left, back right, andback left) with the metered pump spray unit twice a 
day 2 weeks prior to chemotherapy and subsequently continue twice-daily until termination of 
chemotherapy. Patients unable or unwilling to wait the 2-week pre-treatment period may elect to 
pre-treat for 7 days ± 2 days. If topical calcitriol is found to be effective in preventing and/or 
diminishing the taxane-based chemotherapy-induced alopecia, as determined by photographic 
assessments and patient self-report, patients will be allowed to continue twice-daily topical 
application for the duration of their chemotherapy treatment, assuming no DLTs related to the 
topical agent are observed. Patients who elect to shave their hair prior to or during chemotherapy 
treatment will be excluded from the trial. The topical solution will be applied to the scalp. Hair 
and scalp should be dry or, if application is immediately after shampooing, the hair and scalp 
should be damp, not wet, to the touch by first towel drying the hair and scalp before application 
of the topical solution. The hair and scalp will not be washed or shampooed for at least 8 hrs 
after each application. Patients will be advised that that they may apply no more than two 
consecutive doses of Compound 31543 (calcitriol USP) before washing or shampooing. 


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Treatment induces catagen phase of hair cycling which will last 2-3 weeks after last application. 
Application of the drug will ensure this catagen phase protection through multiple 
chemotherapeutic treatments. 
 


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5 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Investigational Product 
Berg C31543 (Calcitriol, USP) Topical Solution 
Chemical Name:(5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol  
IUPAC Name: (1α,3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol  
Alternate Names: Calcitriol is also known as: 1α,25-dihydroxycholecalciferol, 1α,25-
dihydroxyvitamin D3, 1(S),25-dihydroxyvitamin D3, 1,25-DHCC, 1,25-(OH)2D3  
Route of Administration: Topical 
Availability: C31543 (Calcitriol, USP) Topical Solution is an investigational agent supplied by 
Berg. 
Clinical Trial Formulation: The clinical trial formulation for Berg C31543 (Calcitriol) Topical 
Solution contains calcitriol, USP in a vehicle of Propylene Glycol, USP and Anhydrous 200 
proof, UndenaturedAlcohol, USP at a ratio of 40:60 by weight propylene glycol/alcohol. The 
concentration ofCalcitriol in the topical solution vehicle for human studies has been determined 
based on the completion of the nonclinical toxicology. The Phase 1 study will utilize C31543, 
withCalcitriol at concentrations of 5, 10 and 20 μg/mL (dose levels complete without DLT), 40, 
60 and 80 μg/mL (additional dosing levels to be evaluated in this amendment).  
Packaging: The Phase 1 clinical drug product is packaged in a 33 mL Type III amber glass bottle 
fitted with a black phenolic screw cap. The drug product will also include a separately packaged 
metered dose dispensing applicator system capable of uniformly dispensing 0.25 mL per 
applicator compression. The total dosage of drug product is intended to be 1.0 mL, or four repeat 
metered unit applications. The application of a total of 1.0mL of drug product will be twice 
daily, morning and night, 10-14 hours between applications. 
Prior to dispensing the drug product to the subjects, the screw cap should be removed and the 
metered dose dispensing applicator will be inserted into the bottle and secured. The bottle and 
the attached applicator should be weighed at this time. The site should document this initial 
weight in the drug accountability records. 
Patients will be supplied with 1-2 amber glass bottles of C31543 Topical Solution containing 
approximately 31.5 mL of drug product of topical solution sufficient to dispense 28 mL of drug 
product (0.25 mL x 4 applications x 2 times/day x 14 days=28 mL). The glass bottle unit will be 
properly labeled with use instructions, use warnings, and a place for patient ID which will be 
assigned by the clinical site. Patients will be provided an application log with instructions on 
how to apply C31543 and record the date and time of each application. Research staff will 
monitor compliance by requesting patients bring their used glass bottle, application log, 
medication application diary, and self-assessment diary at each visit. Research staff will review 
the bottles and application log to ensure compliance of topical treatment administration and 
document oversight by recording their comments, initials and date of each review. The used 
bottles will also be weighed upon return to the pharmacy. The return weight should be 
documented in the drug accountability records. The initial and final weights will be used as a 
tool to assess compliance. Any evidence suggesting non-compliance should be submitted to Berg 
immediately and confirmed with the patient. 


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Patients will be instructed to dispense drug product by depressing the pump three times to prime 
the pump and then spraying 0.25mL of drug product four separate times to each quadrant of the 
scalp followed by massaging the scalp to ensure even distribution of the product. This dosing 
regimen will be repeated twice daily, morning and night, for 14 consecutive days (or 7 days ± 2 
days) prior to initiation of chemotherapy and subsequently twice on a daily basis.  
 
Clinical drug product supplies will be stored upright at controlled room temperature (20-25 ºC) 
and protected from light and heat. 
Storage:Described inTable 2. 
Table 2:  Stability Storage Conditions for Clinical Phase 1 
Storage Conditions: 
20 -25 ºC, protect from heat and light 
Storage Position: 
Upright  
Strengths: 
5 μg/mL*, 10 μg/mL*, 20 μg/mL*, 40 μg/mL, 60 μg/mL 80 
μg/mL 
Intended Dose 
5 μg/mL* – 1.25 μg per actuation 
10 μg /mL* – 2.5 μg per actuation 
20 μg /mL* – 5 μg per actuation 
40 μg /mL – 10μg per actuation 
60 μg/mL – 15 μg per actuation  
80 μg /mL – 20μg per actuation 
 
*Dose level complete without DLT 
Phase 1 Dosing Rationale: The NOAEL (no-‐observed -‐adverse -‐effect -‐level) in the non--
‐clinical animal studies was 10.31 µg/mL. To compare the animal and human doses of C31543, 
a margin of safety (MOS) was calculated using the NOAEL dose in the 4-‐week minipig study 
and the initial dose in the Phase 1 clinical trial. In minipigs, the NOAEL, 10.31 µg/mL is 
equivalent to a dose of 3.33 µg/kg (10.31 µg/mL x 2.1 mL (dose volume) x 2X/day ÷ 13 kg 
[average weight of minipigs in Week 4]).  In humans, the starting dose was 5 µg/mL x 1 mL 
2X/day ÷ 60kg=0.166). Based on these doses, the MOS was 20 which was an adequate margin 
over the initial clinical dose (5µg/ml). The daily dose for 40 µg/ml x 1mL BID is 1.33 µg/kg, at 
60 µg/ml x 1ml BID the daily dose is 2.00 µg/kg, and at 80 µg/ml x 1mL BID 2.67 µg/kg, all 
below the calculated NOAEL of 3.33 µg/kg. 


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6 
CRITERIA FOR SUBJECT ELIGIBILITY 
The study will be conducted in patients with a diagnosis of early stage or locally advanced, 
unresectable and/or metastatic cancer, or patients with operable cancer, who are scheduled to 
receive follow up treatment with a taxane-based chemotherapy regimen (either pre-operatively or 
post-operatively),, as per physician’s discretion. 
6.1 
Subject Inclusion Criteria 
1. Adult patients at least 18 years of age 
2. Able to fully understand and participate in the informed consent process 
3. Patients who are scheduled to receive a taxane-based regimen  for a histologically 
confirmed solid tumor that is: 
a.    Early stage and/or treatment naïve, or 
b.    Relapsed or is refractory to previous therapy, or 
c.    Operable and necessitates adjuvant or neo-adjuvant treatment 
4. Have no evidence of alopecia or mild alopecia (NCI CTCAE Grade 1 alopecia defined as 
hair loss of <50% of normal for that individual that is not obvious from a distance but 
only on close inspection; a different hair style may be required to cover the hair loss but 
it does not require a wig or hair piece to camouflage.)Female/male-pattern baldness or 
age-related hair loss are allowed if not greater than Grade 1, per NCI-CTCAE v4.0. 
Subjects that have previously lost their hair may enroll if they currently have Grade 0 or 1 
alopecia 
5. ECOG Performance Score of 0 or 1 within 14 days prior to registration 
6. Has baseline neutrophil counts of > 1500 cells/mm3 within 72 hrs prior to registration 
7. Has serum calcium < ULN (for patients with an albumin lower than 3.0, a corrected 
calcium serum calcium = serum calcium +[0.8][3.5- serum albumin]) within 72 hrs prior 
to registration. 
6.2 
Subject Exclusion Criteria 
1. Patients receiving calcium-lowering therapy or drugs that may affect calcium levels (eg, 
calcitonin, mithramycin, phosphate, denosumab) within 4 weeks of initiation of topical 
calcitriol. Patients who have been managed with bisphosphonates or calcium-lowering 
therapy for 3 months or greater prior to the start of the trial and have demonstrated 
evidence for stability of calcium metabolism would be considered eligible for 
participation in the trial. 
2. Has a history of drug or alcohol abuse within 1 year of study enrollment as determined by 
the investigator. 
3. Patients who elect to shave the scalp hair prior to the initiation of chemotherapy or who 
plan to do so during the chemotherapy treatment.  
4. Any dermatological condition that in the opinion of the investigator will affect the 
absorption of the study medication, eg, Atopic Dermatitis, etc.  
5. Has been treated with an investigational agent within 30 days or six half-lives of its 
biologic activity whichever is shorter, before the start of study drug. (Patients may not be 
concurrently treated with another investigational agent). 


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6. Patients with a history of hypercalcemia or Vitamin D toxicity, or hospitalization for 
treatment of angina, myocardial infarction, or congestive heart failure or psychiatric 
illness currently or within 30 days of study entry as determined by the investigator.  
7. Has a history of significant allergy to calcitriol as determined by the investigator.  
8. Has any condition that interferes with the ability of the subject to understand or comply 
with the requirements of the study.  
9. Patients taking Vitamin D supplements during the study, unless they have been taking 
Vitamin D supplements for 30 days or more prior to the start of the study and that the 
dose of the Vitamin D supplement remain the same throughout the study. 
10. Patients treated with medications that are known to affect calcium levels within 4 weeks 
of initiation of topical therapy (>500 IU Vitamin A, calcium supplements, fluoride, 
antiepileptics), With the exception of subjects on stable therapy for more than six months. 
11. Patients with hypercalcemia or kidney stones 
12. Patients that indicate they have significant hair breakage or hair damage and associated 
hair loss from hair over processing within the last 30 days due to peroxide applications, 
permanent hair coloring, bleaches, streaking, perms, relaxers and/or hair oxidative dyes.  
13. Current alopecia Grade 2 or greater as per NCI-CTCAE v4.0, or significant hair loss or 
hair breakage. 
14. Prior radiation to the cranium. 
15. Pregnant or breastfeeding. 


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7 
PRETREATMENT EVALUATION 
The following are required within2 weeks prior the start of calcitriol: 
• 
Complete medical history and physical exam, including concomitant medication 
• 
CBC with differential, comprehensive chemistry panel, serum phosphorus level, and 
urinalysis 
• 
Serum 1, 25 dihydroxy Vit D 
• 
Pregnancy test 
o 
Pregnancy tests outlined here are for women of childbearing potential (WCBP) only. 
Please exclude all women that do not meet the criteria for WCBP and meet the 
criteria for women not of childbearing potential. 
Women of Child-Bearing Potential Defined: 
o 
Any female who has experienced menarche and does not meet the criteria for 
“Women Not of Childbearing Potential” 
Women Not of Childbearing Potential Defined: 
o 
Women who are permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) 
o 
Women who are >45 years of age, not using hormone replacement therapy and who 
have experienced total cessation of menses for at least 1 year OR who have a follicle 
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40pg/mL 
(140 pmol/L) 
o 
Women who are >45 years of age, using hormone replacement therapy and who 
have experienced total cessation of menses for at least 1 year OR who have had 
documented evidence of menopause based on FSH >40 mIU/mL and estradiol <40 
pg/mL prior to initiation of hormone replacement therapy) 
• 
Photographic record of hair and scalp prior to chemotherapy (will serve as the baseline 
assessment for the study) 
• 
Patient self-assessment of hair condition 


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8 
TREATMENT/INTERVENTION PLAN 
Eligible patients will be instructed to apply 0.25mL of topical calcitriol to each of the four 
quadrants of the scalp - front right, front left, back right, back left with the provided metered 
pump spray unit twice a day 2 weeks prior to the start of chemotherapy treatment. Patients 
unable or unwilling to wait the 2-week pre-treatment period may elect to pre-treat for 7 days ± 2 
days. Subsequently, application will continue twice daily for three months or until termination of 
chemotherapy. The topical solution will be applied to the scalp. Hair and scalp should be dry or, 
if application is immediately after shampooing, the hair and scalp should be damp, not wet, to 
the touch by first towel drying the hair and scalp before application of the topical solution. The 
scalp will not be washed or shampooed for at least 8 hrs after each application. Patients will be 
advised that that they may apply no more than two consecutive of Compound 31543 (Calcitriol, 
USP) before washing or shampooing. Meaning, they must wash their hair after every other 
application of Compound 31543.Patients will self-administer the topical solution throughout the 
study; except for first dose, in which case application of topical calcitriol will be done by the 
study personnel. On days when pharmacokinetic studies will be performed, patients will self-
administer the topical solution after the pharmacokinetics have been drawn. 
8.1 
Taxane-Based Chemotherapy Administration 
All patients should be pre-medicated prior to administration of the chemotherapeutic agents in 
order to prevent severe hypersensitivity reactions, per institutional guidelines. The taxane 
regimen chosen is at the treating physician’s discretion and should be standard for the patient’s 
cancer type. The taxane regimen chosen should not change significantly while on study and 
receiving C31543 although dose reductions are allowed for toxicities related to chemotherapy. 
8.2 
Dose Escalation 
Patients will be treated with the topical Compound 31543 (Calcitriol, USP) in cohorts of size 
three to six starting at dose level 1 (5 μg/mL). The dosage will be escalated if the clinical toxicity 
is declared acceptable (see below). Two dose levels were considered for escalation (10 and 20 
μg/mL).  These dose levels were completed without DLT.  Amendment 8 will add additional 
dosing levels until MTD is achieved (40, 60, 80, μg/mL.)Determination of dose limiting toxicity 
(DLT, defined in Section 8.4) will be made during the first 28 days of topical treatment. No 
intra-patient dose escalation will be performed. DLT will need to possibly, probably or definitely 
(defined in Section 8.4) be related to topical calcitriol and not the chemotherapeutic regimen as 
best determined by participating investigators. The dose escalation scheme (Table 3) will occur 
as follows: 
One 28-day cycle of treatment will be performed and evaluation of PK Data will occur before 
escalation to the next dose level. 
If none of the initial three patients in a cohort experience dose limiting toxicity (DLT), then a 
new cohort of three patients will be treated at the next higher dose level. 
If one of the three patients in a cohort experiences DLT, then up to three additional patients will 
be treated at the same dose level. Escalation will continue if a maximum of one of the six 
patients experiences DLT. 


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If two or more patients in a cohort experience DLT, then the maximum tolerated dose (MTD) 
will have been exceeded, and no further dose escalation will occur. The previous dose level will 
be considered as the MTD.  
If only three patients were treated at a dose level under consideration as the MTD, then up to 
three additional patients will be accrued to that dose level. If no more than one of six patients at 
that dose level experience a DLT, then that dose level will be confirmed as the MTD.If two or 
more patients in that cohort experience DLT, then the previous dose level will be studied in the 
same fashion. 
The MTD is defined as the dose level at which 0/3 or 1/6 subjects experiences DLT during the 
first 28-days treatment cycle below the dose at which 2/3 or 2/6 subjects experienced DLT. Thus, 
the MTD will have been exceeded when >30% (2/3 or 2/6) of subjects at any dose level develop 
DLT. If the MTD is not established after completing three cohorts of escalating doses, the study 
Sponsor will review the study findings with FDA Division of Dermatology to seek guidance as 
to amending the study protocol to add additional dose-escalating cohorts. 
The Cohort Review Committee (CRC), comprised of the Berg medical monitor, Berg CMO and 
SVP of Regulatory Affairs or designee, and the principal investigator(s), will be fully aware of 
clinical and laboratory data, and must agree if dose escalation to the next cohort is appropriate. 
Pharmacokinetic data from each treatment cohort will also be reviewed by the CRC and 
considered in any decision to dose-escalate. Adverse event data from the treatment extension 
period will be presented, when available (at least monthly), to the CRC. These data will be 
considered for dose escalation decisions. In the event that MTD has not been reached after three 
cohorts have been treated, any further dose escalations will require a protocol amendment.  
The CRC will review all available data from previous cohorts to assure that the actual dose 
escalation determined in this fashion does not expose subjects to unreasonable risk. The CRC 
may reduce or halt dose escalations for any reason (eg, observation of non-linear PK, AEs in 
subjects who receive more than one dose of C31543 Topical Solution). The decision to proceed 
with the next cohort will require unanimous agreement of the members of the CRC. 
The nonclinical toxicology has been reviewed and the Cohort 1 drug concentration established 
by Berg, LLC and the FDA is approximately 1/20 or less of the expected MTD based on the 
nonclinical studies. As there is no presupposed risk of dose limiting toxicities at the Cohort 1 
dosing detailed in the Phase 1 protocol, it has been determined that there will be no minus 1 
dosing cohort. If two or more of the initial patients experience unacceptable toxicities at the 
initial Calcitriol dose, the CRC will review all available data and may elect to discontinue the 
study. 
 
 


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Table 3: 
Dose Escalation 
Number of Subjects per Cohort with DLT 
during Treatment Period 
Dose Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next dose level 
1 out of 3 
Enter at least 3 more subjects at this dose level. 
If none of the 3 additional subjects has DLT, proceed to the next 
dose level. 
If 1 or more of the 3 additional subjects has DLT, then dose 
escalation is stopped, and this dose is declared the maximum 
administered dose (MAD). Three additional subjects will be 
entered at the next lowest dose level if only 3 subjects were 
treated previously at that dose. 
2 out of 6 
Dose escalation will be stopped. This dose level will be declared 
the MAD (highest dose administered). Three additional subjects 
will be entered at the next lowest dose level if only 3 subjects 
were treated previously at that dose. 
1 out of 6 at highest dose level below the 
maximally administered dose 
This is generally the recommended Phase 2 dose. 
 
8.3 
Pharmacokinetics (All Patients) 
For the purpose of pharmacokinetic (PK) studies, blood samples will be collected on Day 1 of 
topical treatment at the following time points: pre-dose, at 2 hrs (± 30 minutes), 4 hrs (± 30 
minutes), and 8 hrs (± 1 hr post dose) after a single application on the morning of Day 1. The 
second application of drug product will be applied 10-14 hrs after the initial application and after 
the 8 hr PK sample. Thereafter, topical application frequency will be twice daily, morning and 
night. Subsequently, a PK sample will be taken 12 hrs (±2 hrs) after the last dose of each 28-day 
treatment, before the first application of Day 1 of the next 28-day treatment cycle. This schedule 
will continue for three consecutive 28-day topical treatment cycles. (PKs will be drawn at Weeks 
1, 5, 9, 13. In addition if patients are still on study, a PK will also be drawn at Week 54.) Vital 
signs will be obtained approximately 5 minutes before each blood collection, and the actual 
collection times will be recorded. 
At each collection, collect blood by venipuncture in a serum separator tube(s). Centrifuge at 
1200 RCF for 10 ± 5 minutes, and aliquot 1.5 mL of serum each into 2 labeled externally 
threaded cryogenic vials and immediately freeze. Ship frozen samples to Berg Diagnostics. 
Samples collected from each cohort will be shipped frozen on dry ice to Berg Diagnostics for 
analytical determination ofC31543 concentrations in serum. Serum samples will be transported 
with a sufficient amount of dry ice to keep the samples frozen for at least 2 days, and should not 
be shipped to arrive over weekends or holidays. World Courier will provide all shipping 
materials. Please contact World Courier 3 days in advance for pre-filled waybills and to schedule 
pick-up. 
 
 


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Samples will be shipped to: 
Berg Diagnostics 
500 Old Connecticut Path 
Building B, 3rd Floor 
Framingham, MA, 01701 
Attention: Sample Accessioning 
The serum PK of C31543 will be calculated from serum collected from all subjects who receive 
C31543.The following serum PK parameters will be calculated using non-compartmental 
analysis: 
• 
UC0-t:  Area under the concentration — time curve up to the last measurable 
concentration calculated by the trapezoidal rule and expressed in units of concentration 
— time 
• 
AUC0-inf: Area under the serum concentration-time curve from time of dosing to infinity 
calculated by dividing the last quantifiable concentration by Kel and adding the result to 
AUC0-t, expressed in units of concentration-time. 
• 
Cmax:  The observed peak drug concentration obtained directly from the experimental data 
without interpolation, expressed in concentration units 
• 
Tmax:  The observed time to reach peak drug concentration obtained directly from the 
experimental data without interpolation, expressed in time units (hr) 
• 
Kel:  The apparent elimination rate constant, determined by regression analysis of the 
log-linear segment of the serum concentration-time curve, expressed in time-1 units 
(1/hr) 
• 
t1/2:  The terminal half-life, calculated as -ln 2/Kel, expressed in time units(hr) 
• 
CL:  Clearance calculated as the drug dose/AUC0-inf, expressed in units offlow (L/hr) 
• 
Vd:  Volume of distribution calculated as CL divided by Kel and expressed in units of 
volume (L) 
Descriptive statistics (including number, mean, median, standard deviation, and range) for PK 
parameters will be tabulated by dose level. Estimated renal elimination will be tabulated by dose 
level. 
8.4 
Definition of Dose-Limiting Toxicity (DLT) and Treatment Modifications 
Toxicities will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE v4.0). 
8.4.1 
Dose-Limiting Toxicity Related to Calcitriol 
Dose-limiting toxicity is defined as a clinically significant grade 3 or 4 non-hematologic toxicity 
occurring during the first 28-day treatment cycle of the topical agent application, and needs to be 
possibly, probably, definitely related to calcitriol (and not the chemotherapeutic regimen) as best 
determined by investigators.  
Excessive dosage of calcitriol induces hypercalcemia and in some instances hypercalciuria. If the 
patient presents with symptoms of hypercalcemia, serum calcium should be determined and 
treatment should be stopped immediately. Hypercalcemia defined using CTCAE version 4.0 


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grade 3 is serum calcium > 12.5-13.5 mg/dL; > 3.1-3.4 mmol/L or Ionized calcium > 1.6-1.8 
mmol/L, hospitalization is indicated. 
For patients with hypercalcemia determined by elevated serum calcium, if the ionized calcium 
level is in fact elevated, the study drug will be stopped and the patient removed from the study. If 
the ionized calcium level is normal, the patient will remain on the study and ionized calcium will 
be followed rather than serum calcium. If the patient is removed from the study for this reason, 
serum calcium and phosphate levels will be checked with daily blood draws at the testing center 
until they are normal for two consecutive days.  
8.4.2 
Dose-Limiting Toxicity 
If patients develop toxicities related to their chemotherapeutic regimen, the dose reductions will 
be followed per institutional guidelines. During modifications in the chemotherapeutic regimen, 
calcitriol doses will remain stable unless modifications are deemed necessary by the investigator. 


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9 
EVALUATION DURING TREATMENT/INTERVENTION 
9.1 
Clinical 
History and physical examination will be performed as detailed in the table below. Following the 
start of application of topical calcitriol 2 weeks or 7 ± 2 days prior to initiation of chemotherapy, 
patients will be seen by an investigator for interim medical history, concomitant medication, 
physical exam including weight, vital signs (blood pressure, temperature, respiration rate, heart 
rate), and adverse events at Weeks 1, 2, 3, 5, 7, 11, 15, 27, and 54.  
9.2 
Laboratory 
Laboratory evaluation will be performed as described in Table 4and Table 5below.  
9.3 
Dermatology Evaluation. 
The subjects will be seen by a dermatologist during Weeks 2 and 7 as detailed in the tables 
below (Table 5 and Table 6). This review will include the following:  
• 
A visual inspection of the scalp (oiliness/ dryness, erythema, inflammation, scaling, 
papules, pustules, erosions, pustules, excoriations, rash; including perifollicular changes) 
• 
Palpation of the scalp 
• 
Examination of hair (quantity/ length, density, color, texture, hair pull test, hair shaft, 
morphology, distribution) including eyelashes/eyebrows 
• 
Interval dermatologic history: issues with use of agent (skin, hair etc.) 
Any abnormalities will be documented in the medical record along with any problems reported 
by the patient with use of calcitriol (itchiness, stinging, irritation, burning, hair loss). All 
abnormalities and problems will be reviewed by the investigator to determine if they meet the 
criteria for adverse events.  
9.4 
Photographic Record of Hair and Scalp 
Alopecia is defined as any hair loss. In this study centralized photographic review by a single 
dermatologist will be conducted using the Canfield Clinical Photography assessment images that 
will be acquired by the research staff to ensure standardization and uniformity among all enrolled 
patients. Please refer to the Canfield User Manual and Quick Reference Guide for instructions 
detailing the use of the Canfield equipment provided to photographically record the hair and 
scalp. These documents outline how to prepare the subjects, complete and use the ID card and ID 
card holders, photograph and upload the photos onto the Canfield portal.  
The following five views will be obtained at each photographic assessment: bilateral sides of 
head/scalp view, front of head/face view, back of head/scalp view, and top of head/scalp view. 
Additionally, close-up photographs will be taken at the same times points. They will include the 
mid-pattern of the scalp from a superior view and a vertex view with hair parted in the center and 
combed away from the center part. Photographs will be standardized for lighting, camera angle, 
and position to the participants head. 
Centralized photographic review will be conducted by one dermatologist reviewer and 
photographs will be evaluated using a 7-point evaluation scale for hair volume (Table 9-1).The 
reviewer will compare the photographs acquired at baseline, Week 7 and Week 15. Comparisons 


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may be made to Week 27 and Week 54, if applicable. The dermatologist reviewer scoring the 
photographs will be blinded to time sequence of the photographs aside from the baseline 
photographs to which all others will be compared. 
Table 4: 
Evaluation Scale for Photographic Review of Hair Loss/Gain 
7-point scale 
Increase/decrease 
% of Hair Gain/Loss 
-3 
Greatly decreased 
> 75% hair loss 
-2 
Moderately decreased 
50-75% hair loss 
-1 
Slightly decreased 
25-49% hair loss 
0 
No change 
0-24% hair loss/gain 
1 
Slightly increased 
25-49% hair gain 
2 
Moderately increased 
50-75% hair gain 
3 
Greatly increased 
> 75% hair gain 
 
9.5 
Subjective Record of Hair and Scalp 
Alopecia will also be subjectively recorded through the patient self-reported diaries. All patients 
are asked to complete this self-assessment diary weekly that will require assessment of hair 
thickness, hair fullness, hair breakage, and hair cosmetic qualities (ease of styling, etc.) on an 
analog 10 point scale throughout treatment to assess patient-reported efficacy of the study drug. 
These will be completed weekly and returned to the research staff at every visit during C31543 
treatment. The study is expected to take place over a period of approximately 12 months, 
including the screening period. 


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Table 5: 
Study Evaluation Schedule Part A – The Basic Information 
(All study assessments will be performed ± 72 hrs from the scheduled date unless otherwise noted.) 
14-Day Pre-treatment Schedule: 
Basic Information 
Chemo 
Week 
Sign 
Informed 
Consent 
Demo-
graphics MedicalHistory 
Concomitant 
Meds 
Physical 
Examination 
Urinalysis and 
Pregnancy 
Test 
Weight 
Vital 
Signs 
Adverse 
Events 
Evaluation 
Pre-study 
– 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Week 1 
(topical application 
prior to chemo) 
– 
 
 
* 
* 
* 
 
* 
* 
* 
Week 2 †† 
(topical application 
prior to chemo) 
– 
 
 
* 
* 
* 
 
* 
* 
* 
Week 3 
(start of chemo) 
1 
 
 
* 
* 
* 
 
* 
* 
* 
Week 4 
2 
 
 
 
 
 
 
 
 
 
Week 5 
3 
 
 
* 
* 
* 
 
* 
* 
* 
Week 6†††† 
4 
 
 
 
 
 
 
 
 
 
Week 7 †† 
5 
 
 
* 
* 
* 
 
* 
* 
* 
Week 8 
6 
 
 
 
 
 
 
 
 
 
Week 9 
7 
 
 
 
 
 
 
 
 
 
Week 10†††† 
8 
 
 
 
 
 
 
 
 
 
Week 11  
9 
 
 
* 
* 
* 
 
* 
* 
* 
Week12  
10 
 
 
 
 
 
 
 
 
 
Week 13 
11 
 
 
 
 
 
 
 
 
 
Week 14†††† 
12 
 
 
 
 
 
 
 
 
 
Week 15 
13 
 
 
* 
* 
* 
 
* 
* 
* 
Week 27††††††† 
 
 
 
* 
* 
* 
 
* 
* 
* 
Week 54††††††† 
 
 
 
* 
* 
* 
 
* 
* 
* 
 


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7-Day Pre-treatment Schedule: 
Basic Information 
Chemo 
Week 
Sign 
Informed 
Consent 
Demo-
graphics MedicalHistory 
Concomitant 
Meds 
Physical 
Examination 
Urinalysis and 
Pregnancy 
Ttest 
Weight 
Vital 
Signs 
Adverse 
Events 
Evaluation 
Pre-study 
– 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Week 1 
(topical application 
prior to chemo) 
– 
 
 
* 
* 
* 
 
* 
* 
* 
Week 2†† 
(start of chemo) 
1 
 
 
* 
* 
* 
 
* 
* 
* 
Week 3 
2 
 
 
 
 
 
 
 
 
 
Week 4 
3 
 
 
 
 
 
 
 
 
 
Week 5†††† 
4 
 
 
* 
* 
* 
 
* 
* 
* 
Week 6 
5 
 
 
 
 
 
 
 
 
 
Week 7†† 
6 
 
 
* 
* 
* 
 
* 
* 
* 
Week 8 
7 
 
 
 
 
 
 
 
 
 
Week 9†††† 
8 
 
 
 
 
 
 
 
 
 
Week 10  
9 
 
 
 
 
 
 
 
 
 
Week 11  
10 
 
 
* 
* 
* 
 
* 
* 
* 
Week 12 
11 
 
 
 
 
 
 
 
 
 
Week 13†††† 
12 
 
 
 
 
 
 
 
 
 
Week 14 
13 
 
 
 
 
 
 
 
 
 
Week 15 
14 
 
 
* 
* 
* 
 
* 
* 
* 
Week 27††††††† 
 
 
 
* 
* 
* 
 
* 
* 
* 
Week 54††††††† 
 
 
 
* 
* 
* 
 
* 
* 
* 


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† PK will be collected in the following manner: On Day 1 of topical treatment: PK will be collected pre-dose (before the first dose), and 2 hrs (± 30 minutes), 4 hrs (± 30 minutes) 
& 8 hrs (± 1 hr post-dose).  
For study Weeks 5, 9, 13, and 54 of calcitriol, PK will be collected on Day 1 pre-dose. This should be 12 hrs (±2 hrs) after the last application of topical calcitriol. 
†† For the Weeks 2 and 7 visits, patients will be seen by a study Dermatologist at their site. 
††† All patients will be asked to maintain the self-assessment diary for up to approximately 7 months from initial application of study drug. The diary will be filled out weekly for 
the first 15 weeks after initiating calcitriol and at Weeks 19, 23, and 27. 
†††† Note that some patients may be placed on a 3-week-on one-week-off regimen. The indicated weeks will be off-chemo weeks. 
††††† Photographs for patients in each cohort representing baseline, and treatment Weeks 7 and 15 will be presented blind to the study PI after at least 3 patients have completed 
15 weeks of treatment. Photographs will also be taken at Week 27 and Week 54 of the study but will be included in the final photographic assessment as secondary 
information. The PI clinical assessment of the baseline, and Weeks 7 and 15 photographs will be used, together with the patient self-assessment diary information, for the 
primary assessment of alopecia. 
†††††† A patient self-assessment is required this week if treatment continues beyond Week 15. 
††††††† Study assessments will be performed ± 7 days from the scheduled date. 
 
 
 


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Table 6: 
Study Evaluation Schedule Part B – The Tests and the Study Drug Application 
14-Day Pre-treatment Schedule: 
Tests and Study Drug 
Application 
Chemo 
Week 
PK blood 
samples† 
Application of 
C31543 
(Calcitriol) 
CBC 
with 
diff 
Comprehensive 
chemistry panel 
Photographic 
record of hair and 
scalp 
Serumphosphorus 
and Vitamin D 
Patient self-
assessment diary 
††† 
Pre-study 
– 
 
 
* 
* 
* 
* 
* 
Week 1 
(topical application 
prior to chemo) 
– 
* 
* 
* 
* 
 
* 
* 
Week 2 †† 
(topical application 
prior to chemo) 
– 
 
* 
 
 
 
 
* 
Week 3 
(start of chemo) 
1 
 
* 
* 
* 
 
* 
* 
Week 4 
2 
 
* 
 
 
 
 
* 
Week 5 
3 
* 
* 
* 
* 
 
* 
* 
Week 6†††† 
4 
 
* 
 
 
 
 
* 
Week 7†† 
5 
 
* 
* 
* 
* 
* 
* 
Week 8 
6 
 
* 
 
 
 
 
* 
Week 9 
7 
* 
* 
 
 
 
 
* 
Week 10†††† 
8 
 
* 
 
 
 
 
* 
Week 11  
9 
 
* 
* 
* 
 
* 
* 
Week12  
10 
 
* 
 
 
 
 
* 
Week 13 
11 
* 
* 
 
 
 
 
* 
Week 14†††† 
12 
 
* 
 
 
 
 
* 
Week 15††††† 
13 
 
* 
* 
* 
* 
* 
* 
Week 19†††††† 
 
 
 
 
 
 
 
* 
Week 23†††††† 
 
 
 
 
 
 
 
* 
Week 27††††††† 
 
 
* 
* 
* 
* 
* 
* 
Week 54††††††† 
 
* 
* 
* 
* 
* 
* 
 


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7-Day Pre-treatment Schedule: 
Tests and Study Drug 
Application 
Chemo 
Week 
PK blood 
samples† 
Application of 
C31543 
(Calcitriol) 
CBC 
with 
diff 
Comprehensive 
chemistry panel 
Photographic 
record of hair and 
scalp 
Serumphosphorus 
and Vitamin D 
Patient self-
assessment diary 
††† 
Pre-study 
– 
 
 
* 
* 
* 
* 
* 
Week 1 
(topical application 
prior to chemo) 
– 
* 
* 
* 
* 
 
* 
* 
Week 2†† 
(start of chemo) 
1 
 
* 
* 
* 
 
* 
* 
Week 3 
2 
 
* 
 
 
 
 
* 
Week 4 
3 
 
* 
 
 
 
 
* 
Week 5†††† 
4 
* 
* 
* 
* 
 
* 
* 
Week 6 
5 
 
* 
 
 
 
 
* 
Week 7†† 
6 
 
* 
* 
* 
* 
* 
* 
Week 8 
7 
 
* 
 
 
 
 
* 
Week 9†††† 
8 
* 
* 
 
 
 
 
* 
Week 10  
9 
 
* 
 
 
 
 
* 
Week 11  
10 
 
* 
* 
* 
 
* 
* 
Week 12 
11 
 
* 
 
 
 
 
* 
Week 13†††† 
12 
* 
* 
 
 
 
 
* 
Week 14 
13 
 
* 
 
 
 
 
* 
Week 15 
14 
 
* 
* 
* 
* 
* 
* 
Week 19†††††† 
 
 
 
 
 
 
 
* 
Week 23†††††† 
 
 
 
 
 
 
 
* 
Week 27††††††† 
 
 
* 
* 
* 
* 
* 
* 
Week 54††††††† 
 
* 
* 
* 
* 
* 
* 
 
 
 


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† PK will be collected in the following manner: On Day 1 of topical treatment: PK will be collected pre-dose (before the first dose), and 2 hrs (±30 minutes), 4 hrs (± 30 minutes) a
hr post-dose).  
For study Weeks 5, 9, 13, and 54 of calcitriol, PK will be collected on Day 1 pre-dose. This should be 12 hrs (± 2 hrs) after the last application of topical calcitriol. 
†† For the Weeks 2 and 7 visits, patients will be seen by a study Dermatologist at their site. 
††† All patients will be asked to maintain the self-assessment diary for up to approximately 7 months from initial application of study drug. The diary will be filled out weekly 
for the first 15 weeks after initiating calcitriol and at Weeks 19, 23, and 27. 
†††† Note that some patients may be placed on a 3-week-on one-week-off regimen. The indicated weeks will be off-chemo weeks. 
††††† Photographs for patients in each cohort representing baseline, and treatment Weeks 7 and 15 will be presented blind to the study PI after at least 3 patients have completed 
15 weeks of treatment. Photographs will also be taken at Week 27 and Week 54 of the study but will be included in the final photographic assessment as secondary 
information. The PI clinical assessment of the baseline, and Weeks 7 and 15 photographs will be used, together with the patient self-assessment diary information, for 
the primary assessment of alopecia. 
†††††† A patient self-assessment is required this week if treatment continues beyond Week 15. 
††††††† Study assessments will be performed ± 7 days from the scheduled date. 
 


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10 
POST-TREATMENT EVALUATION 
Post-treatment physical examinations will be performed by an investigator and will take place 
within 30 days from the completion of the study treatment date. Exams will include: 
• 
Weight measurement 
• 
Vital signs 
• 
Blood sample draws (complete blood count, comprehensive chemistry panel, serum 
phosphorus, and serum Vitamin D) 
• 
Adverse Event evaluation 


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11 
TOXICITIES/SIDE EFFECTS 
NCI CTCAE v4.0 will be used to grade all toxicity. Below are some side effects that may be 
observed: 
• 
Common side effects (20-30%) 
o 
Pruritus 
o 
Skin discomfort  
o 
Skin stinging or burning 
o 
Eye irritation or stinging  
• 
Less common side effects (<20%) 
o 
Scalp xerosis and flaking 
o 
Erythema 
o 
Irritant dermatitis 
• 
Rare but serious side effects (1-5%) 
o 
Hypercalcemia  
o 
Hypercalciuria  
o 
Renal stones  
o 
Increased thirst 
o 
Increased frequency of urination 
o 
Changes in pulse 
o 
Weakness 
o 
Drowsiness 
o 
Bone pain 
o 
Renal Insufficiency 
 
 


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12 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
This trial is a Phase 1 study and thus primarily a safety study of C31543 Topical Solution in 
patients with metastatic or recurrent cancer who are undergoing chemotherapy with a taxane-
based regimen. This study will focus on determining an MTD.  
Therapeutic response of C31543 Topical Solution will be assessed by photography and by 
patient self-assessment. 
 


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13 
CRITERIA FOR REMOVAL FROM STUDY 
All patients may continue therapy unless DLT is documented. In case of death, the cause of 
death should be documented.  
The following events may be considered sufficient reason for discontinuing treatment with the 
study medication: 
• 
Serious toxicity due to the study drug graded according to the NCI Common 
Terminology Criteria for Adverse Events v4.0 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Unacceptable toxicity in the opinion of the patient or investigator even if not 
specifically defined elsewhere 
• 
Personal preference by the patient for any reason 
• 
Subject non-compliance with the defined treatment plan 
• 
Medical or psychiatric illness Any other situation where, in the opinion of the 
investigator, continued participation in the study would not be in the best interest of the 
patient or further therapy is not possible  
• 
Pregnancy 
• 
Loss of all of the patient’s hair after the first three cycles of topical calcitriol application 
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The investigator may withdraw a subject if, in his or her clinical judgment, it is in the best 
interest of the subject or if the subject cannot comply with the protocol. When possible, the tests 
and evaluations listed for the termination visit should be carried out. Berg should be notified of 
all subject withdrawals as soon as possible. 
If a subject fails to return for the protocol defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, a registered letter, at the minimum, should 
be sent to the subject (or the subject’s legal guardian) requesting contact with the clinic. This 
information should be recorded in the CRF. 
The investigator will also withdraw a subject upon Berg’s request or if Berg chooses to terminate 
the study. Upon occurrence of a serious or intolerable adverse effect, the principal investigator 
will confer with the Berg representative. If a subject is discontinued due to an adverse effect, the 
event will be followed until it is resolved, or if not resolved within a reasonable time 
(approximately 30 days), until its clinical relevance and etiology can be reasonably explained. A 
subject may withdraw his or her consent at any time during the study. 
If a subject withdraws from the study at any time either at his or her request or at the principal 
investigator’s discretion, the reason for withdrawal will be recorded in the CRF. All subjects who 
withdraw from the study prematurely will undergo all end-of-study assessments, if possible. 
Every effort must be made to undertake protocol-specified safety follow-up procedures. 


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14 
BIOSTATISTICS 
This is a Phase 1 study designed to determine the maximum tolerated dose (MTD) of C31543 
topical calcitriol in patients with CIA. Three doses of topical calcitriol (5 μg/mL, 10 μg/mL, and 
20 μg/mL) have been tested to date without DLT.  Amendment 8 adds additional dosing levels 
(40 μg/mL, 60 μg/mL 80 μg/mL)until MTD is achieved.   
Patients will be treated in cohorts of size three to six and the dosage will be escalated if the 
clinical toxicity is acceptable. A patient is considered toxicity-free for the purpose of the trial if 
s/he completes the first month of topical agent application without experiencing dose limiting 
toxicity (DLT). If the topical agent is discontinued during the first month for reasons other than 
toxicity, an additional patient may be enrolled at that dose level to ensure adequate evaluation of 
toxicity. No intra-patient dose escalation will be performed. In all cases, including those when 
the topical treatment continues post 4 weeks, the MTD assessment will be based only on the 
DLT recorded during the first month. DLT is defined in Section 8.4and the design is constructed 
to minimize the chances of escalating the dose when the probability of DLT is high, and 
maximize the chance of escalating the dose when the probability of DLT is low. The dose 
escalation scheme is as follows: 
1. If none of the initial three patients at a given dose level experience DLT, the next dose 
level will be studied. 
2. If one of the initial three patients at a given dose level experiences DLT, three additional 
patients will be treated at the same dose level. Escalation will continue only if there has 
been no additional DLT observed. 
3. If two or more patients experience DLT at a given dose, the previous dose will be 
declared the MTD.  
4. If only three patients were treated at a dose under consideration as MTD, an additional 
three patients will be treated at that level to confirm previous results. 
The probability that dose escalation will occur at any stage during MTD determination, is a 
function of the underlying DLT rate at the current dose level. This probability can be calculated 
as the sum of the binomial probabilities of the following two outcomes that would permit 
escalation to occur: 
1. No DLT observed in the first three patients. 
2. One DLT is observed in the first three patients followed by no DLT observed in three 
additional patients at the same dose level. 
The true risk of toxicity is expected to be in the range of 10%-50%.The following table shows 
the corresponding probabilities of dose escalation: 
True Risk of Toxicity 
0.10 
0.20 
0.30 
0.40 
0.50 
Probability of Escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
 
These numbers show the probability of escalating to the next dose level is large when the 
underlying true toxicity rate is small and the probability of escalating decreases appropriately as 
the true toxicity rate increases. 


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14.1 
Safety Analyses 
Selected non-hematologic and hematologic toxicities, as measured by the NCI Common 
Terminology Criteria for Adverse Events (CTCAE v4.0), will be described by frequency and 
grade, by cycle and over all cycles, with the maximum grade over all cycles used as the summary 
measure per patient. 
Adverse event terms recorded on the CRF will be mapped to preferred terms using the medical 
dictionary for regulatory activities (MedDRA) dictionary. All adverse events (AEs) will be listed 
or tabulated for overall incidence and for incidence for each dose cohort, worst reported severity, 
and relationship to study treatment according to system organ class and preferred term. Serious 
adverse events (SAEs) will be similarly summarized. Listings of deaths, SAEs, DLTs, and AEs 
leading to early termination of study treatment, or premature withdrawal from trial will also be 
provided. 
Laboratory variables will be examined using mean change in value from baseline to various time 
points for each dose cohort. Laboratory values will also be categorized according to the CTCAE 
v4.0; listings or tables will be categorized by the worst on-study toxicity grade, dose cohort, and 
relationship. Shift tables will be presented to show the number and percent of subjects with high, 
normal, and low (or normal/abnormal) laboratory results at baseline and last assessment. 
Concomitant medications will be summarized for all subjects, including summary by dose 
cohort. 
14.2 
Significance Level 
Centralized Photographic review by a dermatologist and patient self-reported diaries will be used 
for preliminary statistical analyses. Analyses will look at the efficacy of Topical Compound 
C31543. This will be helpful for further studies looking more closely at the efficacy of C31543. 
While no formal statistical testing is planned for this study, 95% confidence intervals may be 
calculated for selected safety variables. This Phase 1 trial will accrue only three patients per 
cohort, which is not a statistically significant number of patients, nor is the trial design adequate 
to provide objective statistical data sufficient for proof of efficacy. 
14.3 
Exploratory Analyses 
Exploratory variables will be assessed for each subject, and descriptive statistics (including 
number, mean, median, standard deviation, and range) will be calculated for subjects by dose 
level. 
14.4 
Interim Analyses 
No interim analysis is planned. 
14.5 
Sample Size/Accrual Rate 
The Phase 1 portion of the study for 3-6 patients to be treated at each dose level. The original 
assumption was that 3 dose levels would be required resulting in a minimum of 2 and a 
maximum of 18 patients enrolled.  Amendment 8 adds 3 additional dose levels resulting in a 
maximum of 18 additional patients enrolled.  With 12 patients enrolled and treated to date, the 
maximum number of patients enrolled in the study would be 30.  This clinical trial will be 


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conducted at two clinical sites. With the expected accrual rate of approximately 3-6 eligible 
patients per treatment cohort, it was expected that the Phase 1 portion of the trial would take less 
than 1 year. This would allow each 3-patient cohort to be observed for 28 days, the length of 
time for treatment with one cycle of therapy prior to additional patients being accrued.  It is 
anticipated that the enrollment of the 3 additional dosing levels will take less than 1 year.   


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15 
RESEARCH PARTICIPANT REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks and 
discomforts. Human protection committee approval of this protocol and consent form is required. 
Eligible patients who wish to participate will be enrolled into the trial. 
Registration must occur prior to the initiation of protocol therapy. Patient registration and dose 
level assignment will be performed by Berg. The Berg registration desk will assign a patient 
identification number and dose level. The registration desk designee will document the patient 
identification number, dose level, and date of enrollment on the Registration Form and will send 
the completed form back to the site as soon as possible, and no later than 24 hrs following the 
registration request. Thesite coordinator will document the patient identification number, dose 
level, and date of enrollment in the EDC system. 
The site coordinator must complete and submit an Eligibility Packet to the Berg Enrollment desk 
following the instructions outlined in the Enrollment Instructions.  
All Eligibility Packets are to be or emailed to Berg Registration Desk: 
Email: EnrollmentDesk@bergpharma.com 
The enrollment packet will be reviewed by the Berg Medical Monitor for compliance with the 
study protocol screening and inclusion/exclusion criteria. All eligible patients will be authorized 
for participation in the study by Berg via an email confirmation, a copy of which will be 
maintained in the Berg Trial Master File. 


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16 
ADVERSE EVENTS 
16.1 
Clinical Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that may or may not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
investigational product. Pre-existing conditions that worsen during a study will be reported as 
AEs. 
All AEs that occur after the informed consent is obtained will be reported on the AE page of the 
CRF. 
16.2 
Relationship Between the Adverse Event and the Study Drug 
The investigator must also assess the relationship of any adverse event to the use of study drug, 
based on available information, using the following guidelines: 
1. Not related 
a. The AE is not related if exposure to the investigational product has not 
occurred, or 
b. The AE is associated with an alternate cause. 
2. Unlikely Related 
a. The occurrence of the AE is not reasonably related in time, or 
b. The AE is considered unlikely to be related to use of the investigational 
product (ie, there are no facts or arguments to suggest an alternate 
relationship). 
3. Possibly Related 
a. The investigational product administration and the AE are considered 
reasonably related in time, and 
b. There are facts to suggest a reasonable causal relationship between the 
investigational product and the AE. 
4. Probably Related 
a. The investigational product administration and the AE are reasonably related in 
time, and 
b. The AE is more likely explained by exposure to the investigational product 
than by other factors or causes, or is the most likely cause of the AE. 
5. Definitely related 
16.3 
Treatment and Follow-Up of Adverse Events 
All AEswill be monitored until resolution or, if the AE is determined to be chronic, a cause is 
identified. If an AE is considered potentially related to study treatment and remains unresolved at 


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the conclusion of the study, the event will be followed until resolution, stabilization, or initiation 
of treatment that confounds the ability to assess the event. 
16.4 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the Case Report Form 
(CRF), or appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. Laboratory test value abnormalities as such should not be reported on the 
AE page of the CRF as AEs unless they result in a clinically relevant condition. 
16.4.1 
Follow-Up of Abnormal Laboratory Test Values 
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range or an adequate 
explanation of the abnormality is found. If a clear explanation is established, it should be 
recorded on the CRF. 


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17 
SERIOUS ADVERSE EVENTS (SAE) 
Any clinical AE or abnormal laboratory test value that is serious and that occurs during the 
course of the study, irrespective of the treatment received by the subject, must be reported to 
Berg (or designee) within 24 hrs of awareness of the event(expedited reporting). 
The definition and reporting requirements of the International Conference of Harmonisation 
(ICH) Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited 
Reporting, Topic E2A will be adhered to. An SAE is defined as any untoward medical 
occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (ie, in the opinion of the investigator, the AE places the subject at 
immediate risk of death from the event as it occurred; it does not include a reaction that, 
had it occurred in a more severe form, might have caused death). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event that, based upon appropriate medical judgment, may 
jeopardize the subject or may not be immediately life-threatening, or result in death or 
hospitalization, but may jeopardize the subject or require intervention to prevent one of 
the other serious outcomes listed above (eg, intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse). 
17.1 
SAE Reporting 
Any SAE, whether or not considered to be related to treatment with topical calcitriol will be 
reported within 24 hrs from awareness of the event toBerg (or designee) and will be recorded on 
both the SAE initial report form and the CRF. The outcome of the SAE, and medications or 
other therapeutic measures used to treat the event, will be recorded on the appropriate CRF 
page. Forms for reporting SAEs and SAE Report Completion Guidelines will be provided to the 
study sites. 
All SAEs that occur after the first dose of topical calcitriol and through study termination, will 
be reported in accordance with US regulations governing safety reporting (21 Code of Federal 
Regulations (CFR) 312.32 and 312.33). 
Reporting of SAEs by the investigator to his or her internal review board (IRB) will be done in 
accordance with the standard operating procedures and policies of the IRB. Adequate 
documentation must be maintained showing that the IRB was properly notified. 
For notification of an SAE, the following individual must be contacted: 
Berg medical monitor: Brian Berman, MD, PhD 
All SAE reports need to be faxed or emailed to Berg Safety: 
FAX Number (615) 889-8880 
Email (preferred method): Safety@bergpharma.com 


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17.2 
Berg SAE Reporting Requirements 
Berg must inform investigators and regulatory authorities of reportable events in compliance 
with applicable regulatory requirements on an expedited basis (ie, within specific timeframes). 
For this reason, it is imperative that investigational sites provide complete SAE information in 
the manner described above.  
Berg is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations (21 CFR 312.32), and/or local regulatory requirements. Investigators are responsible 
for reporting to their IRBs per local requirements. 


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18 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
18.1 
Informed Consent Procedures 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board. The consent form will include the following:  
• 
The nature and objectives, potential risks and benefits of the intended study.  
• 
The length of study and the likely follow-up required. 
• 
Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
• 
The name of the investigator(s) responsible for the protocol. 
• 
The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
18.2 
IRB Approval 
The trial protocol, ICF, IB, available safety information, patient documents (eg, trial diaries), 
patient recruitment procedures (eg, advertisements), information about payments (ie, PI 
payments) and compensation available to the patients and documentation evidencing the PI‘s 
qualifications should be submitted to the IRB for ethical review and approval prior to the trial 
start.  
18.3 
Confidentiality 
18.3.1 
Patient Confidentiality 
Confidentiality of the patient‘s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPPA) and national data protection laws, 
as applicable. HIPPA regulations require that, in order to participate in the trial, a patient must 
sign an authorization from the trial that he or she has been informed of the following:  
• 
What protected health information (PHI) will be collected from patients in this trial;  
• 
Who will have access to that information and why;  
• 
Who will use or disclose that information;  
• 
That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws; 


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• 
The information collected about the research trial will be kept separate from the patient‘s 
medical records, but the patient will be able to obtain the research records after the 
conclusion of the trial;  
• 
Whether the authorization contains an expiration date; and  
• 
The rights of a research patient to revoke his or her authorization.  
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (ie, that the patient is alive) at the end 
of their scheduled trial period.  
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of Berg, the regulatory 
authorities, and the IRB direct access to review the patient‘s original medical records at the site 
for verification of trial-related procedures and data.  
Measures to protect confidentiality include: 
• 
Only a unique trial number and initials will identify patients on the CRF or other 
documents submitted to Berg.  
• 
This information, together with the patient‘s date of birth, will be used in the database for 
patient identification.  
• 
 Patient‘s name and address will not be entered in the CRF or database.  
• 
 No material bearing a patient‘s name will be kept on file by Berg.  
• 
Patients will be informed of their rights within the ICF. 
18.3.2 
Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the Berg database, 
and shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the investigator or sub-investigator, Berg shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
 


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19 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
19.1 
Amendments to Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by Berg. The written amendment must be reviewed and approved by Berg, and submitted to the 
IRB at the investigator’s facility for the Board’s approval. 
It should be further noted that, if an amendment to the protocol substantially alters the trial 
design or the potential risks to the patients, their consent to continue participation in the trial 
should be obtained. 
19.2 
Trial Documentation and Storage 
Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the patient‘s CRF data are 
obtained. The PI and research staff is responsible for maintaining trial-related (essential) 
documentation, suitable for inspection at any time by representatives from Berg and/or 
applicable regulatory authorities. This should contain at a minimum all relevant documents and 
correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57. In addition, all 
original source documents supporting entries in the CRF must be maintained and be readily 
available. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment/delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
If the investigator relocates, retires, or for any reason withdraws from the trial, both Berg and its 
representative should be prospectively notified. The trial records must be transferred to an 
acceptable designee, such as another investigator, another institution, or Berg. The investigator 
must obtain the Sponsor‘s written permission before disposing of any records, even if retention 
requirements have been met. All trial files will be maintained by Berg or its representative 
throughout the trial, and will be transferred to Berg at the conclusion of the trial. 
19.3 
Data Collection 
The trial eCRF is the primary data collection instrument for the trial. eCRFs will be completed 
using the English language and should be kept current to enable the monitor to review the 
patient‘s status throughout the course of the trial.  
All data requested on the eCRF must be supported by and be consistent with the patient‘s source 
documentation. All missing data must be explained. For any entry errors made, the error(s) must 
be corrected, and a note explaining the reason for change should be provided. The investigator 
will electronically sign and date the patient eCRF casebook indicating that the data in the eCRF 
has been assessed. 
 
 


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19.4 
Trial Monitoring, Auditing, and Inspecting 
The investigator will permit trial-related monitoring, quality audits, and inspections of all trial-
related documents (eg, source documents, regulatory documents, data collection instruments, 
case report forms) by Berg or its representative(s) and government regulatory authorities. The 
investigator will ensure the capability for inspections of applicable trial-related facilities. The 
investigator will ensure that the trial monitor or any other compliance or QA reviewer is given 
access to all trial-related documents and trial-related facilities.  
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by qualified staff chosen by Berg to ensure the human subject protection, trial 
procedures, laboratory, trial intervention administration, and data collection processes are of high 
quality and meet Sponsor, GCP/ICH and, when appropriate, regulatory guidelines. The Site 
Monitoring Plan will outline the details of the monitoring process. 
19.5 
Disclosure and Publication Policy 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential. Berg reserves the right to release 
literature publications based on the results of the trial. Results from the trial will be 
published/presented as per Berg’s publication strategy.  
Berg will register the trial on www.clinicaltrials.gov. In addition, Berg will publish the results of 
the trial. 
Inclusion of the investigator in the authorship of any multicenter publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial. The investigator acknowledges that the trial is 
part of a multicenter trial and agrees that any publication by the investigator of the results of the 
trial conducted at the research site shall not be made before the first multicenter publication. In 
the event there is no multicenter publication within fifteen (15) months after the trial has been 
completed or terminated at all trial sites, and all data has been received, the investigator shall 
have the right to publish its results from the trial, subject to the notice requirements described 
herein and subject to acknowledgement of Berg as appropriate. Investigator shall provide Berg 
thirty (30) days to review a manuscript or any poster presentation, abstract or other written or 
oral material which describes the results of the trial for the purpose only of determining if any 
confidential or patentable information is disclosed thereby. If Berg requests in writing, the 
investigator shall withhold any publication or presentation an additional sixty (60) days solely to 
permit Berg to seek patent protection and to remove any Berg Confidential Information from all 
publications. 


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20 
APPENDICES 
A. Calcitriol Application Diary 
B. Patient Self-Assessment Diary, Baseline 
C. Patient Self-Assessment Diary, On-Treatment 
 


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21 
REFERENCES 
1 
Wang J, Lu Z, Au JL. Protection against chemotherapy-induced alopecia. Pharm Res 
2006; 23: 2505-14. 
2 
Lombardi D, Crivellari D, Scuderi C, Magri MD, Spazzapan S, Sorio R, et al. Long-term, 
weekly one-hr infusion of paclitaxel in patients with metastatic breast cancer: a phase II 
monoinstitutional study. Tumori 2004; 90: 285-8. 
3 
Gasparini G, Gion M, Mariani L, Papaldo P, Crivellari D, Filippelli G, et al. Randomized 
Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as 
first-line therapy of patients with Her-2 positive advanced breast cancer. Breast Cancer 
Res Treat 2007; 101: 355-65. 
4 
Batchelor D. Hair and cancer chemotherapy: consequences and nursing care--a literature 
study. Eur J Cancer Care (Engl) 2001; 10: 147-63. 
5 
Carelle N, Piotto E, Bellanger A, Germanaud J, Thuillier A, Khayat D. Changing patient 
perceptions of the side effects of cancer chemotherapy. Cancer 2002; 95: 155-63. 
6 
Dorr VJ. A practitioner's guide to cancer-related alopecia. Semin Oncol 1998; 25: 562-70. 
7 
Lindley C, McCune JS, Thomason TE, Lauder D, Sauls A, Adkins S, et al. Perception of 
chemotherapy side effects cancer versus noncancer patients. Cancer Pract 1999;7: 59-65. 
8 
McGarvey EL, Baum LD, Pinkerton RC, Rogers LM. Psychological sequelae and 
alopecia among women with cancer. Cancer Pract 2001; 9: 283-9. 
9 
Grevelman EG, Breed WP. Prevention of chemotherapy-induced hair loss by scalp 
cooling. Ann Oncol 2005; 16: 352-8. 
10 
Auvinen PK, Mahonen UA, Soininen KM, Paananen PK, Ranta-Koponen PH, 
Saavalainen IE, et al. The effectiveness of a scalp cooling cap in preventing 
chemotherapy-induced alopecia. Tumori 2010; 96: 271-5. 
11 
Duvic M, Lemak NA, Valero V, Hymes SR, Farmer KL, Hortobagyi GN, et al. A 
randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol 
1996; 35: 74-8. 
12 
Verstuyf A, Carmeliet G, Bouillon R, Mathieu C. Vitamin D: a pleiotropic hormone. 
Kidney Int 2010; 78: 140-5. 
13 
Gruber-Wackernagel A, Bambach I, Legat FJ, Hofer A, Byrne SN, Quehenberger F, et al. 
Randomized double-blinded placebo-controlled intra-individual trial on 1,25-(OH)2 
vitamin D3 analogue in polymorphic light eruption. Br J Dermatol 2011. 
14 
Brown AJ, Slatopolsky E. Vitamin D analogs: therapeutic applications and mechanisms 
for selectivity. Mol Aspects Med 2008; 29: 433-52. 
15 
Hershberger PA, Yu WD, Modzelewski RA, Rueger RM, Johnson CS, Trump DL. 
Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro 
and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res 2001;7:1043-
51. 


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16 
Jimenez JJ, Alvarez E, Bustamante CD, Yunis AA. Pretreatment with 1,25(OH)2D3 
protects from Cytoxan-induced alopecia without protecting the leukemic cells from 
Cytoxan. Am J Med Sci 1995; 310: 43-7. 
17 
Hussein AM, Jimenez JJ, McCall CA, Yunis AA. Protection from chemotherapy-induced 
alopecia in a rat model. Science 1990; 249: 1564-6. 
18 
Jimenez JJ, Yunis AA. Protection from chemotherapy-induced alopecia by 1,25-
dihydroxyvitamin D3. Cancer Res 1992; 52: 5123-5. 
19 
Sredni B, Xu RH, Albeck M, Gafter U, Gal R, Shani A, et al. The protective role of the 
immunomodulator AS101 against chemotherapy-induced alopecia studies on human and 
animal models. Int J Cancer 1996; 65: 97-103. 
20 
Sun J, Silva KA, McElwee KJ, King LE, Jr, Sundberg JP. The C3H/HeJ mouse and 
DEBR rat models for alopecia areata: review of preclinical drug screening approaches 
and results. Exp Dermatol 2008; 17: 793-805. 
21 
Schilli MB, Paus R, Menrad A. Reduction of intrafollicular apoptosis in chemotherapy-
induced alopecia by topical calcitriol-analogs. J Invest Dermatol 1998; 111: 598-604. 
22 
Chen G, Baechle A, Nevins TD, Oh S, Harmon C, Stacey DW. Protection against 
cyclophosphamide-induced alopecia and inhibition of mammary tumor growth by topical 
1,25-dihydroxyvitamin D3 in mice. Int J Cancer 1998; 75: 303-9. 
23 
Paus R, Schilli MB, Handjiski B, Menrad A, Henz BM, Plonka P. Topical calcitriol 
enhances normal hair regrowth but does not prevent chemotherapy-induced alopecia in 
mice. Cancer Res 1996; 56: 4438-43. 
24 
Hidalgo M, Rinaldi D, Medina G, Griffin T, Turner J, Von Hoff DD. A phase I trial of 
topical topitriol (calcitriol, 1,25-dihydroxyvitamin D3) to prevent chemotherapy-induced 
alopecia. Anticancer Drugs 1999; 10: 393-5. 
25 
Bleiker TO, Nicolaou N, Traulsen J, Hutchinson PE. 'Atrophic telogen effluvium' from 
cytotoxic drugs and a randomized controlled trial to investigate the possible protective 
effect of pretreatment with a topical vitamin D analogue in humans. Br J Dermatol 2005; 
153: 103-12. 
26 
Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-
blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo 
plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT 
Investigators. J Clin Oncol 2007; 25: 669-74. 
27 
Scher HI, Chi KN, De Wit R, Berry WR, Albers P, Henick B, et al. Docetaxel (D) plus 
high-dose calcitriol versus D plus prednisone (P) for patients (Pts) with progressive 
castration-resistant prostate cancer (CRPC): Results from the phase III ASCENT2 trial. J 
Clin Oncol 28:15s, 2010 (suppl; abstr 4509). 

SAP_001.pdf: 
Berg, LLC 
CONFIDENTIAL 
 
Protocol CTL0211 
 
 
STATISTICAL ANALYSIS PLAN 
 
Page 1 of 21 
 
 
 
PROTOCOL CTL0211 
 
A Multi-Center, Phase 1 Dose-Escalation Study, to 
Evaluate the Safety, Tolerability and Pharmacokinetics 
of a Topical Compound 31543 (Calcitriol, USP) in Adult 
Cancer Patients Receiving Taxane-based Chemotherapy 
Regimens for the Treatment of Advanced or Recurrent 
Disease 
 
STATISTICAL ANALYSIS PLAN 
17 July 2017 
 
 
CONFIDENTIAL 
 
 
Prepared for: 
 
Berg Pharma, LLC 
500 Old Connecticut Path  
Framingham, MA 01701 USA 
 
 
 
 
 
 




Berg, LLC 
CONFIDENTIAL 
 
Protocol CTL0211 
 
 
STATISTICAL ANALYSIS PLAN 
 
Page 3 of 21 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AE(s) 
Adverse event(s) 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CFB 
Change From Baseline 
CIA 
Chemotherapy-Induced Alopecia 
CRC 
Cohort Review Committee 
CRF 
Case Report Form 
DLT 
Dose-limiting toxicity 
FAS 
Full Analysis Set 
MTD 
Maximum tolerated dose 
PK 
Pharmacokinetic(s) 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 


Berg, LLC 
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TABLE OF CONTENTS 
 
 
 
 
 
 
    Page 
1 
INTRODUCTION................................................................................................................. 6 
1.1 
BACKGROUND .................................................................................................................. 6 
2 
TRIAL DESIGN.................................................................................................................... 6 
2.1 
STUDY OBJECTIVES ......................................................................................................... 6 
2.2 
STUDY DESIGN ................................................................................................................ 6 
2.3 
STUDY DRUG DOSAGE AND ADMINISTRATION ................................................................ 7 
3 
SAMPLE SIZE, RANDOMIZATION AND BLINDING ................................................. 8 
3.1 
SAMPLE SIZE .................................................................................................................... 8 
3.2 
RANDOMIZATION AND BLINDING ..................................................................................... 8 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ..................................................... 8 
4.1 
INCLUSION CRITERIA ....................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ...................................................................................................... 8 
4.3 
PREMATURE DISCONTINUATION FROM DOSING ............................................................... 9 
5 
CLINICAL PROCEDURES AND ASSESSMENTS ....................................................... 10 
6 
STUDY ENDPOINTS ......................................................................................................... 14 
6.1 
MAXIMUM TOLERATED DOSE (MTD) ........................................................................... 14 
6.2 
SAFETY AND TOLERABILITY .......................................................................................... 14 
6.3 
PHARMACOKINETICS (PK) ............................................................................................. 14 
6.4 
EFFICACY ....................................................................................................................... 14 
6.4.1  Subjective record of hair and scalp .......................................................................... 14 
6.4.2  Photographic record of hair and scalp ..................................................................... 14 
7 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ................................... 14 
7.1 
ANALYSIS POPULATIONS ............................................................................................... 14 
7.2 
GENERAL ANALYSIS ...................................................................................................... 15 
7.3 
PATIENT DISPOSITION ..................................................................................................... 15 
7.4 
DEMOGRAPHICS, BASELINE CHARACTERISTICS AND MEDICAL HISTORY ...................... 15 
7.4.1  Demographics ........................................................................................................... 15 
7.4.2  Medical History and Baseline Disease Characteristics ........................................... 15 
7.4.3  Concomitant medications.......................................................................................... 15 
7.5 
SAFETY AND TOLERABILITY .......................................................................................... 16 
7.5.1  Adverse events ........................................................................................................... 16 
7.5.2  Dose-Limiting Toxicity (DLT)................................................................................... 17 
7.5.3  Laboratory Assessments............................................................................................ 17 
7.5.4  Pharmacokinetics ...................................................................................................... 17 
7.5.5  Vital Signs ................................................................................................................. 18 
7.5.6  Physical Examinations .............................................................................................. 18 
7.6 
EFFICACY ....................................................................................................................... 18 
7.6.1  Subjective record of hair and scalp .......................................................................... 18 
7.6.2  Photographic record of hair and scalp ..................................................................... 18 
7.7 
INTERIM ANALYSIS ........................................................................................................ 18 


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8 
DATA HANDLING ............................................................................................................ 19 
8.1 
DATA CALCULATIONS AND DEFINITIONS ....................................................................... 19 
8.1.1  Baseline Values ......................................................................................................... 19 
8.1.2  Change from Baseline (CFB).................................................................................... 19 
8.2 
MISSING DATA ............................................................................................................... 19 
9 
CHANGES FROM THE PROTOCOL ............................................................................ 19 
10  APPENDIX A – LABORATORY TESTS ........................................................................ 20 
 
 


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1 
INTRODUCTION 
This analysis plan, Version 4.0, is to be used in conjunction with the protocol (Version 9, 
dated 15 November 2015) and the corresponding e-CRFs. 
1.1 
Background 
Chemotherapy-Induced Alopecia (CIA) is a non-cicatricial alopecia and represents one of 
the most common and distressing dermatological adverse events associated with the use 
of many different chemotherapeutic agents. Despite profound effects on patients, no 
effective preventative or treatment options are available. 
 
2 
TRIAL DESIGN  
This will be a single-arm, dose-escalation study to determine the maximum tolerated dose 
(MTD) and the overall safety and tolerability of Compound 31543 in patients with 
metastatic breast cancer undergoing chemotherapy with paclitaxel. A standard 3+3 dose 
escalation design will be employed with 3-6 patients at each dose level.  
2.1 
Study Objectives  
The primary objective of this study is to: 
1. Determine the maximum tolerated dose (MTD) and the overall safety and 
tolerability of topical calcitriol in patients with metastatic breast cancer receiving 
chemotherapy with paclitaxel. 
 
The secondary objectives of this study are to: 
1. Determine the single and multiple dose pharmacokinetics (PK) of calcitriol at 
different dose levels; and 
2. Evaluate preliminary efficacy of calcitriol for preventing chemotherapy induced 
alopecia. 
2.2 
Study Design 
This is a multi-center, single arm, dose-escalation Phase 1 study. Eligible patients will begin applying 
the topical formulation of Compound 31543 to the scalp twice daily 2 weeks prior to the first dose of 
chemotherapy and continue the application twice daily until termination of chemotherapy treatment. 
Patients unable or unwilling to wait the 2 week pre-treatment period may elect to pre-treat for 
7 days ± 2 days. Dose escalation will occur in stepwise increments of the immediate prior dose 
group, in the absence of grade 3 or greater toxicities attributed to the topical calcitriol, in order to 
determine the MTD for this agent. Dose-limiting toxicity (DLT) will need to possibly, probably or 
definitely (defined in Section 8.4) be related to topical calcitriol and not taxane-based regimen as best 
determined by participating investigators. Similarly, appropriate dose modifications or treatment 
interruption of the chemotherapeutic regimen will be instituted according to the current standard of 
care. Determination of DLTs of the topical calcitriol formulation will be made during the first 
28 days of topical agent application. Subjects will be managed with adequate safety monitoring and 
pharmacokinetic (PK) analysis in order to determine levels of exposure. PK analysis will be done 
before each new cohort moves forward. For the purpose of PK studies, blood samples will be 
collected on Day 1 of topical treatment at the following time points: pre-dose, at 2 hrs 
(± 30 minutes), 4 hrs (± 30 minutes), and 8 hrs (±1 hr post-dose) after a single application on the 
morning of Day 1. The second application of drug product will be applied 10-14 hrs after the initial 


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application and after the 8 hr PK sample. Thereafter, topical application frequency will be twice 
daily, morning and night. Subsequently, a PK sample will be taken 12 hrs (±2 hrs) after the last dose 
of each 28-day treatment, before the first application of Day 1 of the next 28-day treatment cycle. 
This schedule will continue for three consecutive 28-day topical treatment cycles (PKs will be drawn 
at Weeks 1, 5, 9, 13. In addition, if patients are still on study, a PK will also be drawn at Week 54). 
2.3 
Study Drug Dosage and Administration 
Eligible patients will be instructed to apply 0.25mL of topical Compound 31543 to each of the 
four quadrants of the scalp - front right, front left, back right, back left with the provided metered 
pump spray unit twice a day two weeks prior to the start of chemotherapy treatment. Patients 
unable or unwilling to wait the 2 week pre-treatment period may elect to pre-treat for 7 days ± 2 
days. Subsequently, application will continue twice daily for three months or until termination of 
chemotherapy. 
 
Patients will be treated in cohorts of size three to six starting at dose level 1 (5μg/m1). 
The dosage will be escalated if the clinical toxicity is declared acceptable (below). 
Subsequent escalation cohorts will be treated with 10, 20, 40, 60, and 80 μg/ml. 
 
Determination of a DLT will be made during the first 28 days of topical treatment. No 
intra-patient dose escalation will be performed. DLT will need to be possibly, probably or 
definitely related to topical Compound 31543 and not paclitaxel as best determined by 
participating investigators. The dose escalation scheme follows. 
 One 28-day cycle of treatment will be performed and evaluation of PK Data will 
occur before escalation to the next dose level. 
 If none of the initial three patients in a cohort experiences a DLT, then a new 
cohort of three patients will be treated at the next higher dose level. 
 If one of the three patients in a cohort experiences DLT, then up to three 
additional patients will be treated at the same dose level. Escalation will continue 
if only one of the six patients experiences DLT. 
 If two or more patients in a cohort experience DLT, then the MTD will have been 
exceeded, and no further dose escalation will occur. The previous dose level will 
be considered as the MTD. 
 If only three patients were treated at a dose level under consideration as the MTD, 
then up to three additional patients will be accrued to that dose level. If no more 
than one of six patients at that dose level experience a DLT, then that dose level 
will be confirmed as the MTD. If two or more patients in that cohort experience 
DLT, then the previous dose level will be studied in the same fashion. 
The MTD is defined as the dose level at which 0/3 or 1/6 subjects experiences DLT 
during the first 28 days treatment cycle below the dose at which 2/3 or 2/6 subjects 
experienced DLT. Thus, the MTD will have been exceeded when >30% (2/3 or 2/6) of 
subjects at any dose level develop DLT.  
 
The original protocol had 3 dose levels: 5, 10, and 20 μg/ml. Since the MTD was not 
established after completing three cohorts of escalating doses, the Sponsor amended the 
study protocol to add additional dose escalating cohorts: 40, 60, and 80 μg/ml. 


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3 SAMPLE SIZE, RANDOMIZATION AND BLINDING 
3.1 
Sample Size 
A standard 3+3 dose escalation design will be employed with 3-6 patients at each of three 
dose levels. Thus, the maximum number of subjects is 18 (6 per dose level). 
3.2 
Randomization and Blinding 
This study is a non-randomized unblinded single-arm, dose-escalation study. 
 
The dermatologist reviewer scoring the photographs will be blinded to time sequence of 
the photographs aside from the baseline photographs to which all others will be 
compared; otherwise not applicable. 
 
4 SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
Patients must meet the following inclusion criteria: 
1. Adult patients at least 18 years of age 
2. Able to fully understand and participate in the informed consent process 
3. Patients with historically confirmed solid tumor that have relapsed to previous 
therapy and are scheduled to receive a taxane-based regimen at treating 
physician’s discretion. 
4. Have no evidence of alopecia or mild alopecia (NCI CTCAE grade 1 alopecia 
defined as hair loss of <50% of normal for that individual that is not obvious from 
a distance but only on close inspection; a different hair style may be required to 
cover the hair loss but it does not require a wig or hair piece to camouflage.) 
Female/male-pattern baldness or age-related hair loss are allowed if not greater 
than grade 1, per NCI-CTCAE v.4.0. Subjects that have previously lost their hair 
may enroll if they currently have Grade 0 or 1 alopecia. 
5. ECOG Performance Score of 0 or 1 within 14 days prior to registration 
6. Has baseline neutrophil counts of > 1500 cells/mm3 within 72 hours prior to 
registration 
7. Has serum calcium < ULN (for patients with an albumin lower than 3.0, a 
corrected calcium serum calcium = serum calcium +[0.8][3.5- serum albumin]) 
within 72 hours prior to registration 
 
4.2 
Exclusion Criteria  
Patients meeting any of the following criteria will be excluded from the study: 
1. Receiving calcium-lowering therapy or drugs that may affect calcium levels (e.g., 
calcitonin, mithramycin, phosphate, denosumab) within 4 weeks of initiation of 
topical calcitriol. Patients who have been managed with bisphosphonates or 
calcium-lowering therapy for 6 months or greater prior to the start of the trial and 
have demonstrated evidence for stability of calcium metabolism would be 
considered eligible for participation in the trial. 


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2. Has a history of drug or alcohol abuse within 1 year of study enrollment as 
determined by the investigator. 
3. Patients who elect to shave the scalp hair prior to the initiation of chemotherapy 
or who plan to do so during the chemotherapy treatment. 
4. Any dermatological condition that in the opinion of the investigator will affect the 
absorption of the study medication, e.g. Atopic Dermatitis, etc. 
5. Has participated in any investigational trial within 30 days or six half-lives of its 
biologic activity whichever is longer, before the start of study. 
6. A history of hypercalcemia or vitamin D toxicity, or hospitalization for treatment 
of angina, myocardial infarction, or congestive heart failure or psychiatric illness 
currently or within 30 days of study entry as determined by the investigator. 
7. Has a history of significant allergy to calcitriol as determined by the investigator. 
8. Has any condition that interferes with the ability of the subject to understand or 
comply with the requirements of the study. 
9. Patients taking Vitamin D supplements during the study, unless they have been 
taking Vitamin D supplements for 30 day prior to the start of the study and that 
the dose of the Vitamin D supplement remains the same throughout the study. 
10. Treated with medications that are known to affect calcium levels within 4 weeks 
of initiation of topical therapy (>500 IU vitamin A, calcium supplements, 
fluoride, antiepileptics), with the exception of subjects on stable therapy for more 
than six months. 
11. Hypercalcemia or kidney stones 
12. Significant hair breakage or hair damage and associated hair loss from hair over 
processing within the last 30 days due to peroxide applications, permanent hair 
coloring, bleaches, streaking, perms, relaxers and/or hair oxidative dyes. 
13. Any visible signs of androgenic alopecia or alopecia areata or significant hair 
loss, hair thinning, or hair breakage. 
14. Prior radiation to the cranium 
15. Pregnant or breastfeeding 
 
4.3 
Premature Discontinuation from Dosing 
Safety follow-up visits will be performed for patients who discontinue dosing 
prematurely. Patients who discontinue dosing due to AEs will be monitored until 
resolution of all AEs. If a patient discontinues dosing prematurely at any time, either at 
his or her request or at the Investigator’s discretion, the reason(s) for discontinuation will 
be recorded. 
 
All patients may continue therapy unless DLT is documented. The following events may 
be considered sufficient reason for discontinuing treatment with the study medication: 
• 
Serious toxicity due to the study drug graded according to the NCI Common 
Terminology Criteria for Adverse Events v4.0 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Unacceptable toxicity in the opinion of the patient or investigator even if not 
specifically defined elsewhere 
• 
Personal preference by the patient for any reason.  


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• 
Subject non-compliance with the defined treatment plan 
• 
Medical or psychiatric illness or any other situation where, in the opinion of 
the investigator, continued participation in the study would not be in the best 
interest of the patient or further therapy is not possible 
• 
Pregnancy 
• 
Loss of all of the patient's hair after the first three cycles of topical 
Compound 31543 application 
• 
Investigator decision. The investigator may withdraw a subject if, in his or 
her clinical judgment, it is in the best interest of the subject or if the subject 
cannot comply with the protocol. 
• 
Sponsor decision. The investigator may withdraw a subject if, in his or her 
clinical judgment, it is in the best interest of the subject or if the subject 
cannot comply with the protocol. 
 
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The investigator may withdraw a subject if, in his or her clinical judgment, it is in the best 
interest of the subject or if the subject cannot comply with the protocol. When possible, the tests 
and evaluations listed for the termination visit should be carried out. Berg should be notified of 
all subject withdrawals as soon as possible.  
 
If a subject fails to return for the protocol defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, a registered letter, at the minimum, should 
be sent to the subject (or the subject’s legal guardian) requesting contact with the clinic. This 
information should be recorded in the CRF. 
 
The investigator will also withdraw a subject upon Berg’s request or if Berg chooses to terminate 
the study. Upon occurrence of a serious or intolerable adverse effect, the principal investigator 
will confer with the Berg representative. If a subject is discontinued due to an adverse effect, the 
event will be followed until it is resolved, or if not resolved within a reasonable time 
(approximately 30 days), until its clinical relevance and etiology can be reasonably explained. A 
subject may withdraw his or her consent at any time during the study. 
 
If a subject withdraws from the study at any time either at his or her request or at the principal 
investigator’s discretion, the reason for withdrawal will be recorded in the CRF. All subjects who 
withdraw from the study prematurely will undergo all end-of-study assessments, if possible.  
 
Every effort must be made to undertake protocol-specified safety follow-up procedures. 
 
5 
CLINICAL PROCEDURES AND ASSESSMENTS 
The schedule of procedures is given in the following table. Further details are given in the 
protocol. 


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Study Evaluation Schedule  
14-Day Pre-treatment Schedule 
Tests and Study 
Drug Application 
Chemo 
Week 
PK blood 
samples† 
Application of 
C31543 (Calcitriol)
CBC 
with diff 
Comprehensive 
chemistry panel 
Photographic record 
of hair and scalp 
Serumphosphorus and 
Vitamin D 
Patient self-
assessment diary 
††† 
Pre-study 
– 
 
 
* 
* 
* 
* 
* 
Week 1 
(topical 
application prior 
to chemo) 
– 
* 
* 
* 
* 
 
* 
* 
Week 2 †† 
(topical 
application prior 
to chemo) 
– 
 
* 
 
 
 
 
* 
Week 3 
(start of chemo) 
1 
 
* 
* 
* 
 
* 
* 
Week 4 
2 
 
* 
 
 
 
 
* 
Week 5 
3 
* 
* 
* 
* 
 
* 
* 
Week 6†††† 
4 
 
* 
 
 
 
 
* 
Week 7†† 
5 
 
* 
* 
* 
* 
* 
* 
Week 8 
6 
 
* 
 
 
 
 
* 
Week 9 
7 
* 
* 
 
 
 
 
* 
Week 10†††† 
8 
 
* 
 
 
 
 
* 
Week 11  
9 
 
* 
* 
* 
 
* 
* 
Week12  
10 
 
* 
 
 
 
 
* 
Week 13 
11 
* 
* 
 
 
 
 
* 
Week 14†††† 
12 
 
* 
 
 
 
 
* 
Week 15††††† 
13 
 
* 
* 
* 
* 
* 
* 
Week 19†††††† 
 
 
 
 
 
 
 
* 
Week 23†††††† 
 
 
 
 
 
 
 
* 
Week 27††††††† 
 
 
* 
* 
* 
* 
* 
* 


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Week 54††††††† 
 
* 
* 
* 
* 
* 
* 
 
† PK will be collected in the following manner: On Day 1 of topical treatment: PK will be collected pre-dose (before the first dose), and 2 hrs (±30 minutes), 4 hrs (± 30 minutes) and 8 h
post-dose).  
For study Weeks 5, 9, 13, and 54 of calcitriol, PK will be collected on Day 1 pre-dose. This should be 12 hrs (± 2 hrs) after the last application of topical calcitriol. 
†† For the Weeks 2 and 7 visits, patients will be seen by a study Dermatologist at their site. 
††† All patients will be asked to maintain the self-assessment diary for up to approximately 7 months from initial application of study drug. The diary will be filled out weekly for the 
first 15 weeks after initiating calcitriol and at Weeks 19, 23, and 27. 
†††† Note that some patients may be placed on a 3-week-on one-week-off regimen. The indicated weeks will be off-chemo weeks. 
††††† Photographs for patients in each cohort representing baseline, and treatment Weeks 7 and 15 will be presented blind to the study PI after at least 3 patients have completed 15 
weeks of treatment. Photographs will also be taken at Week 27 and Week 54 of the study but will be included in the final photographic assessment as secondary information. 
The PI clinical assessment of the baseline, and Weeks 7 and 15 photographs will be used, together with the patient self-assessment diary information, for the primary 
assessment of alopecia. 
†††††† A patient self-assessment is required this week if treatment continues beyond Week 15. 
††††††† Study assessments will be performed ± 7 days from the scheduled date. 
 
Study Evaluation Schedule  
7-Day Pre-treatment Schedule 
Tests and Study Drug 
Application 
Chemo 
Week 
PK blood 
samples† 
Application of 
C31543 
(Calcitriol) 
CBC 
with 
diff 
Comprehensive 
chemistry panel 
Photographic 
record of hair and 
scalp 
Serumphosphorus 
and Vitamin D 
Patient self-
assessment diary 
††† 
Pre-study 
– 
 
 
* 
* 
* 
* 
* 
Week 1 
(topical application prior 
to chemo) 
– 
* 
* 
* 
* 
 
* 
* 
Week 2†† 
(start of chemo) 
1 
 
* 
* 
* 
 
* 
* 
Week 3 
2 
 
* 
 
 
 
 
* 
Week 4 
3 
 
* 
 
 
 
 
* 
Week 5†††† 
4 
* 
* 
* 
* 
 
* 
* 
Week 6 
5 
 
* 
 
 
 
 
* 
Week 7†† 
6 
 
* 
* 
* 
* 
* 
* 
Week 8 
7 
 
* 
 
 
 
 
* 
Week 9†††† 
8 
* 
* 
 
 
 
 
* 


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Week 10  
9 
 
* 
 
 
 
 
* 
Week 11  
10 
 
* 
* 
* 
 
* 
* 
Week 12 
11 
 
* 
 
 
 
 
* 
Week 13†††† 
12 
* 
* 
 
 
 
 
* 
Week 14 
13 
 
* 
 
 
 
 
* 
Week 15 
14 
 
* 
* 
* 
* 
* 
* 
Week 19†††††† 
 
 
 
 
 
 
 
* 
Week 23†††††† 
 
 
 
 
 
 
 
* 
Week 27††††††† 
 
 
* 
* 
* 
* 
* 
* 
Week 54††††††† 
 
* 
* 
* 
* 
* 
* 
 
† PK will be collected in the following manner: On Day 1 of topical treatment: PK will be collected pre-dose (before the first dose), and 2 hrs (±30 minutes), 4 hrs (± 30 minutes) and 8 h
post-dose).  
For study Weeks 5, 9, 13, and 54 of calcitriol, PK will be collected on Day 1 pre-dose. This should be 12 hrs (± 2 hrs) after the last application of topical calcitriol. 
†† For the Weeks 2 and 7 visits, patients will be seen by a study Dermatologist at their site. 
††† All patients will be asked to maintain the self-assessment diary for up to approximately 7 months from initial application of study drug. The diary will be filled out weekly for the 
first 15 weeks after initiating calcitriol and at Weeks 19, 23, and 27. 
†††† Note that some patients may be placed on a 3-week-on one-week-off regimen. The indicated weeks will be off-chemo weeks. 
††††† Photographs for patients in each cohort representing baseline, and treatment Weeks 7 and 15 will be presented blind to the study PI after at least 3 patients have completed 15 
weeks of treatment. Photographs will also be taken at Week 27 and Week 54 of the study but will be included in the final photographic assessment as secondary information. 
The PI clinical assessment of the baseline, and Weeks 7 and 15 photographs will be used, together with the patient self-assessment diary information, for the primary 
assessment of alopecia. 
†††††† A patient self-assessment is required this week if treatment continues beyond Week 15. 
††††††† Study assessments will be performed ± 7 days from the scheduled date. 
 
 
 
 


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6 
STUDY ENDPOINTS 
6.1 
Maximum Tolerated Dose (MTD) 
The primary objective of this study includes determination of the MTD. A 3+3 dose 
escalation design with 3-6 patients at each dose level is a standard design for this 
objective. The details are given in Section 2.3. 
6.2 
Safety and Tolerability 
The primary objective of this study includes determination of the overall safety and 
tolerability of topical Compound 31543. Safety endpoints include treatment-emergent 
adverse events (AEs), toxicities, and Change from Baseline (CFB) in vital signs, physical 
examinations, and laboratory tests.  
6.3 
Pharmacokinetics (PK) 
Blood samples for PK analysis will be collected at various times, as presented in Section 5. 
Details and results of the PK analyses will be presented in a separate document. 
6.4 
Efficacy  
6.4.1 Subjective record of hair and scalp 
Alopecia will be subjectively recorded through the patient self-reported diaries. All 
patients are asked to maintain this self-assessment diary that will require assessment of 
hair thickness, hair fullness, hair breakage, and hair cosmetic qualities (ease of styling, 
etc.) on an analog 10-point scale throughout treatment to assess patient-reported efficacy 
of the study drug. The diary will be filled out weekly for the first 15 weeks after initiating 
topical Compound 31543l and at Weeks 19, 23, and 27. 
6.4.2 Photographic record of hair and scalp 
Photographic record of hair and scalp will be performed pre-study and Weeks 7, 15, 27, 
and 54. Five views will be obtained at each photographic assessment: bilateral sides of 
head/scalp view, front of head/face view, back of head/scalp view, and top of head/scalp 
view. Additionally, close-up photographs will be taken at the same time points. They will 
include the mid-pattern of the scalp from a superior view and a vertex view with hair 
parted in the center and combed away from the center part. Photographs will be 
standardized for lighting, camera angle, and position to the participants head. 
 
7 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
7.1 
Analysis Populations 
The analyses will be conducted using the populations described below: 
 
The Safety Population consists of all patients who received at least one application 
of topical Compound 31543. Analyses of safety assessments will be performed for 
the Safety Population.  
 


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The Full Analysis Set (FAS) Population is defined as all patients who complete the 
treatment or discontinue due to a DLT. A patient who discontinues due to an AE that 
does not qualify as a DLT will be considered non-evaluable and replaced by another 
patient enrolled at the same dose level. Patients who discontinue for other reasons 
will be considered on a case-by-case basis. In this document, the FAS population will 
be referred to as FAS. 
 
The Evaluable Population is defined as all patients in the Safety Population who 
complete at least one photographic assessment and diary completion through Week 7. 
 
7.2 
General Analysis 
The following standards will be applied for analyses unless otherwise specified. Simple 
descriptive statistics for continuous data are: n (number of non-missing observations), 
mean, SD, maximum, median, and minimum. Categorical data will be summarized by the 
number and percentage of patients in each category. All data will be listed and sorted by 
investigator number, patient number and, where appropriate, by day. Calculation of CFB 
is discussed in Section 8.1.2. If the FAS is the same as the Safety Population, then the 
table or listing will be presented only once. 
7.3 
Patient disposition 
The total number of patients will be presented with the number and percentage of patients 
in each analysis population by cohort and overall. The number and percentage of patients 
who were enrolled, eligible for the study, treated, treated and eligible, not eligible but 
treated, completed the study, discontinued, and primary reason for discontinuation will be 
summarized for all patients enrolled for each dose cohort and overall. 
 
Protocol deviations will be listed. 
7.4 
Demographics, Baseline Characteristics and Medical History 
7.4.1 Demographics 
Demographic parameters, including age, sex, race, and ethnicity will be summarized for 
the Safety and FAS for each dose cohort and overall.  
7.4.2 Medical History and Baseline Disease Characteristics 
Previous therapy for breast cancer (chemotherapy, radiation therapy, surgery, hormone 
therapy, or immunotherapy) will be summarized using frequencies and percentages 
(“Yes” or “No”) for each dose cohort and overall. The above questions will be included 
in a listing, with Therapy Type, Therapy Details, Start Date, End Date, and Occurrence of 
Hair Loss. Detailed cancer history will include time since diagnosis, cancer type, planned 
taxane, and confirmation of ECOG status. General medical history will be coded by 
MedDRA preferred term and body system, and will be summarized. 
7.4.3 Concomitant medications  
Concomitant medications will be summarized by dose cohort and overall. 


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7.5 
Safety and Tolerability 
Safety endpoints include treatment-emergent adverse events (AEs) and CFB for vital 
signs, physical examinations, and laboratory tests. All safety data will be listed. Listings 
of deaths, SAEs, DLTs, and AEs leading to early termination of study treatment will also 
be provided. 
7.5.1 Adverse events 
The original reported (verbatim) terms used by the Investigator to identify adverse events 
will be entered into the database and coded by Preferred Term using the MedDRA coding 
dictionary. Adverse events will then be grouped by MedDRA Preferred Term into 
frequency tables according to System Organ Classification (body system).  
  
Adverse events that started after the initiation of treatment (on or after the day of the 
baseline visit) and those that were present at Baseline and increased in severity during the 
treatment period will be considered as treatment-emergent adverse events. Events ending 
prior to the day of the baseline visit and events present at Baseline that do not increase in 
severity during treatment will be considered as medical history and will not be included 
in the presentation of treatment-emergent adverse events. 
 
The following AE will be produced: 
 All treatment-emergent AEs; 
 Treatment-emergent AEs by relatedness; 
 Treatment-emergent AEs by severity (CTCAE grade); 
 Serious treatment-emergent AEs; 
 Grade 3 or higher treatment-emergent AEs 
 Treatment-emergent AEs of special interest; 
 Common treatment-emergent AEs by cycle. 
 
The number and percentage of patients experiencing treatment-emergent adverse events 
will be presented for the Safety Population for each body system and preferred term by 
treatment group. Treatment-emergent adverse events will also be summarized for each 
severity, and relationship to study medication. When an adverse event occurs more than 
once, the maximum severity and causality will be counted. Deaths, serious adverse 
events, DLTs, and discontinuations due to an adverse event will be provided in separate 
listings for the Safety Population. 
 
 
 


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The maximum grade of the following adverse events of special interest will be 
summarized in separate tables: 
 
Common side effects  
• 
Pruritus 
• 
Skin discomfort 
• 
Skin stinging or burning 
• 
Eye irritation or stinging  
Less common side effects 
• 
Scalp xerosis and flaking 
• 
Erythema 
• 
Irritant dermatitis 
Rare but serious side effects  
• 
Hypercalcemia 
• 
Hypercalciuria 
• 
Renal stones 
• 
Increased thirst 
• 
Increased frequency of urination 
• 
Changes in pulse 
• 
Weakness 
• 
Drowsiness 
• 
Bone pain 
• 
Renal Insufficiency 
 
Common side effects will be reported by cycle and grade in separate tables. The rest will 
be reported in a table of AEs of special interest. 
7.5.2 Dose-Limiting Toxicity (DLT)  
Toxicities will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE v 4.0). Dose-limiting toxicity is defined as a clinically significant grade 
3 or 4 non-hematologic toxicity occurring during the first 28-day treatment cycle of the 
topical agent application, and needs to be possibly, probably, definitely related to topical 
Compound 31543 and not the taxane-based regimen as best determined by investigators. 
7.5.3 Laboratory Assessments 
Laboratory variables will be examined using CFB at each time point for the Safety 
Population by dose cohort. A summary of laboratory values categorized according to the 
CTCAE v4.0; categorized by the worst on-study toxicity grade, dose cohort, and cycle. 
Laboratory variables with CTCAE grading for both low and high values will have both 
reported separately; e.g., glucose will be reported as hypoglycemia and hyperglycemia. 
Laboratory variables without CTCAE grading will be presented to show the number and 
percent of subjects with high, normal, and low (or normal/abnormal) laboratory results by 
cycle. The laboratory assessments are given in Appendix A. 
7.5.4 Pharmacokinetics 
Details and results of the PK analyses will be presented in a separate document. 


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7.5.5 Vital Signs 
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate 
(beats/min), respiration rate (breaths/min), temperature (°C), and weight (kg), and CFB in 
each vital sign, will be listed and summarized for the Safety Population by cohort and 
visit. Height will be recorded and included in listings only.  
7.5.6 Physical Examinations 
Physical examination findings (normal or abnormal) for each body system will be listed. 
7.6 
Efficacy 
All efficacy assessments will be provided for the FAS and the Evaluable Population. 
7.6.1 Subjective record of hair and scalp 
Summary statistics for Questions 1a, 1b, and 1c (related to fullness, thickness, and 
volume) and frequencies for Questions 2 and 3 (Yes / No for hair falling out and hair 
thinning) will be provided for the FAS by cohort and visit. Summary statistics for 
Questions 5a, 5b, and 5c (related to comfort with the study drug, overall confidence in 
hair condition, and overall feeling regarding health of a scale of 1-10) will be provided 
for the FAS and the Evaluable Population by cohort and visit. 
7.6.2 Photographic record of hair and scalp 
Global photographic review will be conducted by one dermatologist reviewer and 
photographs will be evaluated using a 7-point evaluation scale given in the following 
table. 
7-point Scale 
Increase/Decrease 
% of Hair Gain/Loss 
-3 
Greatly decreased 
>75% hair loss 
-2 
Moderately decreased 
50-75% hair loss 
-1 
Slightly decreased 
25-49% hair loss 
0 
No change 
0-24 hair loss/gain 
1 
Slightly increased 
25-49% hair gain 
2 
Moderately increased 
50-75% hair gain 
3 
Greatly increased 
>75% hair gain 
 
The reviewer will compare the photographs acquired at baseline, Week 7 and Week 15. 
Photographs acquired at Week 27 and Week 54 will be assessed in a similar manner, if 
applicable. The dermatologist reviewer scoring the photographs will be blinded to time sequence 
of the photographs aside from the baseline photographs to which all others will be compared. 
Summary statistics for photographic assessments will be provided for the FAS and the Evaluable 
Population by cohort and visit. Summary statistics for photographic assessments will be provided 
for the FAS and the Evaluable Population by cohort and visit. 
 
7.7 
Interim Analysis 
The Cohort Review Committee ( CRC), comprised of the Berg medical monitor, Berg Pharma 
Clinical & Regulatory Consultant, and the principal investigator(s), will be fully aware of 


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clinical and laboratory data, and must agree if dose escalation to the next cohort is appropriate. 
Pharmacokinetic data from each cohort will also be reviewed by the CRC and considered in any 
decision to escalate the dose. Adverse event data from the treatment extension period will be 
presented, when available (at least monthly), to the CRC. These data will be considered for dose 
escalation decisions. In the event that MTD has not been reached after three cohorts have been 
treated, any further dose escalations will require a protocol amendment. 
 
The CRC will review all available data from previous cohorts to assure that the actual dose 
escalation determined in this fashion does not expose subjects to unreasonable risk. The CRC 
may reduce or halt dose escalations for any reason (e.g., observation of non-linear PK, AEs in 
subjects who receive more than one dose of topical Compound 31543). The decision to proceed 
with the next cohort will require unanimous agreement of the members of the CRC. 
 
8 
DATA HANDLING 
8.1 
Data Calculations and Definitions 
8.1.1 Baseline Values 
A patient’s Baseline value will be the last measurement taken before initiation of treatment. 
8.1.2 Change from Baseline (CFB)  
CFB will be calculated at each post-baseline visit for non-missing continuous data as: 
CFB = Post-Baseline value – Baseline value. 
8.2 
Missing Data 
There will be no imputation of missing data. 
 
9 
CHANGES FROM THE PROTOCOL 
No changes in the analyses described in the protocol are planned. If changes are made prior to 
completion of the study, this document will be amended and such changes will be described. 
Any changes in the analyses made after completion of the study will be noted in the study report. 
 
 
 


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10 APPENDIX A – LABORATORY TESTS 
 
 
The following laboratory tests will be performed Pre-Study and at Weeks1, 3, 5, 7, 11, 
15, 27 and 54.  
 
CBC WITH DIFF  
COMPREHENSIVE CHEMISTRY PANEL  
WBC 
Platelet Count 
Hemoglobin 
RBC 
Hematocrit 
MCV 
MCH 
MCHC 
RDW 
Lymphocytes 
Monocytes 
Neutrophils 
Eosinophils 
Basophils 
Large Unstained Cells (LUC) 
Absolute Neutrophil Count 
Absolute Lymphocyte Count 
Absolute Monocyte Count 
Absolute Eosinophil Count 
Absolute Basophil Count 
Absolute Large Unstained Cells 
 
Albumin  
Alkaline phosphatase 
ALT (SGPT) 
AST (SGOT) 
Blood urea nitrogen (BUN) 
Calcium 
Carbon Dioxide 
Chloride 
Creatinine 
Glucose 
Potassium 
Sodium 
Total bilirubin 
Total protein 
 
 
 
 


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APPENDIX A– LABORATORY TESTS (Continued) 
URINALYSIS 
MICROSCOPIC URINALYSIS 
Specific Gravity 
Color 
Clarity  
pH, Urine 
Albumin, Urine 
Glucose, Urine 
Ketones, Urine 
Bilirubin, Urine 
Blood, Urine 
Urobilinogen, Urine 
Leukocyte Esterase, Urine 
Nitrite, Urine 
 
RBC, Urine 
WBC, Urine 
Epithelial 
Crystals, Urine 
Casts 
Bacteria 
Yeast 
Small Round Cells 
Pathological Casts 
Sperm 
Other