Preventative Skin Care for Children Undergoing Targeted CNS Tumor Therapy
Phase: PHASE2
Conditions: Pediatric Cancer, CNS Tumor, Childhood, Skin Inflammation
Sponsor: Dana-Farber Cancer Institute

DF/HCC Protocol #: 19-579
TITLE: Preventative Skin Care for Children Undergoing Targeted Therapy for CNS and PNS 
Tumors
Coordinating Center:
Dana-Farber Cancer Institute
*Principal Investigator (PI):
Jennifer Huang
Boston Children’s Hospital 
300 Longwood Avenue
Boston, MA 02115
Phone: 617-355-1477
Fax: 617-730-0308
Email: Jennifer.Huang@childrens.harvard.edu
Other Investigators:
Danny Linggonegoro 
Boston Children’s Hospital 
300 Longwood Avenue
Boston, MA 02115
Phone: 857-218-5296
Fax: 617-730-0308
Email: danny.linggonegoro@childrens.harvard.edu
Susan Chi, MD
Dana-Farber Cancer Institute 
450 Brookline Avenue
Boston, MA 02215
Phone: (617) 632-4386
Email: Susan_Chi@dfci.harvard.edu
1

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Statistician:
Wendy London
Boston Children’s Hospital 
300 Longwood Avenue
Telephone: 617-632-4895
Email: wendy.london@childrens.harvard.edu
Protocol Type / Version # / Version Date: Original / Version 3.0 / 7.24.2023

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SCHEMA
Prospective, Single-Arm Trial
Diseases:
CNS or PNS tumor
Skin 
reactions 
to 
Targeted BRAF, MEK or 
pan-RAF
inhibitor 
therapy
Treatments: 
Preventative Skin 
care
routine 
(PSCR) + dilute 
bleach baths
CNS or PNS tumor + 
treatment with 
targeted
BRAF
or 
MEK
Or pan-RAF 
Inhibitor
(8 participants)
Preventative skin 
care routine + dilute 
bleach baths

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................3
1.
OBJECTIVES......................................................................................................................6
1.1
Study Design............................................................................................................6
2.
BACKGROUND .................................................................................................................7
2.1
Study Disease(s).......................................................................................................7
3.
PARTICIPANT SELECTION...........................................................................................10
3.1
Inclusion Criteria ...................................................................................................10
3.2
Exclusion Criteria ..................................................................................................10
3.3
Inclusion of Children and Minorities.....................................................................10
4.
REGISTRATION AND RANDOMIZATION PROCEDURES.......................................10
4.1
General Guidelines for DF/HCC and DF/PCC Institutions...................................10
4.2
Registration Process for DF/HCC Institutions.......................................................11
5.
TREATMENT PLAN........................................................................................................11
5.1
Pre-Treatment Criteria ...........................................................................................12
5.2
General Concomitant Medication and Supportive Care Guidelines......................12
5.3
Criteria for Taking a Participant Off Protocol Therapy.........................................12
5.4
Duration of Follow Up...........................................................................................13
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................13
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................13
7.2
Adverse Event Characteristics ...............................................................................14
7.3
Routine Adverse Event Reporting .........................................................................14
7.4
Routine Adverse Event Reporting .........................................................................15
8.
PHARMACEUTICAL INFORMATION..........................................................................15
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................15
9.1
Biomarker Studies..................................................................................................15
9.2
Laboratory Correlative Studies..............................................................................15
9.3
Special Studies.......................................................................................................15
10.
STUDY CALENDAR .......................................................................................................16
11.
MEASUREMENT OF EFFECT........................................................................................17
11.1
Antitumor Effect – Solid Tumors ..........................................................................17
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................18
12.1
Data Reporting.......................................................................................................18

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13.
STATISTICAL CONSIDERATIONS...............................................................................18
13.1
Study Design/Endpoints.........................................................................................18
13.2
Sample Size, Accrual Rate and Study Duration ....................................................18
13.3
Stratification Factors..............................................................................................18
13.4
Interim Monitoring Plan ........................................................................................18
13.5
Analysis of Primary Endpoints..............................................................................19
13.6
Analysis of Secondary Endpoints..........................................................................19
13.7
Reporting and Exclusions ......................................................................................19
14.
PUBLICATION PLAN .....................................................................................................19
REFERENCES ..............................................................................................................................20
APPENDIX A
Severity scoring systems............................................................................22

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1. OBJECTIVES
Objective #1. To describe the proportion of children with cutaneous reactions to targeted BRAF, 
MEK, and Pan-RAF inhibitor therapies of a cohort receiving a daily preventative skin care 
regimen (PSCR) including sun protection, gentle skin care and every other day dilute bleach 
baths at 6 and 12 weeks.
Objective #2. To describe the number of different cutaneous reactions to targeted BRAF, MEK, 
and Pan-RAF inhibitor therapies per patient in children receiving daily PSCR including sun 
protection, gentle skin care and every other day dilute bleach baths at 6 and 12 weeks.
Objective #3. To describe the severity of cutaneous reactions to targeted BRAF, MEK, and Pan- 
RAF inhibitor therapies for children receiving PSCR including sun protection, gentle skin care 
and every other day dilute bleach baths at 6 and 12 weeks. using the following severity scales: 
Common Terminology Criteria for Adverse Events (CTCAE), Overall Dry Skin Score (ODS), 
Hand-Foot Skin Reaction and Quality of Life Score (HFS-14), Pediatric Quality of Life 
Inventory (PedsQL), and Children’s Dermatology Life Quality Index (CDLQI).
1.1
Study Design
This prospective, single-arm phase 2 clinical trial will be performed at Dana-Farber 
Cancer Institute/Boston Children’s Hospital***. Additional external sites will conduct the same 
study concurrently. Data from all sites will be pooled at the end of the study and a meta-analysis 
of all aggregated data will be performed. IRB approval will be obtained prior to initiation of the 
study. This study will include patients receiving MEK inhibitor, BRAF inhibitor or pan-RAF 
inhibitor therapies for CNS and PNS tumors. At this time, we do not have the personnel or 
funding required to coordinate with multiple departments to identify all patients receiving these 
therapies.
Baseline data will be obtained from each participant via medical record review, if 
applicable. Baseline data includes, but is not limited to the following: general demographic data 
(age at tumor diagnosis, gender, race), type of primary tumor, type of therapy regimen (targeted 
therapy agents/dose/duration, chemotherapy agents/dose/duration, radiation field 
location/size/dose), past and current immunosuppressive medications, secondary malignancies 
including melanoma and nonmelanoma skin cancer, and family history of skin diseases.
All patients will undergo skin examinations at the initial study visit, mid-study visit (6 
weeks (+/- 2 weeks)), and at 12 weeks after treatment initiation. Weight-based dosing of MEK, 
BRAF, or Pan-RAF inhibitor therapies will be recorded at each visit. If any skin findings are 
present, patients and families will be asked about the timing, frequency, location and severity of 
these skin findings.
Patients will undergo a full mucocutaneous physical examination including skin, mucous 
membranes, hair, and nails during their dermatology visit. Abnormalities will be carefully 
documented, including degree of involvement (% body surface area, number of nails, % of 
scalp).

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Patients receiving targeted therapy will be evaluated specifically for the following skin 
reactions, previously reported in the literature: follicular skin rash, acneiform skin eruption, 
cheilitis, xerosis, hand foot syndrome, eruptive nevi (defined as > 5 new nevi over a 3 month 
period), keratoacanthoma, squamous cell carcinoma, photosensitivity. Undefined skin reactions 
will also be recorded.
No biopsies will be performed for research purposes. Patients who do not have a 
scheduled Dermatology visit, but have concerning findings on skin exam, will be scheduled for a 
complete dermatology evaluation, where any biopsies would be conducted as clinically indicated 
as part of routine dermatologic care.
2. BACKGROUND
2.1
Study Disease(s)
A recent study by Song et al. shows that cutaneous reactions are common in children receiving 
targeted anti-cancer therapies for CNS tumors.5 Anti-cancer therapies for children with CNS 
tumors include BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) and MEK inhibitors 
(refametinib, trametinib, selunetinib, comibetinib). Cutaneous reactions occurred in 96% of the 
22 patients enrolled in this study and included xerosis, follicular eruptions, photosensitivity, 
hand-foot syndrome, eruptive nevi, nail changes, paronychia and alopecia. While most reactions 
are not life threatening, cancer therapy is frequently discontinued due to factors including 
intolerable discomfort (pain, itching) and/or concern regarding one’s appearance.6 MEK 
inhibitors have also been approved for NF-related plexiform neurofibromas, with a similar 
cutaneous reaction profile.21
Given the high incidence of cutaneous reactions to targeted tumor therapy, preventative 
measures to decrease the incidence or severity of reactions should be considered. The most 
common reactions are a result of dry skin and sun exposure; thus it is plausible that a simple 
preventative skin care regimen that addresses gentle skin care and sun protection would be 
beneficial. In addition, follicular reactions and paronychia may be ameliorated by regular use of 
dilute bleach baths, which have been shown to decrease severity of atopic dermatitis in children 
and to decrease inflammation by down-regulating the NF-kappaB pathway.7-9
Compelling in vitro and in vivo data suggests that topical hypochlorite solution markedly blocks 
NFB signaling.9 Furthermore, Leung et al demonstrated that topical hypochlorite inhibits the 
expression of NFB-dependent genes, and decreased incidence and severity of cutaneous 
reactions to anti-cancer therapy in a mouse model.9 The concentrations of hypochlorite used 
therein mirrored those determined to be safe and efficacious in dilute bleach baths used in the 
treatment of atopic dermatitis in children.10 Emerging literature in atopic dermatitis suggests that 
the mechanism by which dilute bleach baths improves skin disease is not antimicrobial,11 but 
rather, anti-inflammatory.
Bleach is an inexpensive and widely available topical agent; its use in swimming pools, medical 
clinics and commercially available cleansers speak to minimal toxicity (in dilute concentrations)

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in humans. Our aim is to determine if dilute bleach baths can attenuate the incidence and severity 
of reactions to targeted anti-cancer therapies. A study by Huang et al. surrounding dilute bleach 
baths for atopic dermatitis included children as young as 6 months of age and showed that 
patients treated with dilute bleach baths had significantly improved eczema severity10.
Cutaneous effects of targeted therapies
Over the last decade, our knowledge of the molecular composition of pediatric CNS tumors has 
increased dramatically.12 In turn, tumor specific “targeted” therapies are being developed and 
utilized at an incredible pace. Given the shared neuroectodermal origin of the brain and skin, the 
advent of these therapies has introduced new and important skin reactions, including the 
development of nevi and skin cancer during active treatment. Other associated skin reactions 
include xerosis, hand foot syndrome, follicular skin eruptions, and scalp pruritus or burning.
These reactions can be severe enough to require discontinuation or modification of therapy. 
There is also evidence in adults receiving targeted cancer therapies that presence of cutaneous 
reactions can be a good prognostic sign.
A recent study was performed by Song et al. at Boston Children’s Hospital under DFCI protocol 
# 15-5415. In this cross-sectional study, patients younger than 21 years of age receiving BRAF, 
MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. 
Full body skin examination, photographs of dermatologic findings, and initial treatment 
recommendations were included at the initial visit, and follow-up skin examinations were 
recommended every three months. Twenty-two patients were enrolled in the study. Ninety-six 
percent (21/22) of all patients had at least one skin reaction. The most common reactions across 
treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK 
inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe 
cutaneous reactions5.
Severity Scores
In order to assess the severity of cutaneous reactions to BRAF, MEK and pan-RAF therapies, we 
will use the following scores: the Common Terminology Criteria for Adverse Events (CTCAE), 
severity of xerosis measured by the Overall Dry Skin Score (ODS), severity of hand foot 
syndrome measured by the Hand-Foot Skin Reaction and Quality of Life Score (HFS-14), 
Pediatric Quality of Life Inventory General Well-Being Scale (PedsQL), and the Children’s 
Dermatology Life Quality Index (CDLQI).
The Overall Dry Skin Score (ODS) is a clinical assessment of the presence and severity of skin 
dryness using a five- point scale. A score of '0' indicates no skin dryness, whereas a score of '4' 
indicates advanced skin roughness, large scales, inflammation and cracks. This score has been 
used in studies assessing skin dryness in nursing homes and pharmacies.13 The Common 
Terminology Criteria for Adverse Events (CTCAE) has a standardized grading system for 
adverse events including cutaneous reactions to anti-cancer therapies that is validated and widely 
used in oncology14. Higher grades of cutaneous reactions have significant impact on quality of 
life and can lead to interruptions in cancer treatment.
The Hand-Foot Skin Reaction and Quality of Life Score (HFS-14) is a scale that has been

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specifically developed and tested for patients with Hand-Foot Syndrome, which has been 
reported as a symptom of targeted cancer therapies. The HFS-14 questionnaire was developed 
using standardized methodology for QoL questionnaire development, which consisted of the 
following steps: gathering patient input, generating an exhaustive list of items, reducing the list 
of items, allocating items to domains, pilot testing, calculation of scores, and validation. A 
working group of experts including oncologists, a dermatologist, a public health physician, and 
health professionals having a good knowledge of HFS and day-to-day experience in the 
management of this condition was constructed for the development of this questionnaire.15 The 
PedsQL is based on a modular approach to measuring HRQOL and consists of a 15-item core 
measure of global HRQOL and eight supplemental modules assessing specific symptom or 
treatment domains. The PedsQL was empirically derived from data collected from 291 pediatric 
cancer patients and their parents at various stages of treatment.16 The Children's Dermatology 
Life Quality Index (CDLQI) is the most widely used instrument for measuring the impact of skin 
disease on quality of life (QoL) in children.17 (Olsen, 2016).
Gaps in care
While cutaneous reactions to targeted therapies are common and can be dose or treatment 
limiting, no guidelines surrounding management of these reactions currently exists. It is 
imperative for pediatric dermatologists to be involved in not only managing individual patients 
with these reactions, but also in developing protocols that assist oncologists in managing this 
population as a whole.
In a recent retrospective study of 39 adult patients who experienced cutaneous reactions to anti- 
cancer therapy, 5 experienced dose interruptions, and one patient discontinued therapy altogether 
due to severe papulosquamous rashes.18 In our experience, it is not uncommon for children to 
have treatment discontinuation due to skin rashes or reactions that are physically or emotionally 
bothersome for them. In their study, Song et al. propose an algorithm for treatment of common 
reactions, including basic skin care guidelines. However, no studies have investigated the 
efficacy of therapeutic or preventative measures.
The current skin care guidelines according to the National Cancer Institute are vague and not 
specific for different types of cancer or pediatric versus adult patients. The guidelines 
recommend using mild soaps and lotions, avoiding heating pads and ice packs, shaving less 
often, and using sunscreen and sun-protective clothing. For dry, itchy skin in reaction to cancer 
treatments, these guidelines recommend the following: “Avoid products with alcohol or perfume, 
which can dry or irritate your skin. Take short showers or baths in lukewarm, not hot, water. Put 
on lotion after drying off from a shower, while your skin is still slightly damp. Keep your home 
cool and humid. Eat a healthy diet and drink plenty of fluids to help keep your skin moist and 
healthy. Applying a cool washcloth or ice to the affected area may also help. Acupuncture also 
helps some people.”19
In addition, while there is data showing that pediatric brain tumor survivors suffer from a lower 
quality of life than healthy peers and even other childhood cancer survivors, there is no scientific 
literature that specifically addresses how cutaneous reactions to targeted anti-cancer therapy 
impact quality of life for these patients.20 Because of the high incidence of cutaneous reactions to

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MEK and BRAF inhibitor therapy, more data is needed on how cutaneous reactions to anti- 
tumor therapy impact quality of life for these patients.
3. PARTICIPANT SELECTION
3.1
Inclusion Criteria

Diagnosed with a CNS or PNS tumor between ages 6 months old -18 years old and will 
undergo treatment with at least one of the following:
1. Targeted BRAF inhibitor therapy to treat the tumor
2. Targeted MEK inhibitor therapy to treat the tumor
3. Targeted pan-RAF inhibitor therapy to treat the tumor

Patients must enroll in this trial prior to starting targeted therapy

Subjects may participate in other studies, including therapeutic trials.

Ability to comply with PSCR including sun protection, gentle skin care and every other 
day dilute bleach baths.

Ability to understand and/or the willingness of their parent or legally authorized 
representative to sign a written informed consent document.
3.2
Exclusion Criteria

Diagnosed with CNS or PNS tumor at > 18 years old

No data in medical records regarding treatment exposures

Treated with a BRAF, MEK or pan-RAF inhibitor in the last three months

Past or present allergic reaction to bleach

Past or present allergic reactions to sunscreen and/or creams, lotions, emollients to be 
utilized in this study
3.3
Inclusion of Children and Minorities
Both male and female children of all races and ethnic groups are eligible for this trial.
4. REGISTRATION AND RANDOMIZATION PROCEDURES
4.1
General Guidelines for DF/HCC*** and DF/PCC*** Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy 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.
Following registration, participants may begin protocol therapy within one month of registration. 
Issues that would cause treatment delays should be discussed with the Overall Principal

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Investigator (PI). If a participant does not receive protocol therapy following registration within 
one month, the participant’s registration on the study must be canceled. Registration 
cancellations must be made in OnCore as soon as possible.
4.2
Registration Process for DF/HCC*** Institutions
Applicable DF/HCC*** Policy REGIST-101 must be followed.
5. TREATMENT PLAN
This study aims to enroll 8 patients who will all receive in-person and written counseling for a 
daily preventative skin care regimen (PSCR) including instructions for daily safe sun protection, 
daily gentle skin care, nail care and every other day dilute bleach baths before the initiation of 
anti-cancer therapy. Patients will be recruited by the neuro-oncology team.
The preventative skin care regimen (PSCR) is detailed below. Patients will not have to purchase 
the following materials: sunscreen, gentle cleansers, moisturizers, emollients, bleach. These 
materials will be given to patients as the first study visit.
Safe sun protection will include instructions for:

Use of SPF 30+ sunscreen with physical blockers (zinc oxide and/or titanium dioxide) 
whenever going outside

Sunscreen to be reapplied every two hours (more often as needed)

Sun-protective clothing including long sleeve, pants, wide-brimmed hat and sunglasses.
Gentle skin care will include:

Daily short, lukewarm showers and water baths

Gentle unscented cleansers (Dove, Cetaphil, Cerave, Vanicream) during bathing

Thick and unscented moisturizing creams (Cerave cream, Vanicream, Cetaphil Cream, 
Dove), and emollients (Aquaphor, Vaseline) immediately following baths or showers 
every day.
Nail care will include:

Trimming nails after bathing (fingernails once a week; toenails once a month)

Keep the fingernails trimmed with a slight curve, but the toenail straight across, to 
prevent hangnails from forming.

Do not pick loose bits off the nail to avoid tearing the nailbed or the cuticle.

Cut them off neatly with a clean, sharp pair of scissors or a nail clipper.

Avoid biting nails and trimming cuticles
Patients will also receive in-person and written counseling for every other day, 10-15 minutes 
dilute bleach baths.
Bleach baths will include:

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
Mixing ¼ cup over-the-counter household bleach with ½ full tub of lukewarm water.

Soak for 10-15 minutes

Gently pat dry

Apply gently moisturizers or emollients immediately following bathing

In the case that patients do not have access to a tub and will make bleach bath 
compresses, or if a small infant tub is used, mix 1 teaspoon of bleach with 1 every 1 
gallon of water
Patients will be asked to keep a diary of their daily skin care regimen and every-other-day dilute 
bleach baths including what products they used, how the bleach bath was made and how long 
they soaked in the bleach bath. This diary will be used to measure compliance.
If any patients develop a skin reaction to dilute bleach, they will discontinue and it will be 
documented.
If any patients develop a skin reaction to a moisturizer or sunscreen, we will recommend an 
alternative product, as we would do clinically.
Products mentioned above to be utilized in the preventative skin care regimen will be paid for by 
the Dermatology Research Fund at the Jimmy Fund Clinic***. External sites will supply their 
own sample products to participants.
5.2
Pre-Treatment Criteria
N/A
5.3
General Concomitant Medication and Supportive Care Guidelines
N/A
5.4
Criteria for Taking a Participant Off Protocol Therapy
Duration of intervention will be 12 weeks for each participant. They will receive skin 
examinations and interviews at the initiation of treatment, at 6 weeks (+/- 2 weeks) and at 12 
weeks. Reasons for taking a participant off protocol intervention include the following

Participant withdraws from targeted therapy

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with intervention 
protocols

Participant decides to withdraw from the protocol therapy

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
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Loss to follow-up

Withdrawal of consent for data submission

Death
Patients have the right to withdraw consent at any given time for any reason and no replacement 
is necessary as this is a single-arm trial. 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.
The participant’s status must be updated in OnCore in accordance with REGIST-OP-1.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Jennifer Huang at 617-355-1477***.
5.5
Duration of Follow Up
N/A
6. DOSING DELAYS/DOSE MODIFICATIONS
N/A
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 Event List(s) for Commercial Agent(s)
Commercial agents for preventative skin care routines include gentle soaps, lotions, 
cleansers, moisturizers, and sunscreen. Adverse events from these agents may include 
skin irritation. Patients will be referred to product information included with purchase 
of these products for possible adverse events.
Commercial agents for dilute bleach bath include OTC bleach, with 1/4 cup to be 
placed into a ½ full bathtub. Adverse events from the this commercial agent may 
include eye irritation if contact with eyes and possible skin irritation. Patients will be

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instructed to carefully avoid eye contact with bath water during dilute bleach baths 
and will be instructed to stop dilute bleach bath if skin irritation occurs following 
bleach baths.
7.2
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 5.0. 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.

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
Routine Adverse Event Reporting
All Adverse Events will be reported in Redcap.
7.3.1
DF/HCC*** Expedited 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.
Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.

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DF/HCC*** Reportable AEs
Attribution
Gr. 2 & 3 
AE
Expected
Gr. 2 & 3 AE
Unexpected
Gr. 4 AE
Expected
Gr. 4 AE
Unexpected
Gr. 5 AE
Expected or 
Unexpected
Unrelated 
Unlikely
Not required
Not required
5 calendar 
days#
5 calendar 
days
24 hours*
Possible 
Probable 
Definite
Not required
5 calendar 
days
5 calendar 
days#
5 calendar 
days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 24 business hours of learning 
of the event.
7.4
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 reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1.
N/A
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
N/A
9.1
Biomarker Studies
N/A
9.2
Laboratory Correlative Studies
N/A
9.3
Special Studies
N/A

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10. STUDY CALENDAR
Section
Baseline
6 week (+/- 2
weeks) visit*
12 week visit
EDC
Timepoints
PSCR counseling
X
X
X
Baseline, 6
week, 12 
week
Informed consent
X
X
X
Baseline, 6
week, 12 
week
Demographics
X
Baseline, 6
week, 12 
week
Medical history
X
X
X
Baseline, 6
week, 12 
week
MEK, BRAF, or Pan-RAF
inhibitor dosing
X
X
X
Baseline, 6
week, 12 
week
Skin exam and interview
X
X
X
Baseline, 6
week, 12 
week
Severity Scores Completed
X
X
X
Baseline, 6
week, 12 
week
Adverse events evaluation
X
X
X
Baseline, 6
week, 12 
week
*6 week visit may be conducted virtually on request. Photographs will be requested prior to visit.

11. MEASUREMENT OF EFFECT
The measurement is the proportion (percentage) of patients with one or more cutaneous reaction 
to targeted BRAF, MEK or Pan-RAF inhibitor therapy. Secondary outcome measures include 
number of different cutaneous reactions experienced by each patient, severity of cutaneous 
reactions measured by the Common Terminology Criteria for Adverse Events (CTCAE), severity 
of xerosis measured by the Overall Dry Skin Score (ODS), severity of hand foot syndrome 
measured by the Hand-Foot Skin Reaction and Quality of Life Score (HFS-14), Pediatric Quality 
of Life Inventory General Well-Being Scale (PedsQL), and the Children’s Dermatology Life 
Quality Index (CDLQI). To view these assessments and scoring in detail, please see Appendix 
A.
11.1
Antitumor Effect – Solid Tumors
N/A
11.1.1 Disease Parameters
Any new or changing skin, hair or nail findings
11.1.2 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.
Clinical lesions. In the case of skin, hair or nail lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
11.1.3 Response Criteria
Severity of skin reactions will be graded according to the following severity scoring systems:
Common Terminology Criteria for Adverse Events (CTCAE) (Appendix A) 
Overall Dry Skin Score (ODS) (Appendix B)
Hand-Foot Skin Reaction Quality of Life Score (HFS-14) (Appendix C) 
Children’s Dermatology Life Quality Index (CDLQI) (Appendix D) 
Pediatric Quality of Life Inventory (PedsQL)
17

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11.1.4 Response Review
Skin exams will be performed by dermatologists and trained research staff.
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
Data will be reported in REDCap.  The original plan was for each of the three sites to independently 
activate the protocol, and have their own separate, but identical, REDCap electronic case report 
forms (eCRFs).  Each site has its own separate IRB approval for the trial.  However, during study 
conduct, paper CRFs from the other two sites were sent to BCH, and the other sites’ data were 
entered into the BCH REDCap eCRFs.  All data for the trial currently reside at BCH; the existence 
of data at BCH is covered by two legal Data Sharing Agreements.  All data is labeled by site.  
Keeping data transcribed as is will facilitate statistical analysis, and minimize further efforts towards 
data transfer.
13. STATISTICAL CONSIDERATIONS
Descriptive analysis of this cohort, including data from three sites, will be performed. 
13.1
Study Design/Endpoints
The primary outcome measure is cutaneous reaction to targeted BRAF, MEK, or Pan-RAF 
inhibitor therapy. Secondary outcome measures include number of different cutaneous reactions 
experienced by each patient, severity of cutaneous reactions measured by the Common 
Terminology Criteria for Adverse Events (CTCAE), severity of xerosis measured by the Overall 
Dry Skin Score (ODS), severity of hand foot syndrome measured by the Hand-Foot Skin 
Reaction and Quality of Life Score (HFS-14), Pediatric Quality of Life Inventory (PedsQL), and 
the Children’s Dermatology Life Quality Index (CDLQI).
13.2
Sample Size, Accrual Rate and Study Duration
Sample Size: 22 participants from three sites (DFCI [8], Toronto Sick Kids [7], Lurie Children’s 
Hospital [7])
Accrual Rate: 6 participants / 1 year
Study duration: ~3 years (3 years of accrual + 12 weeks of treatment on the last patient 
enrolled)
This sample size is limited due to the rare nature of these cancers, but a total of 22 will be 
sufficient for descriptive analyses. The study team believes that accrual of more than 8 patients 
in a one year period at DFCI/BCH*** is not feasible.
13.3
Stratification Factors
N/A

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13.4
Interim Monitoring Plan

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N/A
13.5
Analysis of Primary Endpoints
In the overall cohort, the proportion of patients with one or more cutaneous reactions will be 
calculated, and a 95% exact confidence interval will be placed on this proportion.
13.6
Analysis of Secondary Endpoints
In the overall cohort, the minimum, maximum, and quartiles of the number of cutaneous 
reactions per patient will be calculated.
In the overall cohort: To describe the severity of cutaneous reactions, the proportion of patients 
at each CTCAE grade of toxicity, and for each grade of the Overall Dry Skin Score (ODS), will 
be calculated. For each of the following severity scales, the minimum, maximum, and quartiles 
of the scores will be calculated: Hand-Foot Skin Reaction and Quality of Life Score (HFS-14), 
Pediatric Quality of Life Inventory (PedsQL), and Children’s Dermatology Life Quality Index 
(CDLQI).
13.7
Reporting and Exclusions
N/A
13.7.1 Evaluation of Toxicity
N/A
13.7.2 Evaluation of the Primary Efficacy Endpoint
N/A
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration.

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REFERENCES
1.
Green AL, Kieran MW. Pediatric brainstem gliomas: new understanding leads to 
potential new treatments for two very different tumors. Curr Oncol Rep. 
2015;17(3):436.DOI: 10.1007/s11912-014-0436-7
2.
Penman CL, Faulkner C, Lowis SP, Kurian KM. Current Understanding of BRAF 
Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade 
Gliomas. Front Oncol. 2015;5:54.DOI: 10.3389/fonc.2015.00054
3.
Boussemart L, Routier E, Mateus C, Opletalova K, Sebille G, Kamsu-Kom N, et al. 
Prospective study of cutaneous side-effects associated with the BRAF inhibitor 
vemurafenib: a study of 42 patients. Ann Oncol. 2013;24(6):1691-1697.DOI: 
10.1093/annonc/mdt015
4.
Sinha R, Larkin J, Gore M, Fearfield L. Cutaneous toxicities associated with vemurafenib 
therapy in 107 patients with BRAF V600E mutation-positive metastatic melanoma, 
including recognition and management of rare presentations. Br J Dermatol. 
2015;173(4):1024-1031.DOI: 10.1111/bjd.13958
5.
Song H, Zhong CS, Kieran MW, Chi SN, Wright KD, Huang JT. Cutaneous reactions to 
targeted therapies in children with CNS tumors: A cross-sectional study. Pediatr Blood 
Cancer. 2019:e27682.DOI: 10.1002/pbc.27682
6.
Boull C, Hook K, Moertel C, Maguiness S. Cutaneous Reactions in Children Treated 
with the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase 
Inhibitor Trametinib for Neural Tumors. Pediatr Dermatol. 2017;34(1):90-94.DOI: 
10.1111/pde.13038
7.
Chopra R, Vakharia PP, Sacotte R, Silverberg JI. Efficacy of bleach baths in reducing 
severity of atopic dermatitis: A systematic review and meta-analysis. Ann Allergy Asthma 
Immunol. 2017;119(5):435-440.DOI: 10.1016/j.anai.2017.08.289
8.
Huang JT, Rademaker A, Paller AS. Dilute bleach baths for Staphylococcus aureus 
colonization in atopic dermatitis to decrease disease severity. Arch Dermatol. 
2011;147(2):246-247.DOI: 10.1001/archdermatol.2010.434
9.
Leung TH, Zhang LF, Wang J, Ning S, Knox SJ, Kim SK. Topical hypochlorite 
ameliorates NF-kappaB-mediated skin diseases in mice. J Clin Invest. 
2013;123(12):5361-5370.DOI: 10.1172/JCI70895
10.
Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of 
Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. 
Pediatrics. 2009;123(5):e808-814.
11.
Sawada Y, Tong Y, Barangi M, et al. Dilute bleach baths used for treatment of atopic 
dermatitis are not antimicrobial in vitro. J Allergy Clin Immunol. 2019;143(5):1946-1948.
12.
Nikiforova MN, Wald AI, Melan MA, Roy S, Zhong S, Hamilton RL, et al. Targeted 
next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of 
central nervous system tumors. Neuro Oncol. 2016;18(3):379-387.DOI: 
10.1093/neuonc/nov289
13.
Kang BC, Kim YE, Kim YJ, Chang MJ, Choi HD, Li K, et al. Optimizing EEMCO 
guidance for the assessment of dry skin (xerosis) for pharmacies. Skin Res Technol. 
2014;20(1):87-91.DOI: 10.1111/srt.12089

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14.
Services. UDoHaH. Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0.
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q 
uick_Reference_5x7.pdf. Published 2017. Accessed July 25, 2019.
15.
Sibaud V, Dalenc F, Chevreau C, Roche H, Delord JP, Mourey L, et al. HFS-14, a 
specific quality of life scale developed for patients suffering from hand-foot syndrome. 
Oncologist. 2011;16(10):1469-1478.DOI: 10.1634/theoncologist.2011-0033
16.
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality 
of life inventory. Med Care. 1999;37(2):126-139.DOI: 10.1097/00005650-199902000- 
00003
17.
Olsen JR, Gallacher J, Finlay AY, Piguet V, Francis NA. Quality of life impact of 
childhood skin conditions measured using the Children's Dermatology Life Quality Index 
(CDLQI): a meta-analysis. Br J Dermatol. 2016;174(4):853-861.DOI: 10.1111/bjd.14361
18.
Yalici-Armagan B, Tugrul Ayanoglu B, Demirdag HG. Targeted Tumour Therapy 
Induced Papulopustular Rash and Other Dermatologic Side Effects: A Retrospective 
Study. Cutan Ocul Toxicol. 2019:1-27.DOI: 10.1080/15569527.2019.1594874
19.
National Cancer Institute Skin Care Guidelines
https://www.cancer.gov/about-cancer/treatment/side-effects/skin-nail-changes.
20.
Macartney G, Harrison MB, VanDenKerkhof E, Stacey D, McCarthy P. Quality of life 
and symptoms in pediatric brain tumor survivors: a systematic review. J Pediatr Oncol 
Nurs. 2014;31(2):65-77.DOI: 10.1177/1043454213520191
21.
Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, 
Aschbacher-Smith LE, Rizvi TA, et al. Activity of selumetinib in neurofibromatosis type 
1-related plexiform neurofibromas. N Engl J Med. 2016;375(26):2550–60.

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APPENDIX A
SEVERITY SCORING SYSTEMS
1. Common Terminology Criteria For Adverse Events Version 5.0 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

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2. Overall Dry Skin Score (ODS), EEMCO Guidelines
Kang BC, Kim YE, Kim YJ, Chang MJ, Choi HD, Li K, et al. Optimizing EEMCO guidance for 
the assessment of dry skin (xerosis) for pharmacies. Skin Res Technol. 2014;20(1):87-91.DOI: 
10.1111/srt.12089
Score
Description
0
Absent
1
Faint scaling, faint roughness, and dull appearance
2
Small scales in combination with a few larger scales, slight 
roughness, whitish appearance
3
Small and larger scales uniformly distributed, definite roughness, 
possibly slight redness and possibly a few superficial cracks
4
Dominated by large scales, advanced roughness, redness present, 
eczematous redness and cracks

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3. Hand-Foot Skin Reaction Quality of Life Score (HFS-14)
Sibaud V, Dalenc F, Chevreau C, Roche H, Delord JP, Mourey L, et al. HFS-14, a specific 
quality of life scale developed for patients suffering from hand-foot syndrome. Oncologist. 
2011;16(10):1469-1478.DOI: 10.1634/theoncologist.2011-0033
Scoring:
Each item is scored on a three-point Likert scale: 0, “no, never”; 1, “yes, from time to time”; 2, 
“yes, always.” Two separate questions include one to measure limb involvement (type of limb 
affected by HFS, one or both) and one to measure pain. The limb involvement item is scored 
either 1 if only the hands or feet were affected or 3 if both the hands and feet were affected. The 
pain item is scored on a three-point scale: 1, not painful; 2, moderately painful; 3, very painful. 
The total HFS-14 score is calculated by summing the scores of all items, with the higher the 
score, the greater the QoL impairment.

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4. Children’s Dermatology Life Quality Index (CDLQI) 
(Illustrations not included)
Lewis-Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): initial 
validation and practical use. Br J Dermatol. 1995;132(6):942-949
https://astar-register.org/wp-content/uploads/sites/284/2018/10/CDLQI-Cartoon 
English-V1-16Oct18.pdf
How to score it
The scoring of each question is:

Very much = 3

Quite a lot = 2

Only a little = 1

Not at all = 0

Question unanswered = 0

Question 7: 'Prevented school' (text-only questionnaire) = 3


Meaning of scores

0-1 = no effect on child’s life

2-6 = small effect

7-12 = moderate effect

13-18 = very large effect

19-30 = extremely large effect
Please Check EVERY question. 
Over the last week:
1. How itch, ‘scratchy,’ sore or painful has your skin been? 
Very much
Quite a Lot 
A Little 
Not at all
2. How upset or embarrassed, self-conscious, or sad have you been because of your skin? 
Very much
Quite a Lot 
A Little 
Not at all

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3. How much has your skin affected your friendships?
Very much 
Quite a Lot 
A Little 
Not at all
4. How much have you changed or worn different or special clothes/shoes because of your 
skin?
Very much 
Quite a Lot 
A Little 
Not at all
5. How much has your skin trouble affected going out, playing or doing hobbies?
Very much 
Quite a Lot 
A Little 
Not at all
6. How much have you avoided swimming or other sports because of your skin trouble? 
Very much
Quite a Lot 
A Little 
Not at all
7a. If school time: How much did your skin trouble affect your school work?
Very much 
Quite a Lot 
A Little 
Not at all
7b. If holiday time: How much has your skin problem interfered with your holiday plans?
Very much 
Quite a Lot 
A Little 
Not at all
8. How much trouble have you had with your skin with other people calling your names, 
teasing, bullying, asking questions, or avoiding you?
Very much 
Quite a Lot 
A Little 
Not at all
9. How much has your sleep been affected by your skin problem? 
Very much
Quite a Lot

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A Little 
Not at all
10. How much of a problem has the treatment for your skin been? 
Very much
Quite a Lot 
A Little 
Not at all
5. Pediatric Quality of Life Score, General Well-Being Scale 
https://www.pedsql.org/
For scaling and scoring: 
https://www.pedsql.org/PedsQL-Scoring.pdf