Clinical trial NCT04071756
Conditions: Solid Tumor Hand-Foot Skin Reaction (HFSR)
Keywords: Solid Tumor Hand-Foot Skin Reaction (HFSR)
Sponsor: Dana-Farber Cancer Institute
Start date: 2019-12-30; Completion date: 2022-07-14
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research is studying the preventative use of topical 0.1% tazarotene gel daily in addition to best practice standards to reduce the development of hand-foot skin reaction (HFSR).

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved tazarotene for specifically for hand-foot skin reaction but it has been approved for other uses.

In this research study, the investigators are:

-aiming to determine if the use of tazarotene gel daily, in addition to best practice standards:

* reduces the development of HFSR.
* decreases modification of regorafenib dose due to HFSR
* improves health-related quality of life associated with HFSR
* decreases stress associated with HFSR

Arms: arm 1: * Pharmacy teaching call
* DFCI approved teaching sheets will be provided
* 20% urea applied to the palms and soles in the morning + tazarotene 0.1% gel, applied to the palms and soles nightly arm 2: * A substance that has no therapeutic effect, used as a control in testing new drugs
* Pharmacy teaching call
* DFCI approved teaching sheets will be provided
* 20% urea applied to the palms and soles in the morning with placebo gel applied in the evening.
Interventions: intervention 1: Topical Tazarotene intervention 2: Placebo
Intervention descriptions: intervention 1: This medicine works by making the skin less inflamed and reducing the thickness and pain from lesions of the skin intervention 2: A substance that has no therapeutic effect, used as a control in testing new drugs

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #:
N/A
DF/HCC Protocol #: 19-099 
.
TITLE:  A Phase II Randomized Double-Blind Trial of Topical Tazarotene 0.1% Gel Versus Placebo Gel 
for the Prevention of Regorafenib-Induced Hand-Foot-Skin Reaction
Coordinating Center:
Dana-Farber Cancer Institute
450 Brookline Ave
Boston, MA 02215
Principal Investigator (PI):
 Nicole LeBoeuf, MD
Dana-Farber Cancer Institute
450 Brookline Ave
nleboeuf@bwh.harvard.edu
Boston, MA 
Other Investigators:
Cecilia Larocca, MD
 Marianne Tawa, NP
Ashleigh Eberly Puleo, PA-C
 Nicole LeBoeuf, MD, MPH
Christine Cornejo, MD
Stephanie Liu, MD
Manisha Thakuria, MD
Lauren Guggina, MD
Jesse Hirner, MD
Cesar Virgen, MD
John Harran, RN
Zixi Liao, RN
Statistician:
Anita Giobbie-Hurder
NCI-Supplied Agent(s): N/A
Study Exempt from IND Requirements per 21 CFR 312.2(b).  


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Protocol Version Date: 22SEP2022
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Protocol Type / Version # / Version Date:
Version #5/22SEP2022
SCHEMA
*Best Practice Standards (BPS) is defined as pharmacy call, DFCI approved teaching sheets and 20% urea cream 
recommended daily
**Cycle length corresponds to regorafenib cycle length of 28 days. 
 
Included 
Populations: 
Patients with Solid 
Tumors who will 
initiate regorafenib 
REGISTER & RANDOMIZE
Arm A:  
Tazarotene 0.1% gel daily + BPS*
Starting C1D1 of regorafenib therapy
Arm B:  
Placebo gel + BPS*
Starting C1D1 of regorafenib therapy**
Grade ≥ 2 
HFSR
 within 8 
weeks
End of 
Study 
Visit


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TABLE OF CONTENTS
1.
OBJECTIVES......................................................................................................................9
1.1
Study Design............................................................................................................9
1.2
Primary Objectives...................................................................................................9
1.3
Secondary Objectives...............................................................................................9
2.
BACKGROUND .................................................................................................................9
2.1
Study Disease(s).......................................................................................................9
2.2
IND Agent..............................................................................................................10
2.3
Rationale ................................................................................................................10
2.4
Correlative Studies Background ............................................................................11
3.
PARTICIPANT SELECTION...........................................................................................11
3.1
Eligibility Criteria..................................................................................................11
3.2
Exclusion Criteria ..................................................................................................12
3.3
Inclusion of Women and Minorities ......................................................................13
4.
REGISTRATION and Randomization PROCEDURES ...................................................13
4.1
General Guidelines for DF/HCC Institutions ........................................................13
4.2
Registration Process for DF/HCC Institutions.......................................................14
5.
TREATMENT PLAN........................................................................................................14
5.1
Treatment Regimen................................................................................................15
5.2
Pre-Treatment Criteria ...........................................................................................15
5.3
Agent Administration.............................................................................................15
5.4
General Concomitant Medication and Supportive Care Guidelines......................16
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................16
5.6
Duration of Follow Up...........................................................................................17
5.7
Criteria for Taking a Participant Off Study ...........................................................17
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................17
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................18
7.2
Adverse Event Characteristics...............................................................................19
7.3
Adverse Event Reporting.......................................................................................19
7.4
Reporting to the Food and Drug Administration (FDA) .......................................19
7.5
Reporting to Hospital Risk Management...............................................................20
7.6
Adverse Event Characteristics............................................................................20
7.7
Routine Adverse Event Reporting .........................................................................20


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8.
PHARMACEUTICAL INFORMATION..........................................................................20
8.1
Tazarotene..............................................................................................................20
8.2
Placebo...................................................................................................................22
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................23
9.1
Biomarker Studies..................................................................................................24
9.2
Laboratory Correlative Studies..............................................................................24
10.
STUDY CALENDAR .......................................................................................................25
11.
MEASUREMENT OF EFFECT .......................................................................................26
11.1
Antitumor Effect – Solid Tumors ..........................................................................27
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................27
12.1
Data Reporting.......................................................................................................27
12.2
Data Safety Monitoring..........................................................................................27
12.3
Collaborative Agreements Language.....................................................................28
13.
STATISTICAL CONSIDERATIONS...............................................................................28
13.1
Study Design/Endpoints ........................................................................................28
13.2
Sample Size, Accrual Rate and Study Duration ....................................................28
13.3
Stratification Factors..............................................................................................29
13.4
Interim Monitoring Plan ........................................................................................29
13.5
Analysis of Primary Endpoints..............................................................................29
13.6
Reporting and Exclusions ......................................................................................30
14.
PUBLICATION PLAN .....................................................................................................30
15.
APPENDIX A PERFORMANCE STATUS CRITERIA..................................................32
16.
APPENDIX B: Tazarotene or Placebo Drug Diary...........................................................33
17.
APPENDIX C: Examples of potent inhibitors or inducers of cytochrome p450 3a4........34
18.
APPENDIX D: Study Questionnaires 1-5.........................................................................35
19.
APPENDIX E: Tazarotene or Placebo Preparation Instructions.......................................47
REFERENCES ..............................................................................................................................48


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1.
OBJECTIVES
1.1
Study Design
This is a prospective, randomized, double-blind, signal detection trial comparing placebo gel plus best practice 
standards (BPS) with topical tazarotene 0.1% gel plus BPS for the prevention of grade-2 or greater HFSR in 
patients treated with regorafenib monotherapy.  BPS is defined as 20% urea cream + DFCI approved teaching 
sheets + pharmacy call for oral chemotherapy teaching.  
1.2
Primary Objectives
To test the hypothesis that the preventative use of 0.1% tazarotene gel daily in addition to BPS (20% urea cream 
daily, with pharmacy call and DFCI approved teaching sheets) reduces the development of grade-2 or greater 
hand-foot skin reaction (HFSR) compared with placebo gel plus BPS. 
1.3
Secondary Objectives
(1) To test the hypothesis that the preventative use of 0.1% tazarotene gel daily in addition to BPS: 
a.
Decreases regorafenib dose modification due to HFSR
b. Improves health-related quality of life associated with HFSR as assessed by skindex-16 survey, 
dermatology quality life index (DLQI) and hand-foot syndrome 14-item scale (HFS-14) prior to 
initiating the TKI, then at 2-4 week intervals depending on the tool
c.
Decreases global stress associated with HFSR as measured prior to initiating the TKI, then at 4 
week intervals using the 10-item perceived stress scale (PSS), which has been validated in both 
healthy people and cancer patients.
2. BACKGROUND
2.1
Study Disease(s)
Tyrosine kinase inhibitors (TKI) are approved for the management of broad-reaching cancers that include 
colorectal cancer, renal cell carcinoma, gastrointestinal stromal tumors (GIST), pancreatic neuroendocrine 
tumor, thyroid and liver malignancies. Such targeted therapies are associated with different adverse events than 
their cytotoxic predecessors, with a greater frequency of side effects in the skin.  
The most frequent toxicities with TKIs are dermatologic, particularly hand-foot skin reaction (HFSR) occurring 
in all grades in 40-85% of patients on regorafenib1, 34% of patients on sorafenib2 and 19% of patients on 
sunitinib3; grade 3 HFSR is reported at 13-33%1, 9%2 and 6%3 for each of the drugs respectively. The incidence 
of HFSR of any grade from regorafenib is highest in renal cell carcinoma (71.4%) followed by GIST (60.2%), 
hepatocellular carcinoma (50%) and metastatic colorectal carcinoma (46.6%).4 Grade-3 toxicity from HFSR is 
defined by severe skin changes that are painful and may include blisters, bleeding, edema and hyperkeratosis.5  
Grade-3 toxicities limit self-care activities of daily living (ADLs). Importantly, grade-2 HFSR, a more common 
event, is also associated with pain, and limits instrumental ADLs. HFSR is one of the most, if not the most, 
common reason for dose reduction, interruption or discontinuation of regorafenib therapy.6,7,8,9 


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HFSR has been shown to negatively impact health-related quality of life (HRQOL), more severely with higher-
grade disease, as measured using the skindex-16 score, which incorporates symptom, emotion and function 
domains.10  
Importantly, in the absence of evidence from prospective trials on the prevention of this toxicity, the current 
recommendation for patients with grade-3 toxicity is to hold the drug until severity declines.  When the dose is 
restarted, it is done so at a lower level. With grade-2 toxicity, dose reduction is considered first line. 
Recommendations for supportive care are varied and based primarily on expert opinion or consensus from 
historical experience with similar eruptions.  In the oncology literature, the focus tends to be on how best to 
reduce doses and reinstitute the TKI.  
Given the number of malignancies treated with TKIs, the increasing numbers of TKIs in trials, the long-term 
duration of therapy required, the frequency of HFSR with these medications, the impact on dose and therefore 
potential outcomes and the impact on patient quality of life, prospectively evaluated preventative measures are 
imperative such that evidence based, patient-centered guidelines can be developed. Given that regorafenib has 
highest rates of HFSR, the drug’s dose-limiting toxicity, this study aims to provide an evidenced-based 
approach to preventing or reducing severity of HFSR.  
2.2
IND Agent
Tazarotene 0.1% gel is a topical retinoid that was FDA approved in 1997 for the treatment of psoriasis and 
acne.  It is converted via rapid de-esterification to its active form (“tazarotenic acid”) in humans, which binds to 
retinoic acid receptors (RAR).  While relatively selective for RARβ, it binds all three RAR, including RARα 
and RARγ.  In psoriasis models, tazarotene blocks epidermal proliferation as well as inflammation. This class of 
topical medications is thought to be overall anti-hyperproliferative and to normalize differentiation of 
keratinocytes.  
2.3
Rationale
There are no clinical or molecular risk factors that have been shown to predict those patients who are predisposed 
to the development of HFSR. The addition of friction/trauma and heat seems to play a role. Current treatment of 
HFSR is based on avoiding triggers and treating hyperkeratosis with urea-based products. Urea is a keratolytic 
and is thought to soften and breakdown thickened skin. There are no studies or trials published to date that attempt 
to address the underlying pathophysiology of HFSR, rather studies to date have only tried to suppress the clinical 
features and symptoms.
While, the pathophysiology of HFSR is still being elucidated, there have been a multitude of studies proposing 
several mechanisms. Some preclinical evidence suggests that there is dysregulation in keratinocyte 
differentiation, leading to hyperkeratosis, pain and inflammation in the setting of tyrosine kinase inhibition. 
This clinically and histologically resembles palmoplantar psoriasis in many cases.  These findings are supported 
by the histopathology of HFSR as demonstrated by acanthosis, papillomatosis, hyperkeratosis and necrosis.11 
More recently, direct keratinocyte toxicity via anion transporter, OAT6, has been implicated in HFSR in the 
setting of sorafenib use.12 Additionally, several studies have implicated the inhibition of anti-angiogenic 
receptors such as PDGFR and VEGFR in the etiology of HFSR.13 


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Retinoids are vitamin A derivatives that act on the nuclear receptors RAR and/or RXR. These receptors are 
highly expressed in keratinocytes and control a variety of cellular differentiation functions. Topical tazarotene 
gel is FDA approved for use in psoriasis, a hyperproliferative cutaneous disorder. Psoriasis shares many clinical 
and histopathological features with HSFR and both are caused by keratinocyte dysregulation. Tazarotene has 
been shown to have anti-inflammatory properties and normalize keratinocyte differentiation. Most recently, the 
RAR receptor blockade, specifically with tazarotene, has been shown to locally promote angiogenesis and may 
address the anti-angiogenic physiology of HFSR.14  In our experience, patients with established HFSR have 
responded to both topical and oral retinoids with marked improvement in symptoms.  
By pre-emptively normalizing keratinocyte differentiation, decreasing inflammation associated with 
keratinocyte toxicity and locally promoting angiogenesis, we propose that topical retinoids, in addition to best 
practice standards, will diminish the incidence of HFSR, decrease dose modifications due to HFSR, decrease 
impact on patient quality of life and decrease global stress in those treated with regorafenib.  To address our 
objectives, we propose a randomized signal detection trial to assess the preventative effectiveness of tazarotene 
plus best practices standards (BPS) compared with BPS alone.
2.4
Correlative Studies Background
-
The primary goal of the correlative science is to begin to understand the pathways involved in the 
development of HFSR and, ideally, those pathways that are disrupted by our interventions
-
Day 1 and 4 week (+/- 2 weeks) skin biopsies will be obtained from a cohort of 12 patients. Pre-biopsies 
will be taken from the lateral palm.  On study biopsies will be taken from the same area in unaffected 
patients and from diseased areas in affected patients. 
-
A 4mm punch biopsy will be obtained from 12 patients (6 in each study arm); we suspect that half of 
patients in the control arm will develop HFSR on regorafenib and half will not.  This will allow for 
comparison across arms and between affected and non-affected individuals to look for a signal of 
difference. 
-
Biopsies with be analyzed using standard immunohistochemistry and cyclic immunofluorescence, for 
the presence of activation of transcription factors known to be associated with hyper-proliferative 
inflammatory acquired and genetic skin disorders. Additionally, RNA transcriptional profiling will be 
performed to compare those patients who develop HFSR from those who do not using the nanostring 
platform on formalin-fixed, paraffin embedded tissue. 
3. PARTICIPANT SELECTION
3.1
Eligibility Criteria 
3.1.1
Participants must have histologically or cytologically confirmed solid tumors with a plan to initiate regorafenib, 
or having started regorafenib in the last 96 hours, via dose escalation protocol describe in the ReDOS study in 
CRC. The ReDOS study recommends this dose escalation of regorafenib:80mg daily x 1 week, 120mg daily x 1 
week, 160mg daily times one week, off week, then 160mg daily goal, or maximum tolerated dose thereafter. 
This is not a separate study; this is the current standard of care for regorafenib dosing.  In addition, to compare 


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across the cohorts, patients must be ambulatory with full use of all 4 distal extremities.  
3.1.2
Age ≥ 18  
3.1.3
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
3.1.4
Participants must have sufficient organ and marrow function in the opinion of the treating investigator. 
This can be based on lab reports from an outside facility. 
3.1.5
Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of 
study participation
Tazarotene is known to be teratogenic, although the dose required with topical application to affect 
the developing human fetus is unknown.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her treating 
physician immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months after 
completion of administration.
3.1.6
Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test.
3.1.7
Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
 Known hypersensitivity to tazarotene
3.2.2
 Regorafenib use in combination with another TKI  (unless regorafenib was started in the last 96 
hours.)
3.2.3     Pregnancy or non-compliance with contraception (4 weeks before, during and for at least 3 
ovulatory cycles after treatment cessation).  Pregnant women are excluded from this study because 
tazarotene is category X with the potential for teratogenic or abortifacient effects.  
3.2.4        Nursing or lactating:  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with tazarotene, breastfeeding should be discontinued if 
the mother is treated.  
3.2.5       A history of hypervitaminosis A
3.2.6        Other systemic retinoids needed for another condition (ie. Isotretinoin for inflammatory acne, 
acitretin for psoriasis, bexarotene for CTCL).   
3.2.7         Need for treatment dose systemic steroids or systemic immunosuppressive agents (i.e., for 
autoimmune disease or cerebral edema) at the time of enrolment
3.2.8        Psoriasis or other autoimmune disease requiring skin directed or systemic therapy known to 
impact keratinocyte proliferation (UV therapy to the hands or feet, TNF inhibitors, etc). 


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3.2.9
Active skin disease of the hands or feet with redness, scaling or blisters prior to enrolment
3.2.10  Participants who have had any systemic chemotherapy or immunotherapy within 4 weeks prior to 
entering the study AND who have not recovered from adverse events on the hands and feet due to 
the agents administered.  
3.2.11  Participants who are receiving any other investigational agents to treat HFSR.  
3.2.12  Uncontrolled intercurrent illness including, but not limited to, uncontrolled lower extremity edema, 
ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION AND RANDOMIZATION PROCEDURES 
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. 
Registrations must occur prior to the initiation of any protocol-specific therapy or intervention. Any participant 
not registered to the protocol before protocol-specific therapy or intervention begins will be considered 
ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-
specific eligibility checklist.
Regorafenib is not a drug that is prescribed by the Cutaneous Oncology team. This study’s recruitment relies 
entirely on receiving referrals from other disease centers. Due to the fact that patients are referred from these 
outside disease centers (such as Sarcoma and GI) and that regorafenib may require insurance clearance and then 
mailing, we expect that screening and randomization may occur on the same day. 
In an effort to increase accrual and more quickly identify potential participants that have been prescribed 
regorafenib in other departments within the Institute, COC will be utilizing an EPIC report to assist in the 
recruitment of participants. This report has been built in collaboration with pharmacy to identify patients that 
have been prescribed regorafenib within the last 7 days. This report can be run by the study team at any time. 
The COC study team may reach out to the prescribing physician to ask their permission to contact their patient 
directly to describe this research study and see if they would be interested in participating in this study. 
The eligibility checklist(s) and all pages of the consent form(s) will be faxed to the ODQ at 617-632-2295. The 
ODQ will (a) review the eligibility checklist, (b) register the participant on the protocol, and (c) randomize the 
participant. ODQ will send the randomization to the research pharmacy. 
Randomization can only occur during ODQ business hours (8:30am - 5pm Eastern Time, Monday through 
Friday excluding holidays).


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An email confirmation of the registration and/or randomization will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person immediately following the 
registration and/or randomization.
Following registration, participants may begin protocol-specific therapy and/or intervention. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator (PI). If the subject does not 
receive protocol therapy following registration, the subject must be taken off-study in the CTMS (OnCore) with 
an appropriate date and reason entered.
  
Emergency un-blinding during the clinical trial may be required during the course of the trial to assist in the 
proper treatment of an AE or for regulatory reasons (e.g. for expedited safety reporting). For emergency un-
blinding, the PI will need to be contacted. The PI will then send a written request (i.e. email) for an emergency 
un-blinding to the administrative person on call from IDS pharmacy.
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
5.
TREATMENT PLAN
This is a prospective, randomized, double-blind signal detection trial comparing placebo gel plus BPS (20% 
urea + DFCI approved teaching sheets + pharmacy call) to tazarotene 0.1% gel plus BPS for the prevention of 
HFSR in patients treated with regorafenib.  Each study cycle is 28 days long.
At the time of consent for regorafenib, patients will be invited to participate, consented and enrolled. Patients 
may already have had their first dose of regorafenib before consenting to this study, as long as regorafenib was 
started less than 96 hours from first application of tazarotene.  Patients will be randomized 1:1 to receive either 
placebo gel plus best practice standards (BPS) or BPS plus tazarotene 0.1% gel daily.  The current standard of 
care for Regorafenib includes providing patients with oral chemotherapy teaching sheets that include a Hand 
Skin Foot Reaction teaching sheet, pharmacy instruction and 20% urea cream daily.  Participants in both arms 
will have urea recommended as standard best practice standards. It is available over the counter and will not be 
supplied.  
Patients will receive regorafenib for their malignancy per their treating medical oncology team.  Regorafenib is 
not provided as part of this study. The study team will not be making any recommendations for dose, timing of 
dose, concomitant medications associated with regorafenib use or prohibited foods while on regorafenib. All 
patients must have a plan to be treated with dose-escalation of regorafenib based on the reDOS study.  The 
reDOS study uses this regimen: 80mg daily for week 1, 120mg daily for week 2, 160mg daily for week 3, hold 
drug for week 4, and then 160mg daily for each subsequent cycle with escalation and maintenance based on 
tolerability.  All regorafenib dose adjustments are made at the discretion of the treating medical oncology team.  
This study team will not make any regorafenib recommendations.  Treatment with tazarotene 0.1% gel or 
placebo is continued daily during the week that regorafenib is held.
Outcomes will be assessed by a dermatology provider at 2-week intervals until 8 weeks, then again at week 12, 


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16, 20, and 24.  If HFSR develops, with evidence of inflammation, patients will be treated at the discretion of 
the treating physician in both arms of the study.  
Clinical and patient demographic factors will be collected.  These will include age, gender, BMI, malignancy 
characteristics, smoking status, occupation, hobbies, activity level, co-morbidities, marital/relationship status, 
ECOG performance status, prior therapies and prior dermatologic history.  
Surveys listed in the study calendar will be delivered in the clinic setting. They may be given in either paper or 
electronic formats. Every effort will be made to collect the surveys at the required timepoints. Missing data on 
the questionnaires, either an incomplete or missing survey will be documented but will not be considered a 
protocol deviation. Survey data will be collected at the designated clinic visits+/- a 3 days window to increase 
our survey return response rates. Patients may complete the surveys at home, and mail them back to the study 
team.
The primary endpoint is the development of grade-2 or greater HFSR within 8 weeks of starting protocol 
therapy.  This endpoint is chosen based on its significance of this toxicity grade on ADLs and dose 
modification. It is the endpoint time used in the reDOS study, as it allows for 2 full cycles of therapy, one with 
regorafenib dose escalation and one at maximum tolerated dose.  It was also chosen to minimize the risk of drop 
out. 
5.1
Treatment Regimen
Control arm:  Pharmacy teaching call, DFCI approved teaching sheets and 20% urea applied to the palms and 
soles in the morning with placebo gel applied in the evening.  
Intervention arm:  Pharmacy teaching call, DFCI approved teaching sheets and 20% urea applied to the palms 
and soles in the morning + tazarotene 0.1% gel, applied to the palms and soles nightly. 
Both arms will receive standard chemotherapy teaching call from pharmacy as well as the DFCI approved 
teaching sheets in patient education handouts.  No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant's HFSR.
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1
N/A.  There are no pretreatment criteria for this study
5.2.2
Subsequent Cycles 
Patients will continue topical therapy as long as the regorafenib treatment plan is not discontinued permanently. 
5.3
Agent Administration
Administration – Tazarotene 0.1% gel or placebo will be applied topically every night.   Those patients 
experiencing < grade 2 HFSR will be allowed to continue through 24 weeks.  If the endpoint of grade 2 or 


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greater HFSR is reached, this will be treated at the physician’s discretion.  Please note, with participants with 
large hands and feet, it is permissible to dispense two 30 gm tubes of Tazarotene 1% gel/Placebo. Earlier visits 
for dispensing are allowed if participants run out of drug early.  
Dosing – Tazarotene 0.1% gel or placebo gel will be applied at 8 pm +/- 4 hours.  Urea cream, if recommended 
as part of BPS will be applied at 8am +/- 4 hours.  
½ Fingertip unit will be applied per palm/sole (1FTU=2% BSA).  1gram of gel covers 4% BSA.  1 palm is 1%, 
therefore patients will be prescribed 30g per 28-day period.  
Patients will document application in a drug diary.  See Appendix B.
Caregiver Precautions – Tazarotene should not be dispensed by a pregnant woman.  If this is required, the 
caregiver should wear gloves.  
Missed doses should be skipped entirely. 
Please refer to Appendix E: Tazarotene or Placebo Preparation Instructions
5.4
General Concomitant Medication and Supportive Care Guidelines
Concomitant use of systemic retinoids, treatment dose steroids or topical steroids for HFSR prior to the 
development of symptoms is prohibited.  Other systemic agents for the treatment of HFSR are prohibited. 
Topical agents beyond that outlined as best practice standards (“BPS”) are prohibited.  
Because there is a potential for interaction of Tazarotene with other concomitantly administered drugs through 
the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-
counter medications, or alternative therapies.  The Overall PI should be alerted if the participant is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes.  Appendix C presents 
guidelines for identifying medications/substances that could potentially interact with the study agent(s).
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of HFSR development, progression and 
tolerance of tazarotene. In the absence of treatment delays due to adverse event(s), treatment may continue for 
up to 24 weeks or until one of the following criteria applies:

HFSR grade >/=2 develops and fails to respond to supportive interventions at the treating physician 
discretion

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the topical medication regimen 


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and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant unacceptable for 
further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the case 
report form (CRF). Alternative care options will be discussed with the participant.
When a participant is removed from protocol therapy and/or is off the study, the relevant Off-Treatment/Off-
Study information will be updated in OnCore.
Participants may be removed from the protocol therapy, but remain on study for the duration of the follow up 
period. 
5.6
Duration of Follow Up
Participants will be followed for a minimum of 28 days (4 weeks) after removal from protocol therapy or until 
death, or regorafenib discontinuation with resolution of HFSR, whichever occurs first.  Participants who do not 
develop HFSR who discontinue regorafenib do not require follow up after removal from protocol therapy. 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event. Once removed from protocol therapy, study assessments (PE, vitals, 
questionnaires) will take place at visits paired with medical oncology SOC visit schedule. 
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be documented in 
the case report form (CRF). In addition, the study team will ensure Off Treatment/Off Study information is 
updated in OnCore in accordance with DF/HCC policy REGIST-101.
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). 
Dose Modification Table:


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Event
Management/Next Dose for 
Tazarotene/Placebo
≤ Grade 1 (mild 
irritation or peeling 
without pain or 
significant erythema 
on the non-
palmoplantar skin)
No change in dose
Grade 2 (Erythema 
or irritation on the 
non-palmoplantar 
skin requiring 
intervention)
-
Decrease frequency of 
application to every other day.
-
Apply Vaseline to 
dorsal hands and feet prior to 
application of tazarotene to 
palms
Grade 3 (Erosions or 
bullae on the non-
palmoplantar skin)
-
Hold tazarotene until 
grade ≤ 2
-
Apply Vaseline to 
dorsal hands and feet prior to 
application of tazarotene to 
palms
-
Decrease frequency of 
application to two times a 
week.
If drug is held, study assessments will still continue.
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of 
reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting.
7.1.1
Adverse Events List(s)
7.1.1.1
Adverse Event List(s) for Tazarotene
Reported adverse events with tazarotene include pruritus, burning/stinging, erythema, worsening of 
psoriasis, irritation, skin pain, rash, desquamation, irritant contact dermatitis, skin inflammation, 
fissuring, bleeding and skin discoloration.


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7.2
 Adverse Event Characteristics

All adverse events will be graded using CTCAE v 5.0.  Cutaneous AEs due to topicals will also be 
characterized as in the dose modification table (section 6.0 and 7.3.4). Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Adverse Event Reporting 
7.3.1
In the event of an unanticipated problem or life-threatening complications treating investigators must 
immediately notify the Overall PI.
7.3.2
Investigators must report to the Overall PI any adverse event (AE) that occurs after the initial dose of 
study treatment, during treatment, or within 28 days of the last dose of treatment on the local 
institutional SAE form. 
7.3.3
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research 
Studies (OHRS) per the DFCI IRB reporting policy. 
7.3.4
Protocol-Specific Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to the Overall PI 
or the DFCI IRB.  However, they still must be reported through the routine reporting mechanism (i.e. 
case report form).

≤ Grade 1 (mild irritation or peeling without pain or significant erythema on the non-
palmoplantar skin)

Grade 2 (Erythema or irritation on the non-palmoplantar skin requiring intervention)

Any AE definitely or probably related to regorafenib
7.4
Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall PI will 
report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the FDA’s criteria 
for expedited reporting following the reporting requirements and timelines set by the FDA.
7.5
Reporting to Hospital Risk Management


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Participating investigators will report to their local Risk Management office any participant safety reports, 
sentinel events or unanticipated problems that require reporting per institutional policy. 
7.6
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event varies in 
nature, intensity or frequency from the expected toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the next section 
(Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited Adverse 
Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.7
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case 
report forms.  AEs will not be reported to the drug manufacturer. AEs reported through expedited processes 
(e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. AEs should 
be reported using the CTCAE v. 5.
8.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational administered in this study can 
be found in Section 7.1.
8.1
Tazarotene
8.1.1
Description
Tazarotene is a member of the acetylenic class of retinoids and its chemical name is:  Ethyl 6-[2-(4,4-
dimethylthiochroman-6-yl) ethynyl] nicotinate.  The molecular weight is 351.46.
Following topical application, tazarotene rapidly undergoes esterase hydrolysis to form its active 
metabolite, tazarotenic acid.  Tazarotenic acid is highly bound to plasma proteins (>99%) and little 


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parent compound is found after topical application and esterification.  Tazarotene and tazarotenic acid 
are metabolized to sulfoxides, sulfones and other polar metabolites which are eliminated through urinary 
and fecal pathways. The half-life of tazarotenic acid is approximately 18 hours.
8.1.2
Form
Tazarotene 0.1% gel is available in a collapsible aluminum tube with a tamper-evident aluminum 
membrane over the opening and a white polypropylene screw cap, in 15g and 30g sizes. 
8.1.3
Storage and Stability
Store at 25 degrees C (77 degrees F), with excursions permitted between -5 and +30 degrees C (23 and 
86 degrees F)
8.1.4
Compatibility
N/A
8.1.5
Handling
If a person other than the patient is applying the gel, gloves should be worn or hands washed following 
application.  
8.1.6
Availability
Tazarotene 0.1% gel is available from various manufacturers and will be distributed by research 
pharmacy. Bayer will provide funding to cover the cost of the Tazarotene.  
8.1.7
Preparation
A 30 gram tube will be supplied to the patient monthly (every 4 weeks). For participants with larger 
hands and feet, it is permissible to dispense two 30 gm tubes of Tazarotene 1% gel/Placebo. Earlier 
visits for dispensing are allowed if participants run out of drug early.  Please refer to Appendix E: 
Tazarotene or Placebo Preparation Instructions
8.1.8
Administration
½ Finger tip unit will be applied per palm/sole (1FTU=2% BSA).  1gram of gel covers 4% BSA.  1 palm 
is 1%, therefore patients will be treated with 30g per 28 day period.  
One finger tip unit (FTU) is defined as the quantity of medication dispensed from a 5mm standard 
nozzle from the palmar side distal index finger crease to the tip.  


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8.1.9
Ordering
The agent is commercially available and will be ordered to ensure sufficient stock before protocol 
activation.  
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful record 
of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) 
or another comparable drug accountability form.  (See the NCI Investigator’s Handbook for Procedures 
for Drug Accountability and Storage.)
8.1.11 Destruction and Return
Unused supply of tazarotene will be returned to pharmacy and weighed for drug accountability at the 4-
week, 8 week and 12 week study visits. 
8.2
Placebo
8.2.1 Description
Clear Wave Ultrasound Gel will be used as the placebo in this study as it closely matches the color and 
consistency of the active Tazarotene and is alcohol-free.
8.2.2 Form
Clear Wave Ultrasound Gel is available in 8oz tubes
8.2.3 Storage and Stability
Store at controlled room temperature
8.2.4 Compatibility
N/A
8.2.5 Handling
If a person other than the patient is applying the gel, gloves should be worn or hands washed following 


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application.
8.2.6 Availability
Clear Wave Ultrasound Gel is available in 8oz tubes and will be paid for by the study cost center
8.2.7 Preparation
A 30-gram tube will be supplied to the patient monthly (every 4 weeks). For participants with larger hands and 
feet, it is permissible to dispense two 30 gm tubes of Tazarotene 1% gel/Placebo. Earlier visits for dispensing 
are allowed if participants run out of drug early.  Please refer to Appendix E: 
Tazarotene or Placebo Preparation Instructions for study drug preparation.
8.2.8 Administration 
One half finger tip unit will be applied per palm/sole (1FTU=2% BSA). 1-gram gel covers 4% BSA. 1palm is 
1%, therefore patients will be treated with 30gm per 28-day period.
One finger tip unit (FTU) is defined as the quantity dispensed from a 5mm standard nozzle from the palmar side 
distal index finger crease to the tip.
8.2.9 Ordering
Clear Wave Ultrasound Gel is commercially available and will be ordered to ensure sufficient stock and paid 
for by the study cost center.
8.2.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful record of the 
inventory and the disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another 
comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage)
8.2.11 Destruction and Return
Unused supply of tazarotene or placebo will be returned to pharmacy and weighed for drug accountability at the 
4-week, 8 week, and 12-week study visits.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Correlative studies are optional.  
Patients will be asked if they would like to participate until 16 patients are identified.  
-
Day 1  and 4-week (+/- 2 weeks) skin biopsies will be obtained and processed in formalin fixed, paraffin 
embedded blocks.  The pre-biopsy will be obtained from the non-dominant lateral palm.  The 4-week 
biopsy will be obtained from the same area or an area of HFSR, if present.  
-
A 4mm punch biopsy will be obtained from up to 16 patients (up to 6 will be analyzed in each study 
arm); we suspect that half of patients in the control arm will develop HFSR on regorafenib and half will 
not.  This will allow for comparison across arms and between affected and non-affected individuals to 
look for a signal of difference. 


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Biopsies will be analyzed using standard immunohistochemistry and cyclic immunofluorescence, for the 
presence of activation of transcription factors known to be associated with hyper-proliferative inflammatory 
acquired and genetic skin disorders. 
Additionally, RNA transcriptional profiling will be performed to compare those patients who develop HFSR 
from those who do not using the Nanostring platform on formalin-fixed, paraffin embedded tissue.  Gene sets 
previously developed for inflammatory skin disorders will be used. 
Skin biopsy specimen collection and shipment will be paid for by Bayer Pharmaceuticals. 
Left over specimens will be banked for future use.
The study team will have access to banked specimens.
 
9.1
Biomarker Studies
N/A
9.2
Laboratory Correlative Studies
9.2.1
Optional Correlative Skin Biopsies #1
9.2.1.1
Collection of Specimen(s): 4 mm skin punch biopsy. Skin biopsy will be placed in formalin at time 
of collection.
9.2.1.2
Handling of Specimens(s): Skin biopsy will be sent to the pathology core on the same day of 
collection to be made into a FFPE block. 
Specialized Histopathology Core
Brigham and Women’s Hospital
75 Francis St. Thorn 604/603b
Boston, MA 02115
FFPE blocks will be stored in the PI’s office at 375 Longwood Ave, LW510 Boston, MA 02215 
until all patient FFPE blocks have been obtained. At that time, they will be sent in a batch to be cut 
into slides.
9.2.1.3
Shipping of Specimen(s): Slides will be couriered over to the Sorger Lab for analysis once all patient 
biopsies have been obtained.
9.2.1.4
Site(s) Performing Correlative Study: 
Sorger Lab
Peter Sorger, PhD.Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, Room 440
Boston, MA 02115
 Tel: (617) 432-6901
Peter_sorger@hms.harvard.edu
Administrative Coordinator:
Christopher Bird
 Tel: (617) 432-6902
Christopher_bird.hms.harvard.edu


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10. STUDY CALENDAR
Baseline evaluations are to be conducted within 1 month prior to start of protocol therapy.  
Assessments must be performed prior to administration of any study agent. Study assessments and agents 
should be administered within + 3 days of the protocol-specified date, unless otherwise noted.


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11. MEASUREMENT OF EFFECT
Response criteria in this study are the CTCAE toxicity criteria measuring palmo-plantar erythrodysethesia.  
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Pre-
Study
Day 1 
(Wk0)
Day 
15 
(Wk
2)
Day 28 
(Wk 4)
Day 42 
(Wk 6)
Day 56 
(Wk 8)
Day 84 
(Wk 12)
Day 112 
(Wk 16)
Day 140 
(Wk 20)
Day 168 
(Wk 24)
Off Studyf
-28 days
+/-3 
days
+/-3 
days
+/-3 
days
+/-3 
days
+/-7 
days
+/-7 
days
+/-7 
days
+/-7 
days
28 days +/- 7
First dose of  Regorafenib
X
First dose of Tazarotene
X (no more 
than +/- 96 
hours from 
first 
Regorafenib 
dose)
Study Drug Dispensation: 
Tazarotene or placeboa
X
X
X
X
X
X
X
Study Drug Accountability: 
Tazarotene or placebo
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X------------------------------ ------------------------------------------------------------------------------X
Physical exam
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
Questionnaires: HFS-14, 
Epidemiology Questionnaire, 
DLQI, Skindex16, Perceived 
Stress Scale Assessments b
X
X
X
X
X
X
X
X
X
Adverse event evaluation
X---------------------------------------------------------------------------------------------------------X
X
B-HCGc
X
Other optional correlative 
skin biopsiesd
X
X (+/- 
2 wk)
ODQ Randomizatione
X
a:
Tazarotene or placebo dispensation. Tazarotene will be dispensed at the pre-study visit. Tazarotene dosing starts on Day 1 along with the first dose of 
regorafenib. Day 1 regorafenib and tazarotene/placebo dosing could possibly occur on the same day as the pre-study visit, after the patient has been 
registered and randomized; this would not be considered a protocol deviation. The starting dose of regorafenib is what is considered Day 1 and all other 
timepoints are based on that. There is no required order for the Day 1 regorafenib and tazarotene/placebo doses. It is preferred that the patients begin their 
tazarotene/placebo dose on the same day as their start of regorafenib dose (on Day 1). If however for whatever reason patients begin their 
tazarotene/placebo dose +/- 96 hours (4 days) from their first regorafenib dose, this will not be considered a protocol deviation, but will be noted in the 
data. 
b:
Epidemiology questionnaire should be completed once at screening. All other questionnaires should be collected at the indicated timepoints. These may be 
collected in either paper or electronic formats.
c:      Serum pregnancy test (women of childbearing potential ONLY).
d:      Optional skin biopsies will be obtained from a cohort of 6 patients in each arm (first 6 patients in each arm that consent to these optional biopsies)
e:      Randomization occurs after all screening assessments have been completed and the patient’s eligibility has been confirmed. This could be the same day as 
the screening visit or anytime up to and including Day 1. ODQ will send the randomization to the research pharmacy.   
f:      Off-study treatment evaluation. This will occur 28 days +/- 7 days after the last regorafenib and tazorotene/placebo.
 


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CTCAE
Grade 1
Grade 2
Grade 3
Palmo-plantar 
Erythrodysthesia
Minimal skin changes 
(e.g. erythema, edema 
or hyperkeratosis 
without pain
Skin changes (e.g. peeling, 
blisters, bleeding, fissures, 
edema, or hyperkeratosis) 
with pain; limiting 
instrumental ADLS
Severe skin changes 
(e.g. peeling, blisters, 
bleeding, fissures, 
edema, or 
hyperkeratosis) with 
pain; limiting self-care 
ADLS
11.1
Antitumor Effect – Solid Tumors
N/A; tumor response is not an objective of this study. 
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The clinical research coordinators will collect and manage the data on this study.  The Office of Data 
Quality (ODQ) may audit this study to perform quality checks on the data for this study.
12.1.2 Responsibility for Data Submission
Clinical research coordinators will enter data and surveys into RedCap.  
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study progress, toxicity, 
safety and other data from this study. The Board is chaired by a medical oncologist from outside of DF/HCC 
and its membership composed of internal and external institutional representation. Information that raises any 
questions about participant safety or protocol performance will be addressed by the Overall PI, statistician and 
study team. Should any major concerns arise, the DSMB will offer recommendations regarding whether or not 
to suspend the study.
The DSMB will meet twice a year to review accrual, toxicity, response and reporting information. Information 


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to be provided to the DSMB may include: participant accrual; treatment regimen information; adverse events 
and serious adverse events reported by category; summary of any deaths on study; audit results; and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be provided upon request. 
12.3
Collaborative Agreements Language
N/A. This is not a CTEP/NCI study
13. STATISTICAL CONSIDERATIONS
In this randomized, double-blind, signal-detection trial, patients will be randomly assigned (1:1) to tazarotene 
gel plus BPS or placebo gel plus BPS.  
13.1
Study Design/Endpoints
Endpoints
The primary endpoint will be the proportion of patients in each arm who develop grade-2 or higher HFSR 
within the first 8 weeks of protocol therapy.  A parallel secondary endpoint will be the proportion of patients in 
each intervention arm who develop HFSR of any grade.
Efficacy Analysis
Primary Endpoint: For each comparison, the proportion of patients with grade-2 or higher HFSR will be 
compared between placebo gel plus BPS and tazarotene gel plus BPS using a two-group chi-squared test. The 
difference between the two proportions will be summarized with a 90% confidence interval. 
13.2
Sample Size, Accrual Rate and Study Duration
The total maximum sample size will be 70 patients (35 per arm); the minimum sample size will be 28 patients 
(14 per arm).  The sample size for the comparison is based on a superiority design for the difference in 
proportions and includes one interim look for futility.  We expect this study to be open to accrual for 24 months. 
We anticipate accruing 3 participants/month.
Based on our prior experience with BPS alone, we expect that 40-50% of patients will develop grade-2 or 
higher HFSR during treatment with regorafenib.  The addition of tazarotene to BPS would be worthy of further 
study if the observed rate of HFSR is reduced to 25%.  When the sample size in each arm is 35 patients, a two-
group, chi-squared test with a 0.10 one-sided significance level will have 80% power to detect the difference 
between a proportion of 50% with HFSR using placebo gel plus BPS and 25% with tazarotene plus BPS.  
An interim look for futility will be conducted after a total of 28 patients have been treated (14 with tazarotene 
gel plus BPS and 14 with placebo gel plus BPS; 40% information).  Based on a power family beta spending 
function (parameter=0.3), if the chi-squared p-value at the interim look is greater than or equal to 0.458 (Z-score 


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> -0.107) then there will be insufficient evidence in favor of the tazarotene arm and enrollment will stop.   
Under this design, the probability of stopping at the time of the interim look is 0.543 if the true rate of HFSR is 
50% (EaST 5.4). 
Secondary comparisons will be based on the incidence of all-grade HSFR in patients treated with regorafenib.  
Our prior experience would suggest that the incidence of all-grade HSFR to be about 55% for patients using 
placebo gel plus BPS.  For sample sizes of 35 patients per arm, a two-group chi-squared test with a 0.10 one-
sided significance level would have 82% power when the incidence of HSFR in the intervention arm is 30%.   
We will also summarize the proportions of patients who develop non-HSFR adverse events that require 
cessation of study therapy. 
13.3
Stratification Factors
There are no stratification factors. 
13.4
Interim Monitoring Plan
An interim look for futility will be performed, as above. 
13.5
Analysis of Primary Endpoints
Please see 13.2 Analysis of Secondary Endpoints
Additional secondary endpoints include investigation of whether tazarotene plus BPS improves health-related 
quality of life associated with HFSR as assessed using Skindex-16 survey, dermatology quality life index 
(DLQI) and hand-foot syndrome 14-item scale (HFS-14) prior to initiating the TKI, then at 2-4 week intervals 
depending on the tool.  
Secondary endpoints also include investigation of whether the intervention decreases global stress associated 
with HFSR as measured prior to initiating the TKI, then at 4 week intervals using the 10-item perceived stress 
scale (PSS), which has been validated in both healthy people and cancer patients.
The DLQI, Skindex-16 and HFSR are validated dermatologic tools that will be administered every 2 weeks and 
collect findings based on the past week.  The PSS is based on the prior month and will be administered every 4 
weeks.  The PSS is a validated measure of global stress in cancer patients.   


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13.6
Reporting and Exclusions
.
13.6.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment.  The incidence of 
events that are new or worsening from the time of first dose of treatment will be summarized according 
to system organ class and/or preferred term, severity (based on CTCAE grade), type of adverse event, 
and relation to study treatment. Deaths reportable as SAEs and non-fatal serious adverse events will be 
listed by patient and tabulated by primary system organ class, and type of adverse event.
13.6.2 Evaluation of the Primary Efficacy Endpoint
Data will be analyzed based on intent-to-treat.  
14. PUBLICATION PLAN
The results of this study will be made public within 24 months of reaching the end of the study follow up 
period, 24 weeks after the last patient initiates therapy.  


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15. APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
29
16. APPENDIX B: TAZAROTENE OR PLACEBO DRUG DIARY
19-099
Drug Diary 
Participant Study ID: ________________________
Cycle: _________
Urea ___%(if recommended by your oncologist)
Tazarotene or Placebo 
Each morning, apply ½ fingertip to each palm & sole at 
8:00 am (+/- 4 hours)
Each night, apply ½ fingertip unit (FTU) to each palm & 
sole at 8:00 pm (+/- 4 hours). If a dose is missed, it should 
be skipped entirely.
On the day that you start your Regorafenib dose 
and Tazarotene/placebo dose, please call the clinical 
research coordinator so that we can schedule your 
Day 15 appointment with us.
Please indicate the date, time, amount taken and any comments in the dosing log below.
Urea
Tazarotene or Placebo
Date
Time of Daily Application 
Time of daily Application
Comments about application
Ex:
6/1/2009
8:00 am
8:00 pm
Itch on palm of left hand
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
________________________
Clinical Research Coordinator
CRC phone: _____________
CRC email:_______________


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
30
17. APPENDIX C: EXAMPLES OF POTENT INHIBITORS OR INDUCERS OF CYTOCHROME P450 3A4
Examples of potent inhibitors or inducers of cytochrome P450 3A4
Potent inhibitors 
Potent inducers 
CYP3A 
Boceprevir
Cobicistat
Conivaptan
Danoprevir and ritonavir
Elvitegravir and ritonavir
Grapefruit juice
Indinavir and ritonavir
Itraconazole
Ketoconazole
Lopinavir and ritonavir
Paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)
Posaconazole
Ritonavir
Saquinavir and ritonavir
Telaprevir
Tipranavir and ritonavir
Troleandomycin
Voriconazole
Clarithromycin
Diltiazem
Idelalisib
Nefazodon
Nelfinavir 
Carbamazepine
Enzalutamide
Mitotane
Phenytoin
Rifampin
St. John’s wort 
Note: Strong inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway 
≥5-fold. Strong inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic 
pathway by ≥80%. 
This table is prepared to provide examples of clinical inhibitors / inducers and is not intended to be an exhaustive 
list. 
Table adapted from: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664
.htm 
Drug-drug interactions data were collected based on a search of the University of Washington Metabolism and 
Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].


N CI Pr ot oc ol #: N/a
D F/ H C C Pr ot oc ol #: 1 9- 0 9 9
Pr ot oc ol Versi o n Date: 2 2 S E P 2 0 2 2
3 1
1 8. A P P E N DI X D: S T U D Y Q U E S TI O N N AI R E S 1- 5
H F S- 1 4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S p e cif y t h e ar e a aff e ct e d b y y o ur h a n d-f o ot s y n dr o m e:
￿1  H a n d s￿2  F e et
￿3  B ot h
W o ul d y o u s a y y o ur h a n d-f o ot s y n dr o m e t e n d s t o b e:
￿1  V er y p ai nf ul
￿2 M o d er at el y p ai nf ul 
￿3 N ot p ai nf ul
Pl e a s e r e s p o n d t o t h e f oll o wi n g st at e m e nt s a s s p o nt a n e o u sl y a s p o s si bl e. T h er e i s n o ri g ht or 
wr o n g a n s w er, j u st w h at e v er c orr e s p o n d s t o w h at y o u e x p eri e n c e o n a d ail y b a si s.
1. I fi n d it h ar d t o t ur n t h e k e y i n m y d o or b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1 Y e s, al w a y s
￿2  Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
2 I fi n d it h ar d t o pr e p ar e m y m e al s b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
3 I h a v e diffi c ult y p erf or mi n g e v er y d a y a cti o n s b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
4 I h a v e diffi c ult y w a s hi n g m y s elf, p utti n g o n m a k e u p ( or s h a vi n g) b e c a u s e of m y h a n d-f o ot 
s y n dr o m e:
￿1  Y e s, al w a y s
￿2  Y e s, fr o m ti m e t o ti m e 
￿3  N o, n e v er
5 I fi n d it h ar d t o dri v e m y c ar b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s     ￿2  Y e s, fr o m ti m e t o ti m e          ￿3  N o, n e v er    ￿4 N ot r el e v a nt t o m e
6 I fi n d it h ar d t o p ut o n m y st o c ki n g s/ti g ht s ( or m y s o c k s) b e c a u s e of m y h a n d-f o ot 
s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
7 I t a k e l o n g er t h a n u s u al t o g et dr e s s e d b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
8 I h a v e diffi c ult y p utti n g o n m y s h o e s b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2  Y e s, fr o m ti m e t o ti m e 
 ￿3 N o, n e v er
9 It i s h ar d f or m e t o st a n d b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
1 0 I h a v e diffi c ult y w al ki n g, e v e n o v er q uit e s h ort di st a n c e s, b e c a u s e of m y h a n d-f o ot 
s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
1 1 I t e n d t o st a y s e at e d or l yi n g d o w n b e c a u s e of m y h a n d-f o ot s y n dr o m e:
Partici pa nt St u d y I D: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Date S ur ve y C o m plete d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Partici pa nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


N CI Pr ot oc ol #: N/a
D F/ H C C Pr ot oc ol #: 1 9- 0 9 9
Pr ot oc ol Versi o n Date: 2 2 S E P 2 0 2 2
3 2
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
1 2 I fi n d it h ar d t o f all a sl e e p b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e 
￿3 N o, n e v er
1 3 M y w or k i s s uff eri n g b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e     ￿3 N o, n e v er     ￿4 N ot r el e v a nt t o m e
1 4 M y r el ati o n s hi p s wit h ot h er s ar e l e s s a mi c a bl e b e c a u s e of m y h a n d-f o ot s y n dr o m e:
￿1  Y e s, al w a y s
￿2 Y e s, fr o m ti m e t o ti m e     ￿3 N o, n e v er


N CI Pr ot oc ol #: N/a
D F/ H C C Pr ot oc ol #: 1 9- 0 9 9
Pr ot oc ol Versi o n Date: 2 2 S E P 2 0 2 2
3 3
E PI D E MI O L O G Y Q U E S TI O N N AI R E
I. P ati e nt D e m o gr a p hi c s
1. I n w hat state di d y o u resi de w he n y o u were:
a. B or n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
b. A ge 1 5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
c. A ge 3 0 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
d. A ge 5 0 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
2. Please pr o vi de y o ur hi g hest le vel of e d ucati o n
￿ Less t ha n hi g h sc h o ol
￿ Hi g h sc h o ol gra d uate
￿ S o me or c o m plete d c olle ge
￿ S o me or c o m plete d gra d uate sc h o ol
3. Fr o m t he c h oices s h o w n, w hat is y o ur race?
￿ Ca ucasia n
￿ Africa n- A merica n
￿ Asia n or Asia n- A merica n
￿ Ot her
￿ A merica n I n dia n / Alas ka n Nati ve
￿ Nati ve Ha waiia n or Ot her Pacific
￿ M ore t ha n o ne race
￿ U n k n o w n or n ot re p orte d
4. Fr o m t he c h oices s h o w n, w hat is y o ur et h nicit y?
￿ His pa nic or Lati n o 
￿ N ot His pa nic or Lati n o
￿ U n k n o w n or n ot re p orte d
5. Fr o m t he c h oices s h o w n, w hat is y o ur maj or a ncestr y?
￿ S o ut her n E ur o pea n / Me diterra nea n
￿ Sca n di na via n
￿ Celtic
￿ N o n- Celtic
￿ Africa n- A merica n
￿ His pa nic, n ot fr o m S pai n
￿ Asia n
￿ Ot her
9. W hat is y o ur c urre nt marital stat us?
￿ Marrie d
Partici pa nt St u d y I D: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Date S ur ve y C o m plete d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Partici pa nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


N CI Pr ot oc ol #: N/a
D F/ H C C Pr ot oc ol #: 1 9- 0 9 9
Pr ot oc ol Versi o n Date: 2 2 S E P 2 0 2 2
3 4
￿ Wi d o we d
￿ Di v orce d
￿ Ne ver marrie d
￿ Se parate d
6. H o w m uc h alc o h ol d o y o u dri n k per wee k? _ _ _ _ _ _ _ _ _ o u nces
( 1 s h ot = 3 o u nces, 1 glass of wi ne = 5 o u nces, or 1 ca n of beer = 1 2 o u nces)
7. Ha ve y o u e ver s m o ke d ci garettes?
￿ Ne ver
￿ Pri or
￿ C urre nt
If y o u s m o ke d i n t he past, w he n di d y o u st o p? (If y o u d o n ot re me m ber t he e xact date, please pr o vi de
t he cl osest esti mate.) _ _ _ _ _ _ _ _ _ _ _ ( date)
If y o u e ver s m o ke d,
a. H o w ma n y years di d y o u s m o ke? _ _ _ _ _ _ _ years
b. H o w ma n y pac ks per da y di d y o u s m o ke? _ _ _ _ _ _ _ pac ks per da y
II. P er s o n al a n d F a mil y Hi st or y of Di s e a s e
8. Ha ve y o u e ver bee n t ol d b y a d oct or or ot her healt h pr ofessi o nal t hat
t he y ha d P S O R I A S I S ,  E C Z E M A / A T O PI C D E R M A TI TI S ,  L U P U S  o r  a n o t h e r  s k i n  c o n d i t i o n ?
If yes please select:
￿ Ps oriasis
￿ Ecze ma / At o pic der matitis
￿ L u p us
9. Ha ve a n y of y o ur cl ose bl o o d relati ves e ver bee n t ol d b y a d oct or or ot her healt h pr ofessi o nal t hat
t he y ha d P S O R I A S I S ,  E C Z E M A / A T O PI C D E R M A TI TI S ,  L U P U S  o r  a n o t h e r  s k i n  c o n d i t i o n ? B y
cl ose bl o o d relati ves, we mea n pare nts, gra n d pare nts, br ot hers, sisters, or nat ural c hil dre n.
￿ ( 1) Yes ￿ ( 2) N o ￿ ( 7 7) Ref use d ￿ ( 9 9) D o n’t k n o w
If Y E S, please pr o vi de t he f oll o wi n g i nf or mati o n ( pr o vi de a d diti o nal i nf or mati o n o n t he ot her si de of
t his pa ge.)
R el ati o n s hi p C o n diti o n A g e at Di a g n o si s
￿ Fat her
￿ M ot her
￿ Gra n d m ot her
￿ Gra n dfat her
￿ F ull br ot her
￿ Half br ot her
￿ F ull sister
￿ Half sister


N CI Pr ot oc ol #: N/a
D F/ H C C Pr ot oc ol #: 1 9- 0 9 9
Pr ot oc ol Versi o n Date: 2 2 S E P 2 0 2 2
3 5
￿ S o n
￿ Da u g hter
￿ P s o r i a s i s
￿ E c z e m a  /  A t o p i c  d e r m a t i t i s
￿ L u p u s
1 0. Ha ve y o u e ver bee n t ol d b y a d oct or or ot her healt h pr ofessi o nal t hat y o u ha d ca ncer, ot her t ha n t h e  d i s e a s e  y o u  
a r e  c u r r e n t l y  b e i n g  t r e a t e d  f o r  a t  D F C I ?
￿( 1) Yes
￿( 2) N o
￿( 7 7) Ref use d 
￿( 9 9) D o n’t k n o w
If Y E S, please gi ve t he f oll o wi n g i nf or mati o n ( please a d d m ore o n t he bac k of t his pa ge if t here is n ot
e n o u g h r o o m here):
T y p e of C a n c er A g e at Di a g n o si s
￿ Le u ke mia
￿ H o d g ki n’s L y m p h o ma
￿ N o n- H o d g ki n’s L y m p h o ma
￿ L u n g
￿ Breast
￿ C ol o n
￿ Pr ostate
￿ Brai n
￿ Es o p ha geal
￿ Re nal
￿ T h yr oi d
￿ U n k n o w n
￿ Ot her, please s pecif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
￿ Le u ke mia
￿ H o d g ki n’s L y m p h o ma
￿ N o n- H o d g ki n’s L y m p h o ma
￿ L u n g
￿ Breast
￿ C ol o n
￿ Pr ostate
￿ Brai n
￿ Es o p ha geal
￿ Re nal
￿ T h yr oi d
￿ U n k n o w n
￿ Ot her, please s pecif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


N CI Pr ot oc ol #: N/a
D F/ H C C Pr ot oc ol #: 1 9- 0 9 9
Pr ot oc ol Versi o n Date: 2 2 S E P 2 0 2 2
3 6
Ex p os ures
1 1. Are y o u c urre ntl y w or ki n g?
￿ Yes       ￿ N o
If Y E S, w hat is y o ur c urre nt occ u pati o n? Please c hec k all t hat a p pl y.
￿ ( 1) Ma na ge me nt
￿ ( 2) B usi ness / Fi na ncial O perati o ns
￿ ( 3) C o m p uter a n d Mat he matical
￿ ( 4) Arc hitect ure / E n gi neeri n g
￿ ( 5) Life p h ysical a n d S ocial Scie nce
￿ ( 6) C o m m u nit y a n d S ocial Ser vices
￿ ( 7) Ot her
￿ ( 8) E d ucati o n, Trai ni n g a n d Li brar y
￿ ( 9) Arts, Desi g n, E ntertai n me nt, S p orts a n d Me dia
￿ ( 1 0) Healt hcare Practiti o ners a n d Tec h nical
￿ ( 1 1) Healt hcare S u p p ort
￿ ( 1 2) Pr otecti ve Ser vice
￿ ( 1 3) F o o d Pre parati o n a n d Ser vi n g Relate d
￿ ( 1 4) B uil di n g a n d Gr o u n ds Clea ni n g a n d Mai nte na nce
￿ ( 1 5) Pers o nal Care a n d Ser vice
￿ ( 1 6) Sales a n d Relate d Occ u pati o ns
￿ ( 1 7) Office a n d A d mi nistrati ve S u p p ort
￿ ( 1 8) Far mi n g, Fis hi n g a n d F orestr y
￿ ( 1 9) C o nstr ucti o n a n d E xtracti o n
￿ ( 2 0) I nstallati o n, Mai nte na nce a n d Re pair
￿ ( 2 1) Pr o d ucti o n
￿ ( 2 3) Tra ns p ortati o n a n d Material M o vi n g
￿ ( 2 4) Militar y S pecific
￿ ( 2 5) St u de nt
￿ ( 2 6) Le gal
￿ ( 7 7) Ref use d
￿ ( 9 9) D o n’t k n o w
If y o u are N O T c urre ntl y w or ki n g, please s pecif y
￿ Retire d
￿ Disa ble d
￿ Ot her, please s pecif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1 2.   D o y o u c urre ntl y e xercise? 
￿ Yes      ￿ N o
If yes, please descri be y o ur e xercise/acti vit y re gi me n
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
37
13. Please describe any hobbies you participate in regularly (>2 hours per week) or for significant periods of time on 
occasion (ie:  rock climbing, skiing, gardening, travel with significant walking, etc.) 


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
38
DERMATOLOGY LIFE QUALITY INDEX
 DLQI
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE LAST 
WEEK.  Please tick  one box for each question.
Participant Study ID:_______________________
Date Survey Completed:____________________
Participant Signature:_______________________


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
39
 


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
40
DERMATOLOGY SURVEY
This survey concerns the skin condition which has bothered you the 
most during the past weeks.
Participant Study ID:_______________________
Date Survey Completed:____________________
Participant Signature:_______________________


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
41
THESE QUESTIONS CONCERN THE SKIN CONDITION WHICH 
HAS BOTHERED YOU THE MOST DURING THE PAST WEEK
Never 
Bothered
Always 
Bothered



During the past week, how often 
have you been bothered by:
______________________________
1.
Your skin condition itching .
.
.
.
.
.
.
.
  0     1     2      3     4      5     6
2.
Your skin condition burning or stinging .
.
.
.
  0     1     2      3     4      5     6
3.
Your skin condition hurting .
.
.
.
.
.
.
.
  0     1     2      3     4      5     6
4.
Your skin condition being irritated .
.
.
.
.
.
  0     1     2      3     4      5     6
5.
The persistence / reoccurrence of your skin condition
  0     1     2      3     4      5     6
6.
Worry about your skin condition (For example: that it will 
spread, get worse, scar, be unpredictable, etc)
.
.
.
  0     1     2      3     4      5     6
7.
The appearance of your skin condition
.
.
.
.
  0     1     2      3     4      5     6
8.
Frustration about your skin condition .
.
.
.
.
  0     1     2      3     4      5     6
9.
Embarrassment about your skin condition
.
.
.
  0     1     2      3     4      5     6
10.
Being annoyed about your skin condition.
.
.
.
  0     1     2      3     4      5     6
11.
Feeling depressed about your skin condition
.
.
  0     1     2      3     4      5     6
12.
The effects of your skin condition on your interactions 
with others (For example: interactions with family, friends, 
close relationships, etc) .
.
.
.
.
.
.
.
.
.
  0     1     2      3     4      5     6
13.
The effects of your skin condition on your desire to be 
with people
.
.
.
.
.
.
.
.
.
.
.
.
  0     1     2      3     4      5     6
14.
Your skin condition making it hard to show affection
  0     1     2      3     4      5     6
15.
The effects of your skin condition on your daily 
activities
.
.
.
.
.
.
.
.
.
.
.
.
.
  0     1     2      3     4      5     6
16.
Your skin condition making it hard to work or do what 
you enjoy .
.
.
.
.
.
.
.
.
.
.
.
.
  0     1     2      3     4      5     6
Have you answered every item? Yes 
No 



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DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
42
Perceived Stress Scale
The questions in this scale ask you about your feelings and thoughts during the last month. In
each case, you will be asked to indicate by circling how often you felt or thought a certain way.
Name ____________________________________________________________ Date _________
Age ________ Gender (Circle): M F Other _____________________________________
0 = Never 1 = Almost Never 2 = Sometimes 3 = Fairly Often 4 = Very Often
1. In the last month, how often have you been upset
because of something that happened unexpectedly?.................................. 0 1 2 3 4
2. In the last month, how often have you felt that you were unable
to control the important things in your life? .................................................. 0 1 2 3 4
3. In the last month, how often have you felt nervous and “stressed”? ............ 0 1 2 3 4
4. In the last month, how often have you felt confident about your ability
to handle your personal problems? ............................................................. 0 1 2 3 4
5. In the last month, how often have you felt that things
were going your way?.................................................................................. 0 1 2 3 4
6. In the last month, how often have you found that you could not cope
with all the things that you had to do? ......................................................... 0 1 2 3 4
7. In the last month, how often have you been able
to control irritations in your life?................................................................... 0 1 2 3 4
8. In the last month, how often have you felt that you were on top of things?.. 0 1 2 3 4
9. In the last month, how often have you been angered
because of things that were outside of your control?................................... 0 1 2 3 4
10. In the last month, how often have you felt difficulties
were piling up so high that you could not overcome them? ......................... 0 1 2 3 4
References
The PSS Scale is reprinted with permission of the American Sociological Association, from Cohen, S., Kamarck, T., and Mermelstein, R. (1983). A
global measure of perceived stress. Journal of Health and Social Behavior, 24, 386-396.
Cohen, S. and Williamson, G. Perceived Stress in a Probability Sample of the United States. Spacapan, S. and Oskamp, S. (Eds.) The Social
Psychology of Health. Newbury Park, CA: Sage, 1988.
Participant Study ID:_______________________
Date Survey Completed:____________________
Participant Signature:_______________________


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
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19. APPENDIX E: TAZAROTENE OR PLACEBO PREPARATION INSTRUCTIONS


NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
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NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
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NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
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NCI Protocol #: N/a
DF/HCC Protocol #: 19-099
Protocol Version Date: 22SEP2022
47
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