Conditions: Stage III Melanoma Stage IV Melanoma Unresectable Melanoma BRAF Mutant Melanoma
Keywords: Melanoma Stage III Stage IV Unresectable BRAF Mutant Dabrafenib Trametinib Kinome Resistance Sequencing Mutations Kinases Mechanism
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

Detailed description:
The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of BRAF and MEK inhibition. Overall response rate and duration to this combination will also be assessed.

Tissue will be collected at baseline and at progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit. We anticipate that up to 50% of patients may continue on therapy post-progression for 2-8 weeks.

BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this combination, and to determine the recommended phase 2 doses (RP2D) for each agent. Expansion cohorts at the RP2D for these drugs in combination were included in the phase I to characterize the safety in more detail, and to explore the efficacy of this combination. The combination was well tolerated as described in section 1.5, with decreased frequency of rash compared to either agent alone and with just 1 report of cutaneous SCC.

This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these patients will also likely go on to develop resistance as a result of new resistance mutations, and given the cooperative signaling network of kinases that sense inhibition of key nodal kinases and induce compensatory responses that offset pharmacological intervention. The study objectives are as follows: Objectives Primary Objective To identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors, and to determine a kinome signature predictive of resistance to BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete response + partial response) as measured via RECISTv1.1 To estimate the duration of ORR as measured via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1 To estimate the rate of overall survival (OS) at 1 year from day 1 of treatment

Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry.

Arms:
arm 1: Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Interventions: intervention 1: BRAF inhibitor dabrafenib and MEK inhibitor trametinib
Intervention descriptions: intervention 1: Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Protocol document:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #5 
 
LCCC 1128: Open Label Phase II Trial of the BRAF inhibitor (Dabrafenib) and the MEK 
inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; 
Correlation of Resistance with the Kinome and Functional Mutations 
 
AMENDMENT INCORPORATES (check all that apply): 
X_    Editorial, administrative changes 
X_    Scientific changes (IRB approval) 
X_    Eligibility Changes (IRB approval) 
 
 
The purpose of this amendment is to allow the collection of progression biopsies from 
subjects who are withdrawn from the LCCC 1128 study for a variety of reasons 
including, but not limited to, a lack of tolerability, need to receive other therapy or 
completion of 3-years of study treatment without progression. The subset of the 
aforementioned subjects who are later re-challenged with dabrafenib and trametinib 
combination therapy and then progress while on this treatment, may be biopsied at the 
time of their clinical or radiological progression. These subjects are required to consent to 
this biopsy collection prior to being placed back on the LCCC 1128 clinical trial. 
Previously in protocol amendment #3, subjects who were withdrawn from study 
treatment due to an inability to tolerate the combination regimen, but who continued on 
BRAF inhibitor targeted therapy, were able to be consented, at the time of progression 
from single agent therapy, to undergo the a progression biopsy. As the protocol’s 
objectives focus on combination therapy, the protocol is also currently being amended to 
remove this scenario. No subjects were biopsied who progressed solely on single agent 
therapy and thus this amendment will not affect previously collected data. 
 
The following modifications were made to this protocol for amendment #5: 
 
Editorial, Administrative Changes: 
• Minor spelling grammar and formatting changes throughout the protocol 
• Removal of Co-Investigators from the Face Page of the protocol 
• Addition of the IND # to the Face Page of the Protocol 
• IRB Reporting Requirements were updated in accordance with the UNC IRB 
SOPs (Section 7.3.3) 
• FDA Expedited Reporting language was updated to better capture FDA guidance 
provided in 21CFR312.32 (IND Safety Reporting) (Section 7.3.3) 
• Required documentation (Section 9.2) was updated to include financial 
disclosures 
• Single Patient/Subject Exceptions (Section 9.5.2) was updated in accordance with 
Lineberger Comprehensive Cancer Center’s Single Subject Exceptions Policy.  
 
Scientific Changes: 
• Updated the study synopsis, study schema, biopsy section, Time and Events Table 
and correlative study procedures to indicate that former LCCC 1128 subjects who 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
progress on standard of care dabrafenib/trametinib off study are eligible for a 
progression biopsy (Section 1.1, 4.1, 4.2, 4.7, 6.1 and 6.7) 
• The biopsy, duration of follow-up, Time and Events Table and follow-up 
assessments sections of the protocol were updated to indicate that subjects wo are 
placed back on study for the purposes of a progression biopsy will remain on 
study for safety monitoring, in relation to the biopsy procedure, for 30 days. 
Subjects who have an ongoing ≥grade 2 or serious AE (SAE) related to the study 
procedure at 30 days will continue to be followed until the event is resolved or 
deemed irreversible by the investigator (Section 4.2, 4.7, 6.1 and 6.5). 
• The assessment of primary endpoint and efficacy section (Section 6.9) was 
updated to clarify that analysis of progression biopsies from subjects placed back 
on study after progressing on standard of care dabrafenib/trametinib will be 
included in the analysis of the primary and correlative secondary objectives. 
• The section on sample size and data analysis plans was updated to clarify that 
tumor samples from patients who progress on study and those who are removed 
from study and later progress on the combination treatment will be analyzed as 
one data set (Section 8.1).  
 
 
Eligibility Criteria: 
• Addition of inclusion criteria for off-study subjects who may be consented to 
come back on study for the purposes of a progression biopsy when they progress 
on standard of care dabrafenib and trametinib treatment (Section 3.3).  
o Subjects must have currently progressed while receiving trametinb and 
dabrafenib combination therapy. 
o Subjects must be willing to undergo a research biopsy 
o Subjects must have a tumor amenable to research biopsy 
o Subjects must provide informed consent 
o Subject must have been previously enrolled on the LCCC 1128 protocol. 
 
 
THE ATTACHED VERSION DATED NOVEMBER 22, 2017 INCORPORATES THE 
ABOVE REVISIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #4 
 
LCCC 1128: Open Label Phase II Trial of the BRAF inhibitor (Dabrafenib) and the MEK 
inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; 
Correlation of Resistance with the Kinome and Functional Mutations 
 
AMENDMENT INCORPORATES (check all that apply): 
X_    Editorial, administrative changes 
X_ Scientific changes (IRB approval) 
_    Eligibility Changes (IRB approval) 
 
 
The following modifications were made to this protocol for amendment #4: 
 
1) This amendment adds a requirement for annual ophthalmic exams while on treatment 
(see section 6.3.4 and time and events table) 
2) Clarification of the duration follow-up period (see section 4.7 and 6.6). Regardless, of 
the reason that a patient comes off treatment, dermatologic exams will continue every 
3 months for the first 6 months following discontinuation from dabrafenib, and may 
be done by a physician local to the patient. Only after these dermatologic exams are 
complete is the patient considered off follow-up, even if they do not require survival 
follow-up for this entire 6 month period. 
3) This protocol amendment also clarifies that whether or not a subject enrolls in LCCC 
1108, they will be asked to provide a single blood sample (approximately 8 mL) for 
research purposes. This blood sample may be collected at any point in the study, 
including during follow-up. 
4) Section 7.3.3 has been updated with the new language in regards to Novartis 
reporting requirements. 
5) Robert G. Dixon, MD, Hyeon Yu, MD, and Kathleen Gordon, MD have been added 
as co-investigators to the protocol title page 
6) A line to provide the version of the protocol was added to the protocol signature page 
 
In addition, the summary of changes for amendment #3 states that the sponsor changed 
from GSK to Novartis.  Novartis is the funding source for this study and not the sponsor.  
No changes were made in protocol amendment #4 based on this clarification. 
 
 
 
. 
 
 
 
 
 
THE ATTACHED VERSION DATEDAUGUST 1, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #3 
 
LCCC 1128: Open Label Phase II Trial of the BRAF inhibitor (Dabrafenib) and the MEK 
inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; 
Correlation of Resistance with the Kinome and Functional Mutations 
 
AMENDMENT INCORPORATES (check all that apply): 
X    Editorial, administrative changes 
X_ Scientific changes (IRB approval) 
X_ Eligibility Changes (IRB approval) 
 
The following modifications were made to this protocol for amendment #3: 
Eligibility criteria were modified to refine the definition of hypertension in exclusion 
criterion 3.2.6   
1) At progression biopsy wording was changed to allow for attainment of biopsies in 
subjects withdrawn from study treatment due to lack of tolerability of the 
combination regimen and continued on BRAF inhibitor targeted therapy.  These 
subjects should be re-consented so that progression biopsy can be obtained at the time 
of relapse on BRAF inhibitor targeted therapy (i.e., dabrafenib or vemurafenib). 
(Sections 4.2 and 6.7 and footnote #11 to Time and Events Table in section 6.1) 
2) The frequency of tumor assessment scans was reduced to every 12 weeks for subjects 
responding to combination therapy after cycle 9 
 
 
 
 
 
 AND 
 
The frequency of tumor assessment scans was reduced to every 6 months for subjects 
responding to combination therapy for > 2 years (Section 6.3.2 and footnote b added 
to Time and Events Table in Section 6.1) 
3) The frequency of ophthalmic exams was reduced and are now only required at 
Screening and as clinically-indicated due to the presence of ocular symptoms (Section 
6.3.2 and Time and Events Table in Section 6.1) 
4) Sponsor changed from GlaxoSmithKline to Novartis 
5) Blood Sample:  
 
For those patients who do not co-enroll into LCCC1108, we will ask for a blood sample 
(~8mLs) to ensure sufficient germline DNA in the event tissue samples are insufficient or 
request blood samples collected under LCCC9001 with IRB # 90-0573. This change is 
reflected in section 1.6, section 6.1 footnote #13, and 6.7 
6) In anticipation of the pending switch from investigative product to commercial supply by the 
sponsor the following language was added: Trametinib/Dabrafenib commercially available 
product with auxiliary labeling will be provided by Novartis.  The study drug should be 
administered and stored as per the instructions specified on the label (refer to the label, the PI 
or the IB for more detailed information). In addition, MSDS will now be available upon 
request from Novartis and not GSK (See sections 5.1.1, 5.1.2, 5.2.1, and 5.2.2 
7) Sponsor SAE reporting requirements for GSK were deleted and replaced with SAE reporting 
requirements for Novartis in section 7.3.3. 
 
THE ATTACHED VERSION DATED SEPTEMBER 15, 2015 INCORPORATES THE 
ABOVE REVISIONS 
 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #2 
 
 
LCCC 1128: Open Label Phase II Trial of the BRAF inhibitor (Dabrafenib) and the MEK 
inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; 
Correlation of Resistance with the Kinome and Functional Mutations 
 
AMENDMENT INCORPORATES (check all that apply): 
X    Editorial, administrative changes 
X_ Scientific changes (IRB approval) 
X_ Eligibility Changes (IRB approval) 
 
Minor editorial changes made throughout; changed biostatistician to Joseph Ibrahim, PhD; 
Requirement of tissue collection taking place at UNC have been removed as no other sites are 
involved in this study (sections 1.1, 1.7)  
 
Safety and Efficacy 
The 2 medications in the study were FDA approved in combination as of January 2014, and new 
Investigator Brochures were issued for dabrafenib, trametinib, and the combination.  Based on 
these documents (including the updated package inserts), additional information on safety and 
efficacy on the combination has been incorporated into the protocol.  These changes are reflected 
in sections 1.3, 1.4, 1.5, 5.1 and 5.2.  Common AEs using combination therapy are listed in 
section 5.2.9. Section 1.7 was updated to include recent data indicating a possible survival benefit 
if patients are continued on BRAF inhibition post disease progression. 
 
Eligibility 
• 
Clarified that patients with elevated bilirubin due to Gilbert’s disease will not be excluded 
(section 3.1.6) 
• 
Clarified exclusion criteria 3.2.6 to  “Patients with history of hypertension should have 
hypertension adequately controlled (BP < 140/90) with appropriate anti-hypertensive therapy 
or diet prior to study entry” 
• 
Changed central serous retinopathy to new name: retinal pigment epithelial detachment 
(RPED) (section 3.2.13; also 1.5; 4.4.3)  
• Revised section 3.1.3 to indicate that patients with BRAFV600K are also eligible in 
addition to BRAFV600E, as the dabrafenib/trametinib combination is FDA approved in 
both populations. 
• Added section 3.1.7 clarifying that prior anti-cancer treatment related toxicities must 
have resolved prior to enrollment. 
• Detailed information added to section 3.1.9 on what constitutes effective 
contraception, and statement referencing this information added to inclusion criteria 
3.1.10. 
• Exclusion criteria 3.2.2 added (History of malignancy with confirmed activating RAS 
mutation at any time. Note: Prospective RAS testing is not required. However, if the 
results of previous RAS testing are known, they must be used in assessing eligibility) 
• Minor clarifications added to exclusion criteria 3.2.8, 3.2.11, and 3.2.14  
 
 
Correlatives 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
Biopsies 
Modified section 4.2 on timing of biopsies and removed statement that biopsy must be ‘core’ 
biopsy.  (section 6.6 and 6.8) Clarified that biopsies may be delayed beyond point of disease 
progression if patient remains on therapy.  The decision to continue therapy should be based on 
clinical benefit and safety considerations. Also updated in key to table of time and events (section 
6.1, 6.4.1 and 6.7).   
 
Deleted statement that maximum number of biopsy passes is 4.  The maximum number of passes 
will be determined by treating physicians based upon considerations of safety.  
 
Blood Sample 
For those patients who do not co-enroll into LCCC1108, we will ask for a blood sample (~8mLs) 
to ensure sufficient germline DNA in the event tissue samples are insufficient. This change is 
reflected in section 1.6, section 6, 6.2 and 6.8 
 
Management and Dose Modifications (section 4.4) 
Deleted ‘interstitial lung disease’ as safety issues mostly for pneumonitis 
Updated information on management based on most recent template language from GSK (section 
4.4.3.1 on hypertension; 4.4.1.1 table on rash; 4.4.2 malignancies, 4.4.3.2 table on QTc 
prolongation; 4.4.3.3 reduced LVEF; 4.4.4  visual changes; section 4.4.5 pneumonitis; section 
4.4.6 renal insufficiency; 4.4. 7 diarrhea; 4.4.8 pyrexia; 4.4.9.1 (liver chemistry stopping criteria) 
and added sections on new primary melanoma (4.4.2.2)  non-cutaneous malignancies (4.4.2.3), 
pancreatitis (4.4.10) and hyperglycemia (4.4.11). Updated section 4.4.12 (non-specific toxicities 
attributable to drug therapy) 
 
Concomitant Medications (section 4.5) 
Added investigational drugs to the list of prohibited medications, and added section 4.5.3 on 
dabrafenib and radiation. 
 
Time and Events Table 
In footnotes to table (section 6.1) clarified biopsy timing and timing of tumor imaging. At 
recommendation of manufacturer, added additional ophthalmic exams at cycles 2, 8 and annually 
thereafter. Regardless of progression/non-progression, clarified that patients will be evaluated 
(receive mandated study assessments) every 2 cycles or 6 weeks after cycle 9. (sections 6.1, 6.3 
and 6.3.5) Consolidated study assessments. Widened study window for lab screening assessments 
to within 21 days prior to therapy initiation. Widened study windows for cycle 9 and beyond to 
+/-5 days.   
 
Safety reporting 
Included information on trametinib overdose (section 5.1)   
Added new toxicities that should be reported as an SAE (section 7.1) 
 Glaxo fax number updated:  610-200-1767 
Appendix B: updated list of prohibited medications 
Appendix G added: Ophthalmic Exam Worksheet for documentation of exam findings. 
Appendix H added: safety information from ongoing randomized Phase 3 trial 
 
THE ATTACHED VERSION DATED NOVEMBER 23 2014, INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #__1_ 
 
 
LCCC 1128: Open Label phase II trial of the BRAF inhibitor (Dabrafenib) and the MEK 
inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; 
Correlation of Resistance with the Kinome and Functional Mutations 
 
AMENDMENT INCORPORATES (check all that apply): 
X    Editorial, administrative changes 
X_ Scientific changes (IRB approval) 
___Therapy changes (IRB approval) 
X_ Eligibility Changes (IRB approval) 
 
The main driver for this amendment was to increase the window of time for screening for all but 
the laboratory evaluations and baseline tumor biopsy from 1 week to 3 weeks, to 
expand/reorganize the T&E table so that we each study visit for the first 6 months is included in 
the table, to clarify the timing of the biopsies at progression, and to include specific information 
for affiliate sites as the study is changing to multicenter.  These changes are reflected in sections 
4.2, 6.0 (Time and Events table), and sections 6.2-6.7. 
 
In addition, the 2 medications included in the study were FDA approved as of May 2013, and this 
information has been incorporated into the study.  These changes are reflected in sections 1.1, 1.3, 
and 1.4.  
 
Safety and drug interaction information: Since this trial was initially approved in 2012, new 
IBs for each individual agent were issued by the manufacturer.  In addition, a new IB for the 
combination of trametinib and dabrafenib was issued in May of 2013.  Updated safety 
information (including drug interaction information) from each of these documents was 
incorporated into the protocol. These changes are reflected in sections 1.4.1, 1.5, 4.4.2.2., 4.4.3, 
4.4.4, 4.4.7, 4.5.2, 5.1.5, 5.2.5, 5.2.7, and 5.2.8, and Appendix C section 11.3.  
 
Eligibility 
Section 3.1.7 was revised to indicate that the pre-treatment biopsy required by the protocol should 
not be performed until all other eligibility criteria are confirmed. 
 
Section 3.1.8: females of child-bearing potential must continue effective contraception until 16 
(not 4 weeks) post the last dose of study medication.  Men with a female partner of childbearing 
potential must agree to effective contraception from D1 of study treatment (not 14 days prior to 
D1 as written previously). 
 
Biopsies: 
Section 4.2, Time and Events footnote 11, and sections 6.4, 6.7.: These sections were revised to 
indicate that tissue at baseline does not have to be from the original diagnostic specimen, but 
from any site.  If tissue is not available, a core biopsy can be obtained from any site, not restricted 
to target lesions.  Repeat biopsies were already required at progression. However, the timing was 
clarified with amendment #1 to indicate they should be performed within 7 business days of 
documented progression, and optimally within 4 hours of that day’s study medication.  Post-
treatment biopsies will be not required for patients removed from the study for reasons other than 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
disease progression.  Sections 4.1, 4.2, 6.4 and 6.7 were revised to indicate that patients will be 
requested to stay on study medication until the post progression biopsy is performed. 
 
Section 6.9.3 Evaluation of Target lesions: 
A note was added to this section NOTE: Whenever possible, a biopsied lesion should not be 
considered a target lesion for RECIST tumor assessments.  If the biopsied lesion is the only site 
of measurable disease, it may only be followed as a target lesion if a core biopsy was 
performed.  Lesions that have been completely removed or subjected to excisional biopsy should 
not be followed as target lesions.   
 
Time and Events: 
In addition to the logistical changes and details on biopsies noted above, the footnotes were revise 
to specify that the end of treatment visit should be performed 30 days after the last dose of study 
medication, and to allow dermatologic evaluations to be performed at an MD office local to the 
patient if the patient is not scheduled to come to the clinic.  It was also emphasized that a scan of 
the brain is not required post-baseline unless clinically indicated.   
 
In addition, the following editorial changes were made: 
 
The PI was changed from Frances Collichio, MD to Carrie Lee MD, MPH.  Dr. Collichio remains 
as a co-investigator.   
 
Section 4.3: This section was revised to indicate that if a patient misses a dose of dabrafenib, they 
may make this dose up, provided it is >6 hours until the next dose.  If a patient misses a dose of 
trametinib, they may make this dose up, provided it is >12 hours until the next dose.   
 
Sections 4.8 and 4.9 (Removal of Patients, Patient Replacement, and Study Withdrawal) were 
added to reconcile with the newest LCCC protocol template. 
 
Section 6.9 was revised to emphasize that tissue at progression must be available to render a 
patient evaluable for the primary endpoint.  The following statement was added: If a patient drops 
out of the study prior to progression, they may be replaced. 
 
 
 
 
 
THE ATTACHED VERSION DATED JUNE 11, 2013, INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
 
 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC 1128: Open Label Phase II Trial of the BRAF inhibitor (Dabrafenib) and the 
MEK inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant 
Melanoma: Correlation of Resistance with the Kinome and Functional Mutations 
 
Principal Investigator  
Carrie Lee, MD, MPH 
The University of North Carolina at Chapel Hill 
Physician’s Office Building, 3rd Floor 
170 Manning Drive CB #7305 
Chapel Hill, NC 27599-7305 
(919)966-0405 
carrie_lee@med.unc.edu 
 
 
Biostatistician  
Joseph G. Ibrahim, PhD 
Professor, Biostatistics 
(919) 843-2715 
jibrahim@email.unc.edu 
 
 
 
 
 
 
 
 
Clinical Protocol Office 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 7295 
Chapel Hill, NC 27599-7295 
Phone: 919-966-4432 
 
 
 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
IND: 115,704 
Funding Source: Novartis  
Version: November 22, 2017 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER                                                           LCCC 1128 
CLINICAL ONCOLOGY RESEARCH PROGRAM                                                                          November 22, 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
LCCC 1128: Open Label Phase II Trial of the BRAF inhibitor (Dabrafenib) and the 
MEK inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant 
Melanoma: Correlation of Resistance with the Kinome and Functional Mutations 
 
 
 
Principal Investigator  
Carrie Lee, MD, MPH 
The University of North Carolina at Chapel Hill 
Physician’s Office Building, 3rd Floor 
170 Manning Drive CB #7305 
Chapel Hill, NC 27599-7305 
(919) 966-0405 
carrlie_lee@med.unc.edu 
 
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name: Carrie Lee, MD, MPH 
 
PI Signature: ___________________ 
 
Date:____________________ 
 
Version: November 22, 2017 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
1 
 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ................................................................ 1 
1.1 
Study Synopsis 
1 
1.2 
Melanoma 
1 
1.3 
Trametinib 
1 
1.4 
Dabrafenib 
3 
1.5 
Safety and Efficacy when Dabrafenib Combined with Trametinib 
6 
1.6 
Correlative Studies 
11 
1.7 
Rationale 
14 
2.0 
STUDY OBJECTIVES 15 
2.1 
Primary Objective 
15 
2.2 
Secondary Objectives 
15 
2.3 
Primary Endpoint 
15 
3.0 
PATIENT ELIGIBILITY 15 
3.1 
Inclusion Criteria 
15 
3.2 
Exclusion Criteria 
17 
4.0 
TREATMENT PLAN 20 
4.1 
Schema 
20 
4.2 
Biopsies 
21 
4.3 
Treatment Dosage and Administration 
22 
4.4 
Dose Modifications for Trametinib and Dabrafenib for Toxicity 
23 
4.5 
Concomitant Medications/Treatments 
43 
4.6 
Duration of Therapy 
45 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
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4.7 
Duration of Follow Up 
45 
4.8 
Removal of Patients from Protocol Therapy 
45 
4.9 
Patient Replacement 
46 
4.10 
Study Withdrawal 
46 
5.0 
DRUG INFORMATION 
46 
5.1 
Trametinib Description and Management 
46 
5.2 
Dabrafenib Description and Management 
51 
6.0 
EVALUATIONS AND ASSESSMENTS .......................................................... 60 
6.1 
Time and Events Table 
60 
6.2 
Pre-Study Assessments 
64 
6.3 
Treatment Assessments 
65 
6.4 
Continued Treatment after Disease Progression 
65 
6.5 
End of Treatment 
66 
6.6 
Follow-up Assessments 
66 
6.7 
Correlative Study Procedures 
67 
6.8 
Assessment of Safety 
72 
6.9 
Assessment of Primary Endpoint and Efficacy 
72 
7.0 
ADVERSE EVENTS 
75 
7.1 
Definitions 
75 
7.2 
Documentation of non-serious AEs or SARs 
77 
7.3 
SAEs or Serious SARs 
78 
7.4 
Data and Safety Monitoring Plan 
82 
8.0 
STATISTICAL CONSIDERATIONS .............................................................. 83 
8.1 
Sample Size and Data Analysis Plans 
83 


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CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
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9.0 
STUDY MANAGEMENT 84 
9.1 
Institutional Review Board (IRB) Approval and Consent 
84 
9.2 
Required Documentation 
85 
9.3 
Registration Procedures 
85 
9.4 
Data Management and Monitoring/Auditing 
85 
9.5 
Adherence to the Protocol 
86 
9.6 
Amendments to the Protocol 
88 
9.7 
Record Retention 
88 
9.8 
Obligations of Investigators 
88 
10.0 
REFERENCES 
89 
11.0 
APPENDICES 
90 
11.1 
Appendix A Grading of Visual Changes 
90 
11.2 
Appendix B Prohibited Drugs, and Drugs to be used with Caution 
91 
11.3 
Appendix C AEs of Special Interest in Study BRF113220 
93 
11.4 
Appendix D Liver Events 
94 
11.5 
Appendix E Supportive Care and Preventive Measures for Rash 
96 
11.6 
Appendix F: Model Patient Diary for Compliance* 
97 
11.7 
Appendix G. Ophthalmic Exam Source Worksheet 
98 
11.8 
Appendix H AEs of Special Interest in Study MEK115306 
99 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
1 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This multicenter phase II study in 20 patients with BRAFV600mutant disease 
(specifically BRAFV600E or BRAFV600K designated as BRAFV600E/K), unresectable 
stage III/IV melanoma is designed to explore the mechanisms by which tumors 
acquire resistance to the combination of a BRAF inhibitor (dabrafenib;Tafinlar®) 
and MEK inhibitor (trametinib;Mekinist®).  Tissue will be collected at baseline 
and at progression. If a subject is removed from the study for one of a variety of 
reasons including, but not limited to, an inability to tolerate the combination of 
dabrafenib and trametinib, a need to receive other therapy or completion of 3-
years of study treatment without progression, and the subject later receives, as 
part of his/her standard of care, the combination of dabrafenib and trametinib and 
progresses on the standard of care regimen, then the subject may be contacted by 
the  treating physician to be put back on to the LCCC 1128 protocol and have a 
progression biopsy at this progression time point.   Markers of resistance will be 
explored by performing near kinome-wide profiling on tumor samples, and in 
patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors 
using NextGen DNA sequencing technology.  Overall response rate and duration 
to this combination will also be assessed.   
1.2 
Melanoma 
Melanoma is the sixth most common malignancy in the United States and its 
incidence is increasing faster than any other cancer [1, 2].  Patients with 
metastatic melanoma have a median life expectancy of only 8 months.  In the 
extension cohort from a recent phase I trial of the BRAF inhibitor vemurafenib, 
81% (26 of 32) of patients with BRAFV600E/K melanoma experienced at least 30% 
tumor shrinkage by RECIST with a complete response seen in two patients [3].  
However, resistance to PLX4032 emerged after response durations of 2 to more 
than 18 months.  Several key resistance mechanisms have been described and 
warrant further investigation.  These mechanisms include new functional 
mutations in one of five established resistance genes (BRAF, NRAS, MEK1, 
MAP3K8 or COT, and PTEN).   
 
MEK is a key protein integral to the RAS/RAF/MEK/ERK signaling pathway. In 
BRAF mutant melanoma, MEK activation drives disease proliferation.  Therefore, 
it is hypothesized that the combination of BRAF and MEK inhibition is likely to 
have less downstream resistance than BRAF inhibition alone.   
1.3 
Trametinib 
Trametinib is a reversible and highly selective allosteric inhibitor of 
MEK1/MEK2.  These characteristics, along with its long half-life, small 
peak/trough ratio and limited inter-subject variability in its pharmacokinetic (PK) 
profile, render it an excellent MEK1/MEK2 inhibitor to evaluate in human 
trials.[4]  Trametinib is approved as monotherapy and in combination with 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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dabrafenib for the treatment of patients with unresectable or metastatic melanoma 
with BRAF V600E or V600K mutations. 
1.3.1 Effects in Humans 
The effect of trametinib in subjects with a variety of cancers has been evaluated in 
a number of studies, and additional studies are ongoing.[4]  Trametinib has been 
administered as monotherapy in at least 9 of these studies, and as combination 
therapy in at least 10 additional studies. Please also review the package inserts for 
trametinib and dabrafenib for updated background information on each product.  
 
Preliminary trametinib pharmacokinetics (PK) was determined after single- and 
repeat dose oral administration of trametinib tablets in subjects with solid tumors. 
Trametinib is absorbed rapidly with median Tmax generally occurring within 1-3 
hours after oral administration of trametinib under fasting conditions. Following 
repeat-dosing the mean area under the curve (AUC0-τ) and maximum 
concentrations (Cmax) increased in an approximately dose proportional manner. 
Trametinib accumulates with repeat dosing with a mean effective half-life at a 
dose of 2 mg of approximately 4 days. 
 
In vitro, the metabolism of trametinib is mediated predominantly by non-CYP-
mediated processes, via deacetylation alone, or with monooxygenation or in 
combination with glucuronidation biotransformation pathways. No formal clinical 
trials have been conducted to evaluate human cytochrome P450 (CYP)  
enzyme-mediated drug interactions with trametinib. Co-administration of 
trametinib (2mg per day) with the CYP3A 4 inducer dabrafeninb (150mg BID) 
resulted in no clinically relevant pharmacokinetic drug interactions (trametinib 
package insert; January 2014). This protocol prohibits or cautions against the use 
of medications with the potential for drug interactions with dabrafenib.  See 
section 4.5 (Concomitant Medications) and section 11.2 (Appendices) for the 
categories of medications that are prohibited and/or to be used with caution.  
 
Based on the adverse events (AEs) observed in the dose escalation phase of the 
first-time-in-human (FTIH) study MEK111054, the maximum tolerated dose was 
established at 3.0 mg once daily (QD), and the recommended Phase II dose 
(RP2D) of trametinib was identified as 2.0 mg QD. 
 
Pharmacodynamics 
Pre- and post- (day 15) treatment tumor biopsies were performed for evaluation of 
pharmacodynamic (PD) markers in patients with metastatic melanoma in the first 
monotherapy trial of trametinib conducted (MEK111054).   Doses remained 
stable for the 15 days of treatment and were 0.5, 1.0 or 2.0mg/day.  PD markers 
evaluated included percent change from baseline of pERK, Ki67, and p27.  
Trough levels of trametinib were also obtained at day 15.   PD responses in this 
study were dose-related, with minimal PD effects seen at 0.5mg/day, and robust 
changes reported at 2.0mg/day. The median change observed at a dose of 2 mg 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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daily was 62% inhibition of pERK, 83% inhibition of Ki67, and a 175% increase 
in p27, confirming inhibition of the MAPK/ERK pathway.   Correlations were 
also reported between PD response and trough concentrations of trametinib on 
day 15.  Monte Carlo simulations predict that 86% of subjects will exceed the 
target concentration of 10ng/mL at the 2mg/day dose.  
 
Trametinib 2.0 mg once daily was administered in the Phase II and Phase III 
studies. After accounting for the effect of lactate dehydrogenase (LDH), a known 
prognostic marker in subjects with melanoma, subjects with exposure above the 
median value had longer progression-free survival (PFS) than those below the 
median exposure with hazard ratio (HR) <1. The relationship with exposure was 
more pronounced in the Phase II study compared to the Phase III study which 
may be related to the lower exposure observed in subjects enrolled in the Phase II 
study. The higher exposure in the Phase III study may suggest that the drug 
response is starting to plateau and data are less likely to show /an exposure-
response.[4]   
 
Safety and Efficacy 
The most common adverse reactions in the trametinib arm (n=211) from the 
randomized, open-label study of trametinib versus chemotherapy in patients with 
BRAF V600E or V600 K mutation –positive melanoma included the following:  rash 
(57%), dermatitis acneiform (19%), dry skin (11%), pruritus (10%), paronychia 
(10%),  diarrhea (43%), stomatitis (15%), abdominal pain (13%), lymphedema 
(32%), hypertension (15%), and hemorrhage (13%). 
 
See section 5.1 and the trametinib Investigator’s Brochure for additional safety 
information on trametinib and section 1.5 for safety and efficacy data when 
trametinib is combined with dabrafenib in BRAF mutant melanoma.  
1.4 
Dabrafenib 
Dabrafenib is a potent and selective inhibitor of BRAF kinase, and  
inhibits phosphorylation of MEK and ERK in vitro, inhibits cell proliferation, and 
achieved tumor regression in xenograft cancer models that encode BRAFV600E.[5]  
Dabrafenib is approved as monotherapy for the treatment of patients with 
unresectable or metastatic melanoma with BRAF V600E mutations, and in 
combination with trametinib for the treatment of patients with unresectable or 
metastatic melanoma with BRAF V600E or V600 K mutations 
 
Dabrafenib is under development for the treatment of advanced cancer subjects 
with BRAF mutant tumors, which have been identified at a high frequency in 
specific cancers including approximately 40-60% of melanoma, 30 to 50% of 
papillary thyroid, 5 to 20% of colorectal cancer, and approximately 30% of 
ovarian cancer.  
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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Please also review the latest version of the Investigator’s Brochure for trametinib 
and dabrafenib for updated background information on each product and the 
number of clinical trials ongoing. 
1.4.1 Effects in Humans 
The effect of dabrafenib in subjects with a variety of cancers has been evaluated 
in a number of studies, and additional studies are ongoing. [5] 
 
Pharmacokinetics 
Two metabolites of dabrafenib were characterized and may contribute to the 
clinical activity of this drug. GSK2285403 (hydroxy-metabolite) 
pharmacokinetics paralleled that of parent while the desmethyl- (GSK2167542) 
metabolites exhibited a longer half-life and accumulated following repeat dosing. 
Similar to parent concentrations, exposure for all metabolites showed a less than 
dose proportional increase with repeat dosing. 
 
Results following single dose administration showed a total recovery of 
radioactivity of 93.8 % of the dose with fecal excretion being the major route of 
elimination, accounting for 71.1% of the dose. 
 
The current recommendation is to administer dabrafenib under fasting conditions, 
either one hour before or 2 hours after a meal. Preliminary results of the food 
effect study showed a decrease in dabrafenib Cmax and AUC(0-∞) after single 
dose administration. 
 
Preliminary results of the effect of repeat dose administration of dabrafenib 150 
mg BID on the single dose pharmacokinetics of midazolam, a CYP3A4 probe, 
showed a decrease in midazolam exposure, indicating that dabrafenib induces 
CYP3A4-mediated metabolism (moderate to potent).  It may also induce other 
enzymes such as CYP2B6, CYP2C8, CYP2C9, and CYP2C19, as well as UDP 
glucuronosyl transferase (UGT) and transporters.  Co-administration of dabrafenib 
and drugs that are affected by the induction of these enzymes may result in 
decreased concentrations and loss of efficacy. In preliminary studies, dabrafenib 
was a substrate for human P-glycoprotein (Pgp) and murine breast cancer resistant 
protein 1 (Bcrp1) in vitro. However, these transporters have minimal impact on 
dabrafenib oral bioavailability and elimination, and the risk of a drug-drug 
interaction is minimal. [5] 
 
In addition, CYP2C8, CYP3A4 and to a lesser extent CYP2C9 and CYP2C19 are 
involved in the oxidative metabolism of dabrafenib. In vitro, selective inhibitors 
of CYP 2C8 and CYP3A4 reduced the intrinsic clearance of dabrafenib. These 
results suggested that dabrafenib has the potential of being a victim of drug-drug 
interactions upon co-administration with strong CYP2C8 and CYP3A4 inhibitors 
and inducers.[5] 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
5 
This protocol prohibits or caution against the use of medications with the potential 
for drug interactions with dabrafenib and/or trametinib.   See section 4.5 
(Concomitant Medications) and section 11.2 (Appendices) for the categories of 
medications that are prohibited and/or to be used with caution.   
 
Pharmacodynamics 
Based on results from the dose escalation part of Study BRF112680 (Part 1) in 
patients with V600 mutant-positive melanoma, 150mg BID is predicted to 
provide, on average, adequate inhibition of pERK (80%). [5]  
 
Safety as Monotherapy 
As summarized in the table below (from the dabrafenib 2014 IB)[5] the following 
adverse events were considered related to dabrafenib when administered as 
monotherapy across company-sponsored clinical trials (n=578).  Approximately 
30% of these patients received dabrafenib treatment for >6 months. Frequencies 
are as follows: very common (≥10%), common (≥1% and <10%), uncommon 
(≥0.01% and <1%), and rare (≥0.01% and <0.1%). 
 
Frequency 
Adverse Event 
Very Common 
Skin papilloma, papilloma 
Decreased appetite 
Headache 
Cough 
Nausea, vomiting, diarrhea 
Skin effects (rash, hyperkeratosis), alopecia, palmar-
plantar erythrodysesthesia syndrome 
Arthralgia, myalgia, pain in extremity 
Asthenia, fatigue, pyrexia, chills 
Common 
Squamous cell carcinoma (SCC), including SCC 
of the skin, SCC in situ (Bowen’s disease), and 
keratoacanthoma Acrochordon (skin tags) 
Seborrhoeic keratosis 
Hypophosphataemia 
Constipation 
Skin effects (Actinic keratosis, Skin lesion,Dry 
skin, Erythema) 
Influenza-like illness 
Uncommon 
New primary malignant melanoma 
Hypersensitivity 
Uveitis 
Pancreatitis 
Renal failure, acute renal failure 
 
See section 5.2.5 for additional safety information on dabrafenib and section 1.5 
for safety and efficacy data when dabrafenib is combined with trametinib in 
BRAF mutant melanoma.  


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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1.5 
Safety and Efficacy when Dabrafenib Combined with Trametinib 
To date over 1000 subjects, most with BRAF V600-mutated melanoma, have 
received the combination of these two drugs across the manufacturer’s sponsored 
studies.  Most of the safety data (as summarized in the June 2014 Investigator’s 
Brochure of this combination) are from the randomized phase III double blind 
placebo controlled trial comparing this combination (n=209) to dabrafenib 
monotherapy (n=211), and study BRF113220.  Study BRF113220 is designed to 
investigate the safety, PK and PD of dabrafenib in combination with trametinib in 
patients with BRAF V600 mutation positive solid tumors.  The study consists of 4 
parts: Part A evaluated the effect of repeat doses of trametinib on the PK of 
single-dose dabrafenib;  Part B was a dose-escalation phase to determine the 
safety, tolerability and range of tolerated doses for the drugs in combination; Part 
C is a randomized phase II study to determine the clinical activity of the 
combination in patients with BRAF mutation positive melanoma; andPart D 
evaluated the PK of dabrafenib administered in combination with trametinib. 
Administration of dabrafenib and trametinib in combination had no clinically 
relevant effect on the exposure of trametinib or of dabrafenib relative to 
administration of either compound alone. [6] 
1.5.1 Summary Safety Information of the Combination 
Most subjects treated with combination therapy experienced an adverse event. In 
both studies, pyrexia was the most frequently reported AE, and the most 
frequently reported grade 3 event (presented with *) in subjects treated with 
combination therapy (51%/6%*) in Study MEK115306 and 57%/4%* in Study 
BRF113220). AEs that occurred in >30% of subjects treated with combination 
therapy in either study included pyrexia, fatigue, vomiting, chills, nausea, and 
headache. 
 
Grade 4 AEs reported in more than a single subject treated with combination 
therapy included neutropenia (3 subjects in Study BRF113220) pyrexia (2 
subjects in Study BRF113220). AEs leading to permanent discontinuation were 
reported in <10% of subjects treated with combination therapy in either study. 
 
The most common SAEs in both studies were pyrexia and chills. Fatal SAEs have 
been reported in 4 subjects in the combination therapy arm in Study MEK115306 
and 3 subjects in the 3 subjects in the 150mg/2mg combination therapy arm in the 
Study BRF113220 pooled combination therapy population. One fatal SAE was 
reported in 2 subjects in Study MEK115306 (cerebral hemorrhage).  
 
In general, the overall profile of AEs of special interest observed in subjects 
treated with combination therapy is consistent with the known profiles of each 
separate drug. The most notable differences were the increase in Grade 3 pyrexia 
and hepatic events and the decrease in skin-related toxicities with combination 
therapy relative to monotherapy. 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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1.5.2 Special Warnings for the Combination 
Ocular safety 
Both trametinib and dabrafenib have been associated with ocular toxicities which 
appear to be class effects, including retinal pigment, papilledema, retinal pigment 
epithelial detachment (RPED; previously called central serous retinopathy or 
CSR) and retinal vein occlusion (RVO) associated with trametinib, and uveitis 
(including chorioretinitis, choroiditis, retinitis, vitritis, cyclitis, iridocyclitis, iritis, 
and uveitis) associated with dabrafenib. When all ocular events were considered 
together (blurred vision, dry eye, visual impairment and RPED), the incidence 
was 25%.  With the exception of the single case of grade 3 RPED, all ocular 
events were grade 1 or 2. [6] In the MEK115306 study, ocular events occurred in 
11% of patients in each arm, with no cases of RVO reported. Two subjects in the 
combination therapy arm had grade 3 ocular events (uveitis and iridocyclitis) 
considered related to study treatment. 
 
Cutaneous squamous cell carcinoma (cuSCC) 
In vitro experiments have demonstrated a paradoxical activation of MAP-kinase 
signaling in kerationcytes and potentially other cells harboring a wild-type BRAF 
kinase but a mutated RAS kinase upon exposure to a BRAF inhibitor. This 
paradoxical MAP-kinase pathway activation is potentially associated with a 
higher risk for the development of cuSCC induction. 
 
Cases of cuSCC have been reported in patients treated with dabrafenib in 
combination with trametinib. In BRF113220 Part C, cuSCC occurred in 7% of 
subjects combination therapy arm at the dose used in LCCC1128 compared to 
19% of subjects receiving dabrafenib monotherapy. In patients who received the 
combination dose of dabrafenib in combination with trametinib, events occurred 
later than with dabrafenib monotherapy with the median time to onset of 22 
weeks. All patients on combination therapy who developed cuSCC continued on 
dabrafenib treatment without dose modification.  
 
In the phase III study (MEK115306), the BRAF and MEK inhibitor combination 
was found to significantly reduce the incidence of secondary cuSCC which 
occurred in 9% of patients receiving dabrafenib monotherapy compared with 2% 
with the combination. The median time to onset of the first occurrence of cuSCC 
was 222 days in the combination arm and 57 days in the dabrafenib monotherapy 
arm. 
 
Non-cutaneous secondary/recurrent malignancy 
In vitro experiments have demonstrated paradoxical activation of MAP-kinase 
signalling in BRAF wild type cells with RAS mutations which are exposed to 
BRAF inhibitors, which may lead to increased risk of non-cutaneous 
malignancies in patients treated with dabrafenib. Cases of RAS-driven 
malignancies have been seen with BRAF inhibitors including dabrafenib, and 
with dabrafenib/trametinib combination therapy. Patients should be monitored as 
clinically appropriate. 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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Pyrexia 
The incidence and severity of pyrexia are increased when dabrafenib is combine 
with trametinib. When each drug is prescribe at its approved dose in combination, 
nearly half of the first occurrences of pyrexia occur within the first month of 
therapy, and ~ one-half of patients who experience this side effect had a single 
event. The majority of pyrexia events resolved in both arms[6]. 
 
 
Rash 
In Part C of BRAF113220, 65% of subjects at the doses used in LCCC1128 
experienced at least one event of skin-related toxicity. This incidence of skin-
related events reported with the combination regimen appears to be lower than 
what has been observed in the trametinib monotherapy trials (~88%). The most 
frequent skin-related toxicities affecting over 10% of subjects in Part C were rash, 
dermatitis acneiform, erythema, and generalized rash. The incidence and severity 
of the majority of skin-related toxicities and especially those most often seen with 
either trametinib  or dabrafenib therapy appear to be reduced when both 
compounds are combined.[6] In study MEK115306, the percentage of rash was 
similar between treatment arms (34% in the combination (none grade 3) and 30% 
(~20% grade 3) in the dabrafenib monotherapy arms). Dermatitis acneiform 
occurred with increased frequency in the combination arm (8%) as compared to 
3% in the dabrafenib monotherapy arm. 
1.5.3 Other Safety Considerations for the Combination 
Pre-renal and Intrinsic Renal Failure 
In Part C of study 113220, 1 subject (150mg/1mg) experienced grade 2 renal 
failure and 4 (at the 150mg/2mg doses) experienced grade 3 renal failure.  In 
study MEK115306, the incidence of renal failure events was similar (3% in the 
combination and 2% for dabrafenib monotherapy). 
 
 
Pancreatitis 
Six subjects in BRF113220 had acute pancreatitis or pancreatitis, 3 of which were 
grade 4 and considered related to study treatment. [6] The time to onset to 
pancreatitis occurred at a median of 138 days. One event of pancreatitis was 
reported in each treatment arm of study MEK115306. 
 
Hemorrhage 
Combination treatment resulted in an increased incidence and severity of 
hemorrhagic events: 16% (9/55) of patients treated with the combination 
compared with 2% (1/53) of patients treated with dabrafenib alone. Intracranial 
hemorrhage was fatal in two (4%) patients receiving the combination. 
Venous Thromboembolic Events 
Treatment with the combination of trametinib and dabrafenib resulted in an 
increased incidence of deep vein thrombosis (DVT) and pulmonary embolism 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
9 
(PE): 7% (4/55) of patients compared with none of the 53 patients treated with 
dabrafenib as a single agent. One (2%) patient receiving combination therapy 
experienced a fatal pulmonary embolism. 
 
Hyperglycemia 
Hyperglycemia may increase in occurrence when combination trametinib and 
dabrafenib are used. The incidence of Grade 3 hyperglycemia based on laboratory 
values was 5% (3/55) in patients treated with dabrafenib in combination with 
trametinib compared with 2% (1/53) in patients treated with dabrafenib as a single 
agent.  
1.5.4 AEs of Special Interest 
AEs of special interest were identified independently for both the dabrafenib and 
trametinib programs based on preclinical observations, the frequency of the 
events occurring in early clinical trials, and the potential association with the 
mode of action of BRAF or MEK inhibitors. AEs of special interest that are 
associated with trametinib (MEK category AEs) are: 
• Skin-related toxicities (e.g., rash – generalized, macular, 
maculopapular,pruritic, erythematous; dermatitis acneiform; erythema; 
skin exfoliation; palmar-plantar erythrodysesthesia syndrome (PPES; also 
known as hand foot skin reaction or HFSR) 
• Diarrhea 
• Ocular events (e.g., RVO, chorioretinopathy) 
• Hepatic events (e.g., aspartate aminotransferase [AST], ALT, and blood 
bilirubin increased) 
• Cardiac-related events (e.g., LVEF decreased and left ventricular 
dysfunction) 
• Hypertension 
• Pneumonitis  
 
AEs of special interest that are associated with dabrafenib (BRAF category AEs) 
are: 
• Pyrexia 
• Cutaneous squamous cell carcinoma • PPES 
• Renal failure (renal failure, renal failure acute) 
• Other treatment emergent malignancies 
• New primary malignant melanoma 
• Uveitis 
 
In general, the overall profile of AEs of special interest observed with the 
combination in the Part C 150/2 group is consistent with the known profiles of 
each separate drug, the most notable differences being the increase in pyrexia and 
the decrease in skin-related toxicities with combination therapy relative to 
monotherapy. The incidence of MEK-related AEs of special interest in the Part C 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
10 
150/2 group occurred at a rate (91%) that was similar to the incidence reported in 
the trametinib integrated summary of safety (ISS) population (94%) and higher 
than the incidence in the dabrafenib ISS population (55%).  
 
MEK-related events of skin-related toxicities, diarrhea and hypertension 
 
appeared to be lower in the Part C 150/2 group compared with the trametinib ISS 
population, while the incidence rate of ocular events was higher relative to the 
trametinib ISS population. 
 
For BRAF-related AEs of special interest, the incidence of any event in the Part C 
150/2 group was higher (84%) than either the dabrafenib ISS population (49%) or 
the trametinib ISS population (19%). This increase is predominantly due to the 
increased incidence of pyrexia observed with combination treatment. Also noted 
were an increase in renal failure reports and a decrease in cuSCC and PPES 
reports when comparing the Part C 150/2 group to the dabrafenib ISS 
population.[6] 
 
An overview of AEs of special interest at dose levels in Part C of BRF113220 is 
provided in the appendices, section 0. 
 
Other AEs of special interest noted in the randomized phase III (MEK115306) 
trial (in addition to those listed above) included basal cell carcinoma, 
hemorrhages, deep vein thrombosis/pulmonary embolism, and neutropenia.  An 
overview of AEs of special interest in MEK115306 is provided in the appendices, 
section 11.8. 
1.5.5 Efficacy of Combination 
The dose ranging trial (Part B of BRF113220) evaluated the safety and efficacy of 
150mg dabrafenib twice daily plus trametinib (at doses of 2mg QD or 1 mg BID) 
versus dabrafenib150mg BID. A total of 162 patients with advanced melanoma 
and BRAF V600E/K mutations were randomized in a 1:1:1 ratio, with 54 patients 
in each arm who had not previously received BRAF or MEK inhibitors. Primary 
efficacy outcome was investigator–assessed ORR; median duration of follow-up 
was 14 months.  In the trametinib 2 mg once daily arm, ORR was 76% versus 
54% for dabrafenib monotherapy. Thus, the recommended combination dose is 
150 mg dabrafenib twice daily plus 2mg trametinib once daily. The median 
duration of response was 10.5 months for combination therapy versus 5.6 months 
for patients on single-agent dabrafenib. See the package insert for further 
information.  
   
In January 2014, the FDA approved the combination of trametinib and dabrafenib 
for treatment of unresectable or metastatic melanoma with BRAF V600E or 
V600K mutations. This indication is based upon demonstration of durable 
response rate.  
 


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CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
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The MEK115306 (COMBI-d) study of dabrafenib 150 mg BID and trametinib 
2mgQD in combination versus single-agent dabrafenib sought to verify the 
clinical benefit of combination dabrafenib and trametinib. An analysis of 
investigator-assessed PFS after 211 (out of 423 patients) PFS events showed a 
25% percent reduction in risk of progression or death (HR 0.75; 95% CI: 0.57, 
0.99; per = 0.035).  Median PFS for the combination therapy arm was 9.3 months 
compared with 8.8 months for the dabrafenib monotherapy arm.[6] 
1.6 
Correlative Studies 
As described below, tumors will undergo near kinome-wide profiling using a 
mass-spectrometry-based, unbiased proprietary technology (KinominingTM) 
developed by Dr. Gary Johnson and colleagues at UNC.  Tumor samples from 
patients who co-enroll in LCCC1108 will also be sequenced for approximately 
150-200 genes of known importance in oncogenic signaling using NextGen DNA 
sequencing technology on the Illumina HiSeq platform.  Both of these 
technologies can be performed with minimal amounts of patient sample.  In 
addition, melanoma is a good disease for this study as the relatively young and 
otherwise healthy patients often have accessible disease and are good candidates 
for re-biopsy at the time of progression.  At the time of consent, patients enrolled 
from affiliate sites will be informed that collection of their tumor tissue (both at 
baseline and at progression) is expected to take place at UNC whenever possible. 
For those patients who do not co-enroll into LCCC1108, we will ask for a blood 
sample (~8mLs) to ensure sufficient germline DNA in the event tissue samples 
are insufficient. 
1.6.1 KinominingTM  
Dr. Gary Johnson and colleagues have developed a chemical proteomics approach 
to define the activity of a significant percentage (60%) of the expressed kinome in 
cells and tumors.[7] The technique involves the use of pan kinase inhibitors 
immobilized on beads to capture a large percentage of expressed kinases in cells 
and tumors. The activation state of more than 60% of the expressed kinome, 
defined by RNA-seq, can be analyzed using mass spectrometry analysis of the 
captured kinases.  
 
This technique has been used to study, and then rationally design a kinase 
inhibitor combination therapy for triple negative breast cancer (TNBC). Analysis 
of a patient TNBC tissue sample showed activated RAF-MEK1/2-ERK1/2 
signaling, supporting MEK as a target in TNBC. In TNBC cells and tumors of a 
genetically engineered C3Tag mouse model (GEMM) of TNBC, MEK inhibition 
with the MEK inhibitor AZD6244 led to rapid reprogramming of the expression 
and activity of a group of Tyr and Ser/Thr kinases.  This reprogramming bypassed 
the original MEK-ERK inhibition and demonstrated the resilient nature of the 
kinome.  Mechanistically, we showed that acute MEK inhibitor treatment caused 
MEK-ERK activity loss resulting in rapid c-Myc degradation, inducing the 
expression of multiple receptor tyrosine kinases (RTKs) and ERK reactivation.  
RNAi knockdown of c-Myc induced RTK expression similarly to MEK 


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inhibition.  Based on these results, we predicted and tested a novel small molecule 
combination therapy of MEK inhibitor and sorafenib for TNBC. The combination 
synergistically caused apoptosis and tumor regression in the C3Tag GEMM of 
basal-like/claudin-low TNBC, whereas the single agents of MEK inhibitor or 
sorafenib were largely ineffective. [7] 
 
The research described above, along with siRNA screens of the kinome in cell 
lines, is identifying previously untargeted kinases essential for tumor growth and 
survival.  Our belief is that the approach can be extended to human tumors.  
1.6.2 UNCseqTM 
Clinical sequencing efforts at UNC have settled on the in solution hybrid capture 
methodology using the Illumina platform for downstream sequencing. This 
technology allows gene targets of interest to be isolated from genome-wide high-
throughput sequencing libraries, reducing both sequencing costs and 
bioinformatic complexity downstream. This approach is also highly customizable, 
allow for changes in gene targets with little additional cost or need for re-
optimization.  At UNC in the Clinical Sequencing Program (UNCseqTM), we are 
applying this technology to patients suffering from a diverse variety of 
malignancies with funds provided by the State of NC through the University 
Cancer Research Fund.  UNCseq allows us to tailor therapy to a patient’s cancer 
based on the tumor’s molecular genetics, thereby improving response rate and 
decreasing the toxicity from exposure to ineffective agents.  
 
We have an extensive unpublished experience in melanoma.  For example, we 
have performed UNCseq on 52 melanoma samples with a capture approach 
restricted to 75 genes previously reported to harbor somatic mutations in this 
disease. These samples were run through a UNC-developed sample preparation 
and informatic pipeline to identify diverse kinds of genetic variants.  This process 
was informed by UNC’s efforts in the far-larger tumor sequencing program, the 
Cancer Genome Atlas, of which UNC is one of 8 participating centers in North 
America.  Our results greatly surpassed gold standard Sanger sequencing.  For 
example, we identified all validated BRAF V600 and NRAS Q61 codon 
mutations found by Sanger sequencing: (BRAF 46% of tumors; NRAS 
17%).  Deep sequencing also allowed identification of pathogenic mutations in 
many additional genes reported to be mutated in melanoma (KIT, CDKn2a, 
PTEN, LKB1); and identified novel functional mutations of BRAF and other 
kinases. In one BRAF/NRAS wild-type melanoma, we found a clear codon 12 
activating KRAS mutation (Fig 1), which is reported to be present in ~1% of 
melanoma.  KRAS mutation is not routinely assayed in melanoma at any major 
center, but would have clear implications for the testing of BRAF and MEK 
inhibitors.  
 
Additionally, we found numerous frameshift (Fig 2), missense, nonsense and 
large deletion mutations in tumor suppressor genes (PTEN, CDKN2A, p53, 
LKB1). These mutations, found in many regions along the coding sequence, 


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would be difficult and expensive to assay by other technologies. We have also 
used normalized read counts to identify somatic Copy Number Variations (CNVs 
= deletions and amplifications) and potentially structural variation like 
chromosomal translocations without any modifications to the sample preparation 
pipeline.  Data comparing X chromosome dosage in normal male and female 
tissues indicates that our approach can detect single copy loss with high statistical 
precision, suggesting most pathogenic CNVs will be obvious by this approach. 
 
UNCseq offers a powerful new tool to assay known genetic factors for therapy 
and also to discover novel clinically relevant somatic mutations. The technique 
can effectively assay the diverse mutations that disable tumor suppressor genes, 
allowing an exploration of the clinical consequences of these genetic events 
which to date have been poorly characterized in other contexts. We expect this 
system will become indispensable to all stages of clinical care, including 
diagnosis, prognosis, treatment prediction, and drug discovery. 
 
 
 
Figure 1: Sequencing results demonstrating a rare KRAS mutation in melanoma. This view uses 
Integrated Genome Viewer to show a subset of the deep sequencing reads mapping to the location 
(gray bars) and highlights locations with mutations (A bases where the reference nucleotide is C). 
Sequencing shows homozygous KRAS G12V constitutively active mutant. 


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Figure 2: Sequencing results demonstrating a BRAF mutation novel to melanoma. Reads with 
deletions are marked by a black bar. Coverage at each base (noted along the top) shows complete 
drop within the deletion, suggesting that it is homozygous. 
 
1.7 
Rationale 
BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination 
with the MEK inhibitor trametinib in metastatic melanoma established the safety 
of this combination, and identified the recommended phase 2 doses (RP2D) for 
each agent.  Expansion cohorts at the RP2D for these drugs in combination were 
included in the phase I to characterize the safety in more detail, and to explore the 
efficacy of this combination.  The combination was well tolerated as described in 
section 1.5, with decreased frequency of rash compared to either agent alone.[5, 
8]   This study will utilize the RP2D determined in the Phase I/II study: trametinib 
2mg QD and dabrafenib 150 mg BID.  Despite a very promising overall response 
rate of 81%, these patients will also likely go on to develop resistance as a result 
of new resistance mutations, and given the cooperative signaling network of 
kinases that sense inhibition of key nodal kinases and induce compensatory 
responses that offset pharmacological intervention.   
 
The present phase II study in 20 patients with BRAFV600E/K mutant, unresectable 
stage III/IV melanoma is designed to explore the mechanisms by which tumors 
acquire resistance to the combination of BRAF and MEK inhibition.  Overall 
response rate and duration to this combination will also be assessed.   
 
Tissue will be collected at baseline and at progression (clinical or radiological) or 
beyond progression pending the availability of sufficient tissue and considerations 
of patient safety.  Patients may remain on treatment after progression (at the 
discretion of the investigator) as long as they are still experiencing clinical 
benefit, as targeted therapy post-progression may extend survival. A recent 


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analysis has shown that continuation on a BRAF inhibitor (dabrafenib or 
vemurafenib) as monotherapy after disease progression may improve survival.  
Among 36 patients who continued on treatment, post progression median PFS 
was 6.9 months versus 3.9 months among those (n=56) who discontinued 
treatment at progression (p=0.001).  Furthermore, median OS was 17.8 months 
from start of BRAF therapy versus only 7.0 months in those who stopped 
treatment at progression (p<0.001). [9]  
  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To identify kinases that are differentially expressed pre- and post-treatment with 
BRAF (dabrafenib) and MEK (trametinib) inhibitors, and to determine a kinome 
signature predictive of resistance to BRAF/MEK inhibition in stage III/IV 
melanoma 
2.2 
Secondary Objectives  
2.2.1 To explore whether resistance to BRAF and MEK inhibition is associated with 
new functional mutations in the approximately 150 oncogenes / tumor suppressor 
genes that are assessed in more than 10% of the tumors (using NextGen DNA 
sequencing technology) in the subset of patients who co-enroll in LCCC1108, 
with particular focus on one of five established resistance genes (BRAF, NRAS, 
MEK1, MAP3K8 or COT, and PTEN)  
2.2.2 To determine the overall response rate (ORR: complete response + partial 
response) as measured via RECISTv1.1 
2.2.3 To estimate the duration of ORR as measured via RECISTv1.1 
2.2.4 To estimate progression-free survival (PFS) as defined by RECISTv1.1  
2.2.5 To estimate the rate of overall survival (OS) at 1 year from day 1 of treatment 
2.3 
Primary Endpoint 
2.3.1 Kinome signature pathway will be based on comparison of kinome expression 
from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) 
coupled with mass spectrometry 
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Main Study Inclusion Criteria 
Subject must meet all of the inclusion criteria to participate in this study:  


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3.1.1 Age ≥18 years 
3.1.2 Signed written informed consent 
3.1.3 Histologically confirmed V600E or V600K BRAF mutant melanoma 
3.1.4 Unresectable Stage III/IV melanoma 
3.1.5 ECOG PS 0-2 
3.1.6 Normal organ function as defined by the following: 
• Absolute neutrophil count ≥1.2 × 109/L 
• Hemoglobin  ≥9 g/dL, platelets ≥75 × 109/L 
• PT/INR and PTT  ≤1.5 x ULN (Note: subjects receiving anticoagulation 
treatment may enroll with INR established within the therapeutic range 
prior to D1 of treatment) 
• Albumin ≥2.5 g/dL  
• Total bilirubin ≤1.5 x ULN (patients with elevated bilirubin due to 
Gilbert’s disease will not be excluded) 
• AST and ALT ≤ 2.5× ULN  
• CrCl ≥50mL/min per Cockcroft-Gault 
3.1.7 Prior anti-cancer treatment related toxicities except alopecia and lab values as 
outlined in section 3.1.6 must be ≤ Grade 1 as per NCI CTCAEv4.  
3.1.8 Willing to undergo biopsy for research purposes only (see section 6.6).  Note: If 
possible, the pre-treatment biopsy should be performed after all other eligibility 
criteria are confirmed.  Please also see the note in section 6.9.3 regarding 
assessment of biopsied lesions per RECIST v1.1. 
3.1.9 Females of child-bearing potential: willing to use two forms of effective 
contraception, and to continue use for 16 weeks (4 months) post last dose of study 
medication. Effective contraception is defined as:  
• 
An intrauterine device with a documented failure rate of less than 1% per 
year. 
• 
Male partner sterilization prior to the female subject’s entry, and this male is 
the sole sexual partner for that female. 
• 
Complete abstinence from sexual intercourse for 14 days prior to enrollment, 
throughout study treatment, and for at least 4 months after the last dose of 
study treatment. Abstinence is only acceptable when in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods, etc) and withdrawal are 
not acceptable methods of contraception. 


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• 
Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/cream/suppository). 
Note:  Hormonal-based methods (e.g., oral contraceptives) are not permitted as 
contraception due to potential drug-drug interactions with dabrafenib.   
Female subjects who are lactating must discontinue nursing prior to the first dose 
of study treatment and must refrain from nursing throughout the treatment period 
and for 4 months following the last dose of study treatment. 
   Females of non-childbearing potential are those who are postmenopausal 
(defined as greater than 1 year without menses with an appropriate clinical 
profile, e.g., age appropriate, >45 years in the absence of hormone-replacement 
therapy (HRT).  In questionable cases, the subject must have a follicle-stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 
pmol/L); or who have had a bilateral tubal ligation or tubal occlusion, bilateral 
oophoredtomy or hysterectomy. Men with a female partner of childbearing 
potential must have either had a prior vasectomy or agree to use effective 
contraception as described from D1 of treatment, throughout the treatment period, 
and for 16 weeks after the last dose of study treatment. If a subject becomes 
pregnant during the treatment period of the study, the study treatments should be 
stopped immediately.   
3.1.10 In women of child-bearing potential, negative serum pregnancy test within 48 
hours prior to day 1 of study treatment and agree to use effective contraception as 
outlined in section 3.1.9 
3.1.11 Measurable disease as defined by RECIST v1.1 
3.1.12 Able to swallow and retain oral medication 
3.1.13 Left ventricular ejection fraction by ECHO ≥ institutional lower limit of normal 
Patients with a history of hypertension MUST have hypertension adequately 
controlled (BP < 140/90) with appropriate anti-hypertensive therapy 
or diet prior to study entry.  Note: To be eligible a subject must have an 
average of BP below 140/90 based on 3 separate measures. If the subject 
has a record of BP recordings taken at home, ≤ 20% of BPs taken should 
have numbers > 140/90.  
 
3.2 
Main Study Exclusion Criteria 
Any subject meeting any of the following exclusion criteria at baseline will be 
ineligible for study participation: 
3.2.1 Patients with a history of a prior malignancy are excluded unless they have been 
disease free for 3 or more years or unless they have a completely resected non-
melanoma skin cancer, and/or subjects with indolent second malignancies.  


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3.2.2 History of malignancy with confirmed activating RAS mutation at any time. Note: 
Prospective RAS testing is not required. However, if the results of previous RAS 
testing are known, they must be used in assessing eligibility 
3.2.3 Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib 
(GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor 
(including but not limited to trametinib (GSK1120212), AZD6244, and 
RDEA119); NOTE: There is no limit to the number of other prior therapies, and 
patients may be previously untreated. 
3.2.4 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to study drug, or excipients or to dimethyl sulfoxide 
(DMSO).  
3.2.5 Active GI or intracranial hemorrhage 
3.2.6 History or evidence of cardiovascular risk including any of the following: 
• QTc ≥ 480 msec; 
• History or evidence of current clinically significant uncontrolled 
arrhythmias; 
o Exception:  Subjects with controlled atrial fibrillation for >30 days 
prior to D1 of study treatment are eligible. 
• History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior 
to study entry; 
• Patients with history of hypertension MUST have hypertension adequately 
controlled (BP < 140/90) with appropriate anti-hypertensive therapy or 
diet prior to study entry 
Note: To be eligible a subject must have an average of BP below < 140/90 
based on 3 separate measures. If the subject has a record of BP 
recordings taken at home and in their medical record, ≤ 20% of BPs 
taken should have numbers > 140/90.  
 
• Patients with intra-cardiac defibrillators or permanent pacemakers; 
• Known cardiac metastases; 
• Abnormal cardiac valve morphology (≥grade 2) documented by 
echocardiogram (subjects with grade 1 abnormalities [i.e., mild 
regurgitation/stenosis] can be entered on study).  Subjects with moderate 
valvular thickening should not be entered on study. 
3.2.7 History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency 


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3.2.8 Brain metastases are excluded unless: 
• All known lesions were previously treated with surgery or stereotactic surgery 
(whole-brain radiation is not allowed unless given after definitive treatment 
with surgery or stereotactic surgery), AND 
• Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in 
lesion size) for ≥ 12 weeks prior to D1 of study treatment (stability must be 
confirmed with two consecutive magnetic resonance image (MRI) or 
computed tomography (CT) scans with contrast, AND 
• Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to D1 
of study treatment, AND 
• Treatment with any CYP enzyme inducing anticonvulsants occurred < 4 
weeks prior to D1 of study treatment 
 
NOTE: if study subject has history of brain metastasis, but currently has no 
evidence of disease in brain (NED), confirmation by two consecutive scans 
separated by ≥6 weeks prior to D1 of treatment is required. 
3.2.9 Pulmonary embolism on active therapy 
3.2.10 History of interstitial lung disease or pneumonitis 
3.2.11 Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared 
HBV and HCV infection, which will be allowed provided the following tests are 
done at screening: viral hepatitis serology, Hepatitis B surface antigen and 
Hepatitis B core antibody (IgM) and/or Hepatitis C RNA) 
3.2.12 Currently active GI disease, or prior surgery that may affect ability to absorb oral 
medications 
3.2.13 History or current evidence/risk of retinal vein occlusion (RVO) or retinal 
pigment epithelial detachment (RPED):  
• Predisposing factors to RVO or RPED (e.g. uncontrolled glaucoma or ocular 
hypertension, uncontrolled systemic disease such as hypertension, diabetes 
mellitus, or history of hyperviscosity or hypercoagulability syndromes) 
• Visible retinal pathology as assessed by ophthalmic exam that is considered a 
risk factor for RVO or RPED such as:  
o Evidence of new optic disc cupping 
o Evidence of new visual field defects   
o Intraocular pressure > 21 mm Hg  
3.2.14 Currently receiving cancer therapy (chemotherapy, radiotherapy, immunotherapy, 
or biologic therapy) NOTE: palliative radiation therapy is permitted for non-target 
lesions that are either new or present at baseline provided total dose does not 
exceed 30 Gy; however, radiation skin injury has been reported with concurrent 
use of dabrafenib and radiation.  See concomitant medications section 4.5.3 for 
recommendations when palliative radiation is prescribed. 


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3.2.15 Use of other prohibited medications within 5 half-lives or 14 days prior to the first 
dose of study drugs or requires any of these medications while receiving 
medication on this study (see section 4.5) 
3.2.16 Pregnant or lactating female 
 
3.3 
Inclusion Criteria for Off-Study Subjects to Receive Progression Biopsy 
3.3.1 Currently progressing on Trametinib/Deabrafenib Combination Therapy 
3.3.2 Willing to undergo biopsy for research purposes only. 
3.3.3 Tumor amenable to research biopsy.  
3.3.4 Signed written informed consent to have a progression biopsy performed on the 
LCCC 1128 protocol.  
3.3.5 Previously enrolled on the LCCC 1128 study and did not have a progression 
biopsy previously performed while on study.  
 
4.0 
TREATMENT PLAN 
4.1 
Schema 
 
 


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aPatient must have tumor accessible to biopsy to be eligible if frozen tissue from diagnostic 
specimen is not available.  
bPatient may remain on treatment after progression if evidence of continuing clinical benefit 
cClinical or radiological 
dReasons may include, but are not limited to, inability to tolerate the combination of dabrafenib 
and trametinib, receiving other therapy, or completion of 3-years of study treatment without 
progression 
eThe subject may be placed back on the combination trametinib/dabrafenib therapy as part of 
his/her standard of care treatment plan 
fThe subject may have a progression biopsy taken after progression on standard of care treatment 
if the subject is eligible and consents to this biopsy. Progression can be defined clinically or 
radiologically. 
 
This is an open label study of patients with unresectable stage III and stage IV 
melanoma with mutant V 600E/K melanoma and tumor that is accessible to 
biopsy.  Patients can have had any number of prior lines of treatment (and may be 
previously untreated), but may not have previously received either a BRAF or 
MEK inhibitor for treatment of their melanoma.   
 
Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib 
orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 
2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be 
defined as 3 weeks in duration.   Cycles will be repeated until disease progression 
(clinical or radiological).  Patients may remain on treatment after progression (at 
the discretion of the investigator) as long as they are still experiencing clinical 
benefit. Patients will be requested to remain on study medication until the biopsy 
at progression is performed.   
 
Patients will have a biopsy at baseline and at progression.  Some subjects may be 
removed from study prior to progression for other reasons that include, but are not 
limited to, an inability to tolerate the combination of dabrafenib and trametinib, a 
need to receive other therapy, or completion of 3-years of study treatment without 
progression. If one of these subjects later receives the combination of dabrafenib 
and trametinib per his/her standard of care treatment plan, then the subject may 
re-consented for  a biopsy upon progression. These subjects are required to 
consent to re-enter the study for the purposes of having a progression biopsy. 
 
KinominingTM and NextGen Sequencing (in patients who co-enroll into 
LCCC1108) will be done on baseline and progression biopsies to look for changes 
in kinome expression and mutations in resistance genes. 
4.2 
Biopsies 
At baseline, if patient does not have frozen tissue available (see section 6.6) fresh 
tissue must be obtained.  If possible, the pre-treatment biopsy should be 
performed after all other eligibility criteria are confirmed.   Enough tissue will be 
collected for both kinomining and NextGen sequencing if available (see section 
6.6).    Fresh tissue collection of accessible tumor will be repeated at progression 
(clinical or radiological) whether patient continues treatment post progression or 


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not.  In fact, patients will be requested to remain on study medication until the 
biopsy at progression is performed.  For subjects who are withdrawn from study 
treatment, but are later placed back on the trametinib/dabrafenib combination 
therapy, a biopsy may be collected from the former study subject at the time of 
progression from the standard of care trametinib/dabrafenib therapy.   These 
subjects must be consented and placed back on study to allow for attainment of a 
biopsy at progression. These subjects will then remain on study for safety 
monitoring, in relation to the biopsy procedure, for 30 days. Subjects who have an 
ongoing ≥grade 2 or serious AE (SAE) related to the study procedure at 30 days 
will continue to be followed until the event is resolved or deemed irreversible by 
the investigator. 
 
If possible, biopsies at progression should be performed within 7 business days of 
documented disease progression, and optimally within 4 hours of taking that day’s 
study medication. If treating physician decides to continue treatment because the 
patient exhibits continued clinical benefit from therapy (and the patient agrees) 
then the biopsy can be delayed until the investigator deems the biopsy feasible as 
long as patient safety is not compromised. Post-treatment biopsies will not be 
required for patients removed for reasons other than disease progression; 
although, as mentioned above, if these subjects then go on to eventually receive 
the trametinib/dabrafenib combination in the future, as part of their standard of 
care, of the subject may be re-consented at the time of disease progression 
progression. See section 6.6 and laboratory manual. Please also see the note in 
section 6.9.3 regarding assessment of biopsied lesions per RECIST v1.1. 
4.3 
Treatment Dosage and Administration 
Drug 
Dose, Route & 
Schedule 
Cycle 
Trametinib 
2 mg orally once daily 
Every 3 weeks 
Dabrafenib 
150mg orally twice daily 
Every 3 weeks 
 
• After the pre-treatment biopsy is complete, patients will begin 2.0 mg of 
trametinib orally once per day in combination with dabrafenib 150mg PO 
BID.   
• Patients will be instructed to take their dabrafenib at approximately the 
same time each day. The evening dose of dabrafenib should be 
administered approximately 12 hours after the morning dose.   
• Both drugs should be administered under fasting conditions, either one 
hour before or 2 hours after a meal, and with approximately eight ounces 
of water.   
• If a subject vomits after taking study medication, the subject should be 
instructed not to retake the dose and should take the next scheduled dose. 
• If a patient misses a dose of dabrafenib, it should not be taken if it is less 
than 6 hours until the next dose.  If a dose of trametinib is missed, the dose 
should only be taken if it is more than 12 hours until the next scheduled 
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• Any missed dose should be noted on the patient diary (provided as a 
document separate from the protocol-see Appendices, section 11.6, for a 
model diary).  
 
Note: loperamide should be made available prior to start of study treatment to 
patient so loperamide administration can begin at the first signs of diarrhea (see 
section 4.4.6). 
4.4 
Dose Modifications for Trametinib and Dabrafenib for Toxicity 
See sections 5.1.5, 5.2.5, and appendices (section11.3), and the respective IBs for 
additional information on drug-related toxicities. Any patient who receives 
treatment on this protocol will be evaluable for toxicity.  Each patient will be 
assessed every 3 weeks for the development of any toxicity according to the Time 
and Events table (see Section 6.0).  Toxicity will be assessed according to the NCI 
CTCAE, v 4. 
 
If a patient experiences ≥2 or more AEs simultaneously that require different dose 
reductions, the lower dose should be used.  Unless otherwise noted in the 
following sections, a maximum of 2 dose-level reductions for AEs are allowed on 
this protocol.  If >2 dose reductions are required, protocol therapy is to be 
discontinued and patient is to be followed per protocol.   
 
With the exception of decreased LVEF, both therapies should be reduced 
simultaneously in response to toxicities that are considered by the 
investigator to be treatment related.  Note that if dabrafenib is permanently 
discontinued, trametinib will also be permanently discontinued. 
 
Unless otherwise noted in the tables below, if an AE resolves to grade 1 or 
baseline at the reduced dose level, and no additional toxicities are seen after 4 
weeks of study treatment at the reduced dose, the dose may be increased to the 
previous dose level in consultation with the study PI if so noted in the tables. 
 
For AEs that require dose reductions, please refer to the dose levels in the 
following tables.   
 
 
Trametinib Dose Levels for Toxicity 
Dose 
Levels 
Dose, Route and Schedule 
Dosage Strength  
0 
            2 mg PO QD 
2.0 mg tablets 
-1 
1.5 mg PO QD 
0.5mg tablets 
-2 
            1 mg  PO QD 
0.5mg tablets 
 
 


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Dabrafenib Dose Levels for Toxicity 
Dose 
Levels 
Dose, Route and Schedule 
Dosage Strength  
0 
            150 mg PO BID  
75 mg capsules 
-1 
100 mg PO BID 
50 mg capsules 
-2 
            75 mg PO BID 
75 mg capsules 
 
A dose reduction below 75 mg BID for dabrafenib and 1 mg once daily for 
trametinib is not allowed. If a dose reduction below 75 mg BID for dabrafenib is 
required, trametinib will also be permanently discontinued.  If a dose reduction 
below 1.0 mg once daily for trametinib is required, then trametinib will be 
permanently discontinued, but these subjects will be allowed to continue 
dabrafenib. 
4.4.1 Management and Dose Modifications for Skin Toxicities 
Cutaneous AEs have been observed in subjects receiving dabrafenib, trametinib 
or both therapies in combination.  See IBs for further information.[4, 5] In 
addition to dose modifications detailed below, please also see section 11.5 
(Appendices) for supportive care measures for rash.    See section 6.0; 
dermatologic evaluations will take place at baseline, during treatment and follow-
up.  
4.4.1.1 Rash 
Rash is a frequent AE observed in subjects receiving trametinib, dabrafenib, or 
the combination of both therapies.   See section 11.5 (Appendices) for 
recommended rash prophylaxis for the first 6 weeks of study treatment.    
Guidelines for management and dose reduction for rash considered related to 
study treatment are provided in the table below. 
 
 
 


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CTCAE 
Grade 
Management of Rash 
Action and Dose Modification for 
Dabrafenib and Trametinib 
 
1 
Initiate prophylactic regimen if not already 
started (recommended for the first 6 weeks of 
treatment (see section 11.5 (appendices).  Treat 
with moderate strength topical steroid.* 
 
Reassess after 2 weeks 
Continue current dose. 
 
If rash does not recover to baseline within 2 
weeks despite best supportive care, reduce 
study treatment by one dose level 
2 
Initiate prophylactic regimen if not already 
started (recommended for the first 6 weeks of 
treatment (see section 11.5 (appendices)).  Treat 
with moderate strength topical steroid.* 
 
Reassess after 2 weeks 
 
 
Reduce study treatment by at least one dose 
level.  
 
If toxicity resolves to ≤ Grade 1 within 2 
weeks, increase dose to previous dose level.  
 
If no recovery to ≤Grade 1 within 2 weeks, 
interrupt study treatment until ≤Grade 1.  
When restart, restart at the reduced dose 
level. 
≥3 
Treat with moderate strength topical steroid * 
PLUS oral methylprednisolone dose pack. 
 
Consider obtaining dermatology consultation 
Interrupt study treatment until rash recovers 
to ≤Grade 2.   
 
Restart with study treatment reduced by one 
dose level.  May consider escalating study 
treatment to previous dose level if no rash is 
evident 4 weeks after restarting treatment. 
If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue study treatment.   
*eg, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream 
 
4.4.2 Malignancies 
4.4.2.1 Squamous Cell Carcinoma (SCC)  
Cutaneous SCC (cuSCC;  include those classified as keratoacanthoma or mixed 
keratoacanthoma subtype) have been observed in subjects treated with dabrafenib 
and the combination of dabrafenib and trametinib (see dabrafenib and trametinib 
combination IB)[6]. Approximately 70 % of events occurred within the first 12 
weeks of treatment with a median time to onset of 8 weeks. These treatment-
related cutaneous SCC should be surgically removed according to institutional 
practice.  Dose modifications or interruptions of the study treatment are not 
required for cutaneous SCC.  Occurrence of cutaneous SCC must be reported as 
an SAE (see Section 7.3.3).  
 
Patients should be instructed to immediately inform their physician if new lesions 
develop.  
 


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4.4.2.2 New Primary Melanoma  
New primary melanomas have been reported in patients treated with dabrafenib. 
These were identified primarily within the first 5 months of therapy and did not 
require treatment modification other than excision. Monitoring for skin lesions 
should occur as described for cuSCC. 
 
4.4.2.3 Non-Cutaneous Malignancies 
In vitro experiments have demonstrated paradoxical activation of MAP-kinase 
signalling in BRAF wild type cells with RAS mutations when exposed to BRAF 
inhibitors, which may lead to increased risk of non-cutaneous malignancies in 
patients treated with dabrafenib. Cases of RAS-driven malignancies have been 
seen with BRAF inhibitors. Patients should be monitored as clinically appropriate. 
New non-cutaneous malignancies should be reported as a SAE. 
 
4.4.2.4 Palmar-plantar erythrodysaesthesia syndrome (PPES; also known as Hand-
Foot-Skin-Reaction (HFSR)) 
Episodes of HSFR have been observed in subjects receiving dabrafenib.  
Guidelines for management of HFSR, and dose modifications for study treatment 
for HFSR potentially related to study treatment are listed in the table below.  
Management can differ from the guidelines below based on the clinical judgment 
of the investigator.  The investigator should contact the overall PI to discuss skin 
toxicity as needed.   Dermatologic exams should be performed by the Investigator 
as noted in the Time and Events Table, or may be referred to a dermatologist, at 
the discretion of the investigator.  If possible, the same physician should perform 
each exam for the duration of the study (i.e. if the subject is referred to a 
dermatologist for the screening exam, the dermatologist should do all follow up 
dermatologic assessments) to ensure consistency between evaluations. 
A full-body skin examination and a removal of pre-existing calluses and keratotic 
skin is recommended prior to initiation of study treatment.   
 
Life-style changes recommended for any grade of HFSR include the following:  
• Reduce exposure of hands and feet to hot water,  
• Avoid traumatic activity including vigorous exercise especially in the first 
4 weeks after start of study treatment 
• Avoid constrictive footwear  
• Avoid excessive friction on the skin, when applying topical treatments 
• Wear thick cotton socks and gloves, and shoes with padded insoles 
Symptomatic treatments suggested for any grade of HFSR include the 
following:  
• Use moisturizing creams frequently and especially on hands and feet 
• Consider topical keratolytics: urea 20-40 % cream, or salicylic acid 6%, or 
tazarotene 0.1% cream, or fluorouracil 5% cream 
• For erythematous areas: clobetasol propionate 0.05% ointment 


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• For pain: topical lidocaine 2%, and / or systemic pain medication such as 
nonsteroidal anti-inflammatory drugs, codeine, and pregabalin  
 
Symptoms usually resolve within 2-4 weeks of treatment cessation. 
CTCAE 
Grade 
Management of HFSR 
Action and Dose Modification for HFSR for 
Dabrafenib and Trametinib 
1 
 Lifestyle changes recommended 
 
Initiate symptomatic treatment if clinically 
appropriate 
Continue study treatment at current dose level 
2 
 
Lifestyle changes recommended 
 
Initiate symptomatic treatment  
Interrupt study treatment until recovery to 
≤grade 1 
Recovery to ≤grade 1 within 7 days: Restart 
study treatment at previous dose level 
No recovery to grade ≤1 within 7 days or ≥ 2nd 
occurrence: restart with study treatment 
reduced by one dose levela 
3 
Lifestyle changes recommended 
 
Initiate symptomatic treatment  
 
Consider consulting dermatologist 
Interrupt study treatment until recovery to ≤ 
grade 1 
Restart with study treatment reduced by one 
dose levela 
If 3rd occurrence, discontinue study treatment 
permanently  
aEscalation of study treatment to the previous dose level is allowed if no HFSR is observed in the 4 weeks subsequent 
to dose reduction. 
 
4.4.3 Management and Dose Modifications for Cardiac Toxicities 
Cardiovascular adverse events have been seen in subjects receiving either 
dabrafenib, trametinib or both in combination. (See the IBs for additional 
information[4-6]. 
4.4.3.1 Hypertension 
Increases in blood pressure have been observed in subjects receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided 
below.  
 
Monitoring of Hypertension 
All blood pressure assessments should be performed under the following optimal 
conditions for the study subject: 
• has been seated with back support, ensuring that legs are uncrossed and 
flat on the floor 
• is relaxed comfortably for at least 5 minutes 
• restrictive clothing has been removed from  the cuff area and the right cuff 
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• arm is supported so that the middle of the cuff is at heart level 
• remains quiet during the measurement 
 
In subjects with an initial blood pressure reading within the hypertensive range, a 
second reading should be taken at least 1 minute later, with the 2 readings 
averaged to obtain a final blood pressure measurement. The averaged value 
should be recorded in the eCRF. 
 
Persistent hypertension is defined as an increase of systolic blood pressure 
(SBP) > 140 mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg in three 
consecutive visits with blood pressure assessments from two readings collected as 
described above. Visits to monitor increased blood pressure can be scheduled 
independently from the per-protocol visits outlined in the Time and Events Table 
(see section 6.1). Ideally, subsequent blood pressure assessments should be 
performed within one week.  
 
Asymptomatic hypertension is defined as an increase of SBP  to >140 mm Hg 
and/or DBP >90 mm Hg in the absence of symptoms including headache, light-
headedness, vertigo, tinnitus, episodes of fainting or other symptoms indicative of 
hypertension that resolve after the blood pressure is controlled within the normal 
range.  
 
Management of Hypertension 
For subjects experiencing an increase in systolic and/or diastolic blood pressure 
that is persistent and may be associated with the study treatment, 
recommendations for the clinical management of hypertension are described 
below: 
 


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Hypertension 
Action and Dose Modification  
for  Dabrafenib and Trametinib 
(Scenario A) 
Asymptomatic and persistent  (terms defined 
above) SBP of >140 and <160 mmHg, or DBP 
>90 and <100 mmHg,  
or  
Clinically significant increase in DBP of 20 
mmHg (but still below 100 mmHg). 
Continue study treatment at the current dose  
Adjust current or initiate new antihypertensive 
medication 
Titrate antihypertensive medication(s) during the next 2 
weeks as indicated to achieve well-controlleda BP 
If BP is not well controlled within 2 weeks, consider 
referral to a specialist and go to scenario (B). 
(Scenario B) 
Asymptomatic SBP >160 mmHg, or DBP 
>100 mmHg,  
or  
Failure to achieve well-controlled BP within 2 
weeks in Scenario A 
Interrupt study treatment if clinically indicated 
Adjust current or initiate new antihypertensive 
medication(s) 
Titrate antihypertensive medication(s) during the next 2 
weeks as indicated to achieve well-controlled BPa 
Once BP is well controlleda, restart study treatment 
reduced by one dose levelc 
(Scenario C) 
Symptomaticb hypertension  
or  
Asymptomatic and persistent  (term defined 
above) SBP ≥160 mmHg, or DBP ≥100 mmHg, 
despite  antihypertensive medication and dose 
reduction of study treatment 
Interrupt study treatment  
Adjust current or initiate new antihypertensive 
medication(s) 
Titrate antihypertensive medication during the next 2 
weeks as indicated to achieve well-controlled BPa 
Referral to a specialist for further evaluation and follow-
up is recommended 
Once BP is well controlleda, restart study treatment 
reduced by one dose level  
Scenario D) 
Refractory hypertension unresponsive to above 
interventions or hypertensive crisis. 
Permanently discontinue study treatment  
Continue follow-up per protocol. 
aWell-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings during 
up to three consecutive visits. 
bSymptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within the normal range. 
cEscalation of trametinib to previous dose level can be considered if BPs remain well-controlled for 4 weeks after 
restarting of trametinib.  Approval from study PI is required. 
 
 
4.4.3.2 QTc 
Guidelines for dose modification and stopping criteria due to QTC-prolongation 
are provided in the following table. In studies to date, dabrafenib and trametinib 
do not exhibit an apparent potential to alter the QTc interval. The proportion of 
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of study BRF113220 as compared to trametinib ISS and the dabrafenib ISS 
populations (13% compared to 3% and 3% respectively). [6] 
 
4.4.3.3 Reduced Left Ventricular Ejection Fraction 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in 
subjects receiving trametinib monotherapy and in combination with dabrafenib.  
Therefore, ECHOs must be performed to assess cardiac ejection fraction at 
regular intervals. ECHOs should be performed at baseline and at follow-up 
visit(s)  See Time and Events table (section 6.1 for timing of follow-up ECHOs.  
Dose modification guidance and stopping criteria for LVEF decrease are provided 
in the table below.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTc-Prolongationa 
Action and Dose Modification   
for  Dabrafenib and Trametinib 
QTc≥501 msec OR 
uncorrected QT>600 msec  OR 
QTc>530 msec for subjects with bundle 
branch block 
Interrupt study treatment until QTc prolongation 
resolves to grade 1 or baseline 
Test serum potassium, calcium, phosphorus and 
magnesium.  If abnormal, correct per routine clinical 
practice to within normal limits 
Review concomitant medication usage for a 
prolonged QTc 
Restart at current dose levelb 
If event recurs, permanently discontinue study 
treatment 
aBased on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued. 
bIf the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the site 
investigator and study PI agree that the subject will benefit from further treatment. 
 


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LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Asymptomatic* 
Absolute decrease of >/=10% in 
LVEF compared to baseline and 
ejection fraction below the 
institution’s  LLN 
 
 
*NOTE: symptoms may include 
dyspnea, orthopnea, and other 
signs and symptoms of pulmonary 
congestion and edema 
Interrupt study treatment (both drugs) and repeat ECHO within 2 
weeks.  If LVEF has not recovered in 2 weeks, repeat 2 weeks later.   
If the LVEF recovers within 4 weeks (defined as LVEF ≥LLN and 
absolute decrease ≤10% compared to baseline):  
• 
Restart with trametinib reduced by one dose level in consultation 
with study PI 
• 
Restart dabrafenib at previous dose level 
• 
Repeat ECHO  2 , 4 , 8 and 12 weeks after re-start; continue in 
intervals of 12 weeks thereafter 
 
If  LVEF does not recover within 4 weeks 
• 
Consult with cardiologist 
• 
Permanently discontinue trametinib 
• 
Report as SAE 
• 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until resolution 
• 
Consult with study PI regarding restart of dabrafenib once LVEF 
recovers 
Symptomatic* 
Grade 3: resting LVEF 39-20% or 
>20% absolute reduction from 
baseline 
Permanently discontinue trametinib.   Discontinue dabrafenib. 
Report as SAE 
Consult with cardiologist 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until resolution 
Consult with study PI regarding restart of dabrafenib once LVEF 
recovers 
Symptomatic 
Grade 4: resting LVEF <20% 
 
 
4.4.4 Management and Dose Modifications for Visual Changes 
Episodes of visual changes have been observed in subjects receiving dabrafenib, 
trametinib or the combination of both therapies. Ocular adverse events are known 
to be related to trametinib. The causal relationship between a change in vision and 
the study treatment should be carefully explored and an ophthalmologist should 
be consulted. However, if the visual changes are clearly unrelated to study 
treatment (e.g., allergic conjunctivitis), then monitor closely as it may be 
reasonable to defer ophthalmic examination. Treatment with dabrafenib has been 
associated with the development of uveitis, including iritis. Monitor patients for 
visual signs and symptoms (such as, change in vision, photophobia and eye pain) 
during therapy. For adverse events of uveitis, no dose modifications are required 
as long as effective local therapies can control ocular inflammation. If uveitis 
does not respond to local ocular therapy, interrupt dabrafenib and hold until 
resolution of ocular inflammation. Then restart dabrafenib reduced by one dose 
level. 
 


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Special attention should be given to retinal problems (e.g., retinal pigment 
epithelium detachments (RPED)) or retinal vein abnormalities (e.g., RVO).  
 
Refer to section 11.1 (Appendices) for grading of visual changes. 
 
If visual changes develop, an eye exam is indicated. The exam will include best 
corrected visual acuity, tonometry, slit lamp biomicroscopic examination, visual 
field examination, and dilated indirect fundoscopy with special attention to retinal 
abnormalities.  Optical coherence tomography is strongly recommended at 
scheduled visits, and if retinal abnormalities are suspected. Other types of 
ancillary testing including color fundus photography and fluorescein angiography 
are also recommended if clinically indicated. 
 
 


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CTCAE 
Gradea 
Management of Visual Changes 
Action and Dose Modification  
for  Dabrafenib and Trametinib 
1b 
Consult ophthalmologist within 7 days 
of onset 
Exclude RPED, and RVO 
Consult retinal specialist in case of 
RPED or RVO 
Continue follow up examination(s) by 
retinal specialist for RPED and RVO 
If dilated fundus examination cannot be performed 
within 7 days of onset, interrupt study treatment until 
RPED and RVO can be excluded by retina 
specialist/ophthalmologist  and symptoms resolve 
If RPED and RVO excluded, restart study treatment at 
same dose level 
RPED suspected or diagnosed and Grade 
1(asymptomatic; clinical or diagnostic observations 
only)a: Continue treatment with retinal evaluation 
monthly until resolution. If it worsens follow 
instructions for grade.a 
RVO:  Permanently discontinue study treatment 
and report as SAE 
2 and 3  Consult ophthalmologist immediately  
Interrupt study treatment 
 
If RPED and RVO excluded, restart study treatment at 
same dose level. 
 
If RPED diagnosed (Symptomatic with mild to 
moderate decrease in visual acuity; limiting 
instrumental ADL)a, continue retinal evaluation 
monthly until resolves to ≤Grade 1.  At that point, 
restart study treatment reduced by one dose level.  
RVO: Permanently discontinue study treatment 
and report RVO as SAE 
4 
Consult ophthalmologist immediately  
Interrupt study treatment 
 
If RPED and RVO excluded, may consider restarting 
study treatment at same or reduced dose. 
 
If RVO or RPED diagnosed, permanently 
discontinue study treatment and report as SAE. 
aRefers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’ (also see section 11.1  in Appendices); RPED graded 
as per CTCAE v4 “Retinopathy” 
bIf visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but ophthalmic 
examination is not required. 
4.4.5 Management and Dose Modifications for Pneumonitis  
Pneumonitis has been observed in subjects receiving trametinib in combination 
with dabrafenib. To reduce the risk of pneumonitis, subjects will be monitored 
closely for symptoms, and evaluated with imaging and functional tests. Dose 
modification and supportive care guidelines for pneumonitis are described in the 
table below. 
 


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CTCAE 
Grade 
Management  of Pneumonitis 
Action and Dose Modification for  
Dabrafenib and Trametinib 
 
1 
CT scan (high-resolution with lung windows) 
recommended 
Clinical evaluation and laboratory work-up for 
infection 
Monitoring of oxygenation via pulse-oximetry 
recommended  
Consultation of pulmonologist recommended 
Continue study treatment at current dose 
2 
CT scan (high-resolution with lung windows) 
Clinical evaluation and laboratory work-up for 
infection 
Consult pulmonologist 
Pulmonary function tests -if < normal, repeat 
every 8 weeks until ≥ normal 
Bronchoscopy with biopsy and/or 
bronchioalveolar lavage (BAL)  recommended 
Symptomatic therapy including corticosteroids 
if clinically indicated 
Interrupt study treatment until recovery to 
grade ≤1 
Restart with study treatment reduced by 
one dose level 
Escalation to previous dose level after 4 
weeks possible after consultation with study 
PI   
If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue study 
treatment 
3 
CT scan (high-resolution with lung windows) 
Clinical evaluation and laboratory work-up for 
infection 
Consult pulmonologist 
Pulmonary function tests-if < normal, repeat 
every 8 weeks until ≥ normal 
Bronchoscopy with biopsy and/or BAL if 
possible 
Symptomatic therapy including corticosteroids 
as clinically indicated 
Interrupt study treatment until recovery to 
grade ≤1 
After consultation with study PI, study 
treatment may be restarted reduced by 
one dose level 
If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue study 
treatment 
4 
Same as grade 3 
Permanently discontinue study treatment 
 
 
4.4.6 Management and Dose Modifications for Renal Insufficiency 
Cases of renal insufficiency have occurred in subjects receiving dabrafenib and 
the combination of dabrafenib and trametinib.  
 
Prior to start of study treatment, concomitant medications should be reviewed for 
the potential risk of inducing nephrotoxicity and concomitant medications should 
be modified if clinically possible.  Guidelines regarding management and dose 


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reduction for renal insufficiency considered to be related to study treatment by the 
investigator are provided in the table below. 


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Serum Creatinine   
(SCr) Level 
Management of Renal 
Insufficiency 
Action and Dose Modification 
for  Dabrafenib and 
Trametinib 
SCr increase >0.2 mg/dL (18 
µmol/L) 
 
But 
 
≤0.5 mg/dL (44 umol/L) above 
baseline 
Recheck SCr within 1 week 
SCr  increase  lasts > 1 week: 
contact Study PI; If elevation 
persists beyond 4 weeks, 
recommend evaluation (consider 
renal biopsy) for etiology; consider 
nephrology consultation. 
 
If pyrexia is present, treat pyrexia 
per guidelinesa ; please note 
NSAIDS can induce renal 
insufficiency, especially in 
subjects with dehydration; 
encourage oral fluides 
Continue study treatment at the 
same dose level 
 
SCr  increase >0.5 mg/dL (44 
µmol/L) above baseline  
 
Or 
 
SCr >2 mg/dL (> 177 µmol/L) 
Monitor SCr ≥ 2 times per week  
Hospitalization may be 
necessary  if serum creatinine 
cannot be monitored at least twice 
weekly 
If pyrexia is present, treat pyrexia 
per guidelinesa  
Consult nephrologist if clinically 
indicated 
Perform renal biopsy if clinically 
indicated, for example: 
Renal insufficiency 
persists despite volume 
repletion 
Subject has new rash or 
signs of hypersensitivity 
(such as elevated 
eosinophil count) 
Interrupt study treatment until 
SCr recovers to baseline 
Restart with study treatmentb 
 
aNSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or consider 
intravenous fluids as clinically indicated. See guidelines for pyrexia in section 4.4.7 
bInvestigator may restart at either the same or a reduced dose level.  Escalation of study treatment to previous dose 
level is allowed if another episode of renal insufficiency does not occur after 4 weeks of dose reduction.  
Consultation with study PI is required before restarting study treatment if there is evidence of thrombotic 
microangiography. 
 
 


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4.4.7 Management and Dose Modifications for Diarrhea 
Episodes of diarrhea have occurred in subjects receiving dabrafenib, trametinib, 
or both therapies in combination. Other, frequent causes for diarrhea including 
concomitant medications (e.g., stool softeners, laxatives, antacids), infections by 
C. difficile or other pathogens, partial bowel obstruction, etc., should be clinically 
excluded.  Note: loperamide should be made available prior to start of study 
treatment to patient so loperamide administration can begin at the first signs of 
diarrhea. Guidelines regarding management and dose reduction for diarrhea 
considered to be related to study treatment by the investigator are provided in the 
table below. 
CTCAE Grade 
Diarrhea Management 
Action and Dose Modification 
for  Dabrafenib and Trametinib 
Uncomplicated 
Diarrheaa 
 
Grade 1 or 2 
Diet: stop all lactose containing products; eat small 
meals, BRAT-diet (banana, rice, apples, toast) 
recommended 
Hydration: 8-10 large glasses of clear liquids per day 
(e.g., Gatorade or broth) 
Loperamide: initially 4 mg, followed by 2 mg every four 
hours or after every unformed stool; maximum 16 
mg/day. Continue until diarrhea free for 12 hours 
Diarrhea > 24h: loperamide 2 mg every two hours; 
maximum 16 mg/day.  Consider adding oral antibiotics 
Diarrhea > 48h: loperamide 2 mg every two hours; 
maximum 16 mg/day. Add budesonide or other second-
line therapies (octreotide, or tincture of opium) and oral 
antibiotics 
Continue study treatment 
If diarrhea is grade 2 for > 48h,  
interrupt study treatment until 
diarrhea resolves to grade ≤1 
Restart study treatment at the 
same dose level 
Uncomplicated 
Diarrheaa 
Grade 3 or 4  
OR 
Any Complicated 
Diarrheab 
Clinical evaluation mandatory 
Loperamidec: initially 4 mg, followed by 2 mg every four 
hours or after every unformed stool; maximum 16 
mg/day. Continue until diarrhea free for 12 hours 
Oral antibiotics and second-line therapies if clinically 
indicated 
Hydration: intravenous fluids if clinically indicated 
Antibiotics (oral or intravenous) if clinically indicated 
Intervention should be continued until the subject is 
diarrhea free for ≥ 24 hours 
Intervention may require hospitalization for subjects at 
risk of life-threatening complications 
Interrupt study treatment until 
diarrhea resolves to grade  ≤1 
Restart with study treatment 
reduced by one dose levelc 
 
If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue study 
treatment 
 
a Uncomplicated diarrhea defined by the absence of  symptoms such as cramping, nausea/vomiting ≥grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution 
bComplicated diarrhea is diarrhea in the presence of symptoms noted under footnote (a) 
cEscalation of study treatment to previous dose level is allowed after consultation with the PI and in the absence of 
another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 
 
 


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4.4.8 Management and Dose Modification Guidelines for Therapy-related Pyrexia  
Pyrexia is defined as ≥38.5°Celsius or 101.3°Fahrenheit.  Episodes of pyrexia 
have been observed in subjects receiving dabrafenib monotherapy and is 
increased in incidence and severity in subjects receiving dabrafenib in 
combination with trametinib. (Pyrexia is also a side effect of trametinib, but is 
less frequent than that associated with dabrafenib-see section 5.1.5). [6]  In a 
minority of cases the pyrexia was accompanied by symptoms such as severe 
chills, dehydration, hypotension, dizziness or weakness.  Pyrexia accompanied by 
hypotension, dehydration requiring IV fluids, or severe rigors/chills should be 
reported as an SAE (see section 7.3.3).   Subjects should be instructed on the 
importance of immediately reporting febrile episodes.  In the event of a fever, the 
subject should be instructed to take non-steroidal anti-pyretics (e.g., ibuprofen), 
acetaminophen or other suitable anti-pyretic medication as appropriate to control 
fever. The use of oral corticosteroids should be considered in those instances in 
which anti-pyretics are insufficient. In subjects experiencing pyrexia associated 
with rigors, severe chills, dehydration, hypotension, etc., renal function should be 
monitored carefully. 
 
For each episode of pyrexia (defined above), a thorough clinical examination 
(including blood pressure) for signs and symptoms of infection or hypersensitivity 
is required; laboratory work-up should include full blood count, electrolytes, 
creatinine, BUN, CRP, liver function tests, blood culture, and urine culture. For 
subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical 
evaluation and laboratory work-up is mandatory for each event; anti-pyretic 
treatment should be started immediately at the first occurrence and prophylactic 
anti-pyretic treatment is recommended.  This prophylactic treatment may be 
discontinued after 3 days in the absence of pyrexia.   
 
Oral hydration should be encouraged in subjects without evidence of dehydration.  
Intravenous hydration is recommended in subjects experiencing pyrexia 
complicated by dehydration/hypotension. 
 
 


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Pyrexia  Management 
Action and Dose Modification 
1st Event 
Clinical evaluation for infection and hypersensitivity 
Laboratory work-upa 
Hydration as required 
Administer anti-pyretic treatment if clinically indicated 
and initiate prophylactic treatmente if fever associated 
with rigors, renal failure, dehydration or hypotension 
 
2nd Eventb 
Clinical evaluation for infection and hypersensitivity 
Laboratory work-upa 
Hydration as required 
Within 3 days of onset of pyrexia: 
Optimize anti-pyretic therapy 
Consider oral corticosteroids (i.e., 
prednisone 10 mg) for at least 5 days or as 
clinically indicated 
 
Subsequent Events:  
Clinical evaluation for infection and hypersensitivity 
Laboratory work-upa 
Hydration as requiredd 
Within 3 days of onset of pyrexia: 
Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexiab 
If corticosteroids have been tapered and 
pyrexia recurs, restart steroids  
If corticosteroids cannot be tapered consult 
study PI 
1st Event:  
Interrupt dabrafenib 
Continue trametinib (unless fever >104°F or fever complicated 
by rigors, hypotension, dehydration or renal failure, in which 
case trametinib should be withheld until fever resolves.) 
Resume at same or lower dose level. 
Once pyrexia resolves to baseline, restart dabrafenib at the 
same dose level 
If fever was associated with rigors, renal failure, dehydration or 
hypotension, reduce dabrafenib by one dose level 
 
2nd Event: 
Interrupt dabrafenib 
Continue trametinib  (unless fever >104°F or fever complicated 
by rigors, hypotension, dehydration or renal failure, in which 
case trametinib should be withheld until fever resolves.) 
Resume at same or lower dose level. 
 
Once pyrexia resolves to baseline, restart dabrafenib at the 
same dose level 
If fever was associated with rigors, renal failure, dehydration or 
hypotension, reduce dabrafenib by one dose level 
 
Subsequent  Events: 
Interrupt dabrafenib 
Continue trametinib (unless fever >104°F or fever complicated 
by rigors, hypotension, dehydration or renal failure, in which 
case trametinib should be withheld until fever resolves.) 
Resume at same or lower dose level. 
 
Once pyrexia resolves to baseline, restart dabrafenib reduced 
by one dose levelc 
If dabrafenib must be reduced to <75 mg BID, permanently 
discontinue both study treatments 
 
aTo include CBC with diff, electrolytes, creatinine, BUN, CRP, liver function tests, blood culture, and urine culture. 
bIn subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with anti-pyretic 
medication, oral corticosteroids should be started at the 2nd event and doses should be gradually increased for subsequent 
events. 
cDabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, severe chills, etc., 
which cannot be managed by best supportive care and increasing doses of oral steroids.  Escalation of dabrafenib is 
allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction. 
dOral hydration should be encouraged in subjects without evidence of dehydration.  Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension. 
eProphylactic anti-pyretic treatment may be discontinued after 3 days in the absence of pyrexia 


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4.4.9 Dose Modifications for Liver Toxicities 
Liver chemistry stopping criteria, follow up assessments and monitoring have 
been designed to assure subject safety and evaluate liver event etiology.   
4.4.9.1 Definition of Liver Chemistry Stopping Criteria  
Trametinib and dabrafenib will be permanently discontinued when any of the 
stopping criteria (1-5) listed below is met.   
 
1. Alanine aminotransferase (ALT) ≥3x upper limit of normal (ULN) and 
bilirubin ≥2xULN (>35% direct bilirubin) or ALT≥3xULN and international 
normalized ratio [INR]>1.5, if INR measured. 
a. INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants 
b. Serum bilirubin fractionation should be performed if testing is 
available.  If testing is unavailable, discontinue study treatment, and 
record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. 
NOTE: Any case that meets these criteria and is considered to be drug 
related is considered to be an SAE by GSK.  This is called “Hy’s 
Law.” If a Hy’s Law case occurs but there is a potential explanation 
for it other than drug, please consult with the Study PI. 
2. ALT ≥8xULN. 
3. ALT ≥5xULN but <8 x ULN persists for ≥2 weeks. 
4. ALT ≥3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash or eosinophilia. 
5. ALT ≥ 5xULN but <8 x ULN and cannot be monitored weekly for >2 weeks 
4.4.9.2 Follow-up Action if Liver Chemistry Stopping Criteria are Met:  
• Immediately discontinue subject from study treatment 
• Report the event to GSK within 24 hours of learning of its occurrence 
(see section 7.3.3).   
• Complete the liver event and SAE electronic case report form (eCRF) 
within Oncore® if the event also meets the criteria for an SAE:  
o All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct 
bilirubin) or ALT≥3xULN and INR>1.5, if INR measured, termed 
‘Hy’s Law’, must be reported as an SAE  
o NOTE: if serum bilirubin fractionation is not immediately 
available, study treatment should be discontinued if ALT ≥ 3xULN 
and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be 
performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury 
• Complete the liver imaging and/or liver biopsy eCRFs if these tests are 
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• Perform liver event follow up assessments (see Appendices (section 11.4) 
and monitor the subject until liver chemistries resolve, stabilize, or return 
to baseline values as described below 
• Follow-up  is required until the toxicity is deemed irreversible or for 3 
months, whichever comes first, following permanent discontinuation from 
study treatment for liver toxicity  
• Do not re-challenge with study treatment without IRB approval (see 
appendices, sections 11.4.2 and 11.4.3. 
 
In addition, for criterion 1:  
• Make every reasonable attempt to have subjects return to a clinic within 
24 hours for repeat liver chemistries, liver event follow up assessments 
(see appendices (section 11.4), and close monitoring 
• A specialist or hepatology consultation is recommended 
• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline 
values. 
 
In addition, for subjects meeting any of the criteria 2 - 5: 
• Make every reasonable attempt to have subjects return to a clinic within 
24-72 hrs for repeat liver chemistries and liver event follow up 
assessments (see appendices (section 11.4)  
• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline 
values 
• Subjects meeting criterion 5 should be monitored as frequently as possible 
4.4.9.3 Liver Chemistry Monitoring Criteria  
For subjects with ALT ≥3xULN but <8xULN which exhibit a decrease to ALT 
≥3xULN, but <5xULN and bilirubin <2xULN, without hepatitis symptoms or 
rash, and who can be monitored weekly for 4 weeks, the following actions should 
be taken: 
• Notify study PI within 24 hours of learning of the abnormality to discuss 
subject safety 
• Continue study treatment  
• Return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilize or return to within 
baseline values  
• If at any time the subject meets any of the liver chemistry stopping criteria 
1 – 5 (see section 4.4.8.1), proceed as described above in section 4.4.8.2) 
• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, 
monitor subjects twice monthly until liver chemistries normalize or return 
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4.4.10 Pancreatitis 
In the event of abdominal pain or suspected pancreatitis, amylase and lipase 
laboratory samples should be collected for confirmation of the diagnosis. Patients 
should be closely monitored when re-starting dabrafenib after an episode of 
pancreatitis. 
4.4.11 Hyperglycemia 
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral 
therapy can occur with dabrafenib. Monitor serum glucose levels as clinically 
appropriate during treatment with dabrafenib in subjects with pre-existing 
diabetes or hyperglycemia. Advise patients to report symptoms of severe 
hyperglycemia such as excessive thirst or any increase in the volume or frequency 
of urination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.4.12 Non-specified Toxicities Attributable to Drug Therapy 
 
CTCAE 
Grade 
Action and Dose Modification for  Dabrafenib and Trametinib 
1 or 
tolerable 
Grade 2 
 
Continue study treatment at current dose level 
Monitor closely  
Provide supportive care according to institutional standards 
1st, 2nd, or 
3rd 
occurrence 
of 
intolerable 
Grade 2 or 
any Grade 3 
Interrupt study treatment  
Monitor closely  
Provide supportive care according to institutional standards 
When toxicity resolves to ≤grade 1, restart study treatment reduced by one dose level  
  
4th 
occurrence 
of 
intolerable 
Grade 2 or 
any Grade 3 
Discontinue treatment 
4 
Interrupt study treatment  
Monitor closely  
Provide supportive care according to institutional standards 
Restart with study treatment reduced by one dose level once toxicity resolves to ≤grade 
1  
If the grade 4 toxicity recurs, once resolves to ≤grade 1, restart at two dose levels lower 
than the starting dose or permanently discontinue study treatment at discretion of the 
investigator  
For 3rd occurrence, discontinue treatment  
 
4.5 
Concomitant Medications/Treatments 
4.5.1 Prohibited Medications, Herbal Supplements and Juices 
The use of certain medications for 14 days or 5 half-lives prior to the first dose of 
study therapies and for the duration of the trial will not be allowed.  If a 
prohibited medication is required for single use (such as for a procedure) while 
treatment with study drug is interrupted, the PI can approve such use.  The 
following medications or non-drug therapies are prohibited: 
 
• Other anti-cancer therapy while on treatment in this study  
• Other investigational drugs 
• The concurrent use of all herbal supplements is prohibited during the 
study (including but not limited to St. John’s wort, kava, ephedra (ma 


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huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, or ginseng).  
• Antiretroviral drugs.  Subjects with known HIV are ineligible for study 
participation.  
• Drugs that are clinically relevant strong inhibitors or inducers of CYP3A, 
CYP2C8, p-glycoprotein (Pgp) or breast cancer resistance protein (BCRP) 
transporter because they may alter dabrafenib and/or trametinib 
concentrations.  These include but are not limited to those listed in section 
11.2 (see Appendices); consider therapeutic substitutions for these 
medications. This list may be modified based on emerging data. 
4.5.2 Drugs to be used with Caution 
The following medications should be used with caution as their concentrations 
may be altered by dabrafenib or trametinib or they may alter dabrafenib or 
trametinib concentrations (see section 11.2.2 in appendices): 
 
• Drugs that are mild/moderate inhibitors or inducers of CYP3A, CYP2C8, 
or Pgp or BCRP transporter. 
• Drugs that are substrates of CYP2C8, CYP2C9, and CYP2C19 that are 
highly sensitive to inhibitors or that have a low therapeutic index. 
Dabrafenib has been shown to induce CYP3A4 in vivo and may induce 
CYP2B6.  Other enzymes such as CYP2C8, CYP2C9, CYP2C19 and 
UGT may also be affected. Onset of induction is likely to occur after 3 
days of repeat dosing with dabrafenib. Transient inhibition of CYP3A4 
may be observed during the first few days of treatment. Upon 
discontinuation of dabrafenib, concentrations of these sensitive substrates 
may increase and subjects should be monitored for toxicity and dosage of 
these agents may need to be adjusted.[6] 
•  Co-administration of dabrafenib and medications that are affected by the 
induction of these enzymes (including warfarin, hormonal contraceptives, 
dexamethasone, antiretroviral agents or immunosuppressants) may result 
in loss of efficacy.  If co-administration of these medications is necessary, 
investigators should monitor subjects for loss of efficacy or consider 
substitutions of these medications. 
• Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, 
H2-receptor antagonists, antacids) may alter the solubility of dabrafenib 
and reduce its bioavailability. However, no formal clinical trial has been 
conducted to evaluate the effect of gastric pH-altering agents on the 
systemic exposure of dabrafenib. When dabrafenib is coadministered with 
a proton pump inhibitor, H2-receptor antagonist or antacid, systemic 
exposure of dabrafenib may be decreased and the effect on its efficacy is 
unknown. 
4.5.3 Dabrafenib and Radiation 
Radiation skin injury has been reported with concurrent use of dabrafenib and 
radiation. To reduce this risk, it is recommended that dabrafenib be held for seven 


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days before and two days after radiation in subjects receiving dabrafenib in 
combination with trametinib.  
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue 
until: 
• Disease progression* (*Some patients may remain on treatment after 
progression (at the discretion of the investigator) as long as they are 
still experiencing clinical benefit  
• In patients without progression, therapy may continue up to 3 years 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from the study, OR 
• General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 
4.7 
Duration of Follow Up 
Patients who come off therapy due to progression will enter the follow-up phase 
every 3 months for up to 1 year from study entry to document survival (no tumor 
measurement per study protocol will be necessary after progression).   
 
Patients who come off therapy for reasons other than progression will enter the 
follow-up phase every 3 months for up to 1 year from study entry to document 
survival.  If tumor assessments are available for patients who have not yet 
experienced progressive disease (PD), these evaluations will be documented in the 
eCRF until PD is confirmed. Regardless, of the reason that a patient comes off 
treatment, dermatologic exams will continue every 3 months for the first 6 months 
following discontinuation from dabrafenib, and may be done by a physician local 
to the patient. Only after these dermatologic exams are complete is the patient 
considered off follow-up, even if they do not require survival follow-up for this 
entire 6 month period. 
 
Patients who come off therapy for reasons other than progression, later receive the 
dabrafenib/trametinib off-study and then progress on the combination therapy 
may be re-consented to undergo a progression biopsy. These subjects will then 
remain on study for safety monitoring, in relation to the biopsy procedure, for 30 
days. Subjects who have an ongoing ≥grade 2 or serious AE (SAE) related to the 
study procedure at 30 days will continue to be followed until the event is resolved 
or deemed irreversible by the investigator. 
 
4.8 
Removal of Patients from Protocol Therapy 
Patients will be removed from study treatment when any of the criteria listed in 
Section 4.6 apply.  Notify the Principal Investigator, and document the reason for 
removal from study treatment and the date the patient was removed in the 


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electronic Case Report Form (eCRF).  The patient should be followed-up per 
protocol.     
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
 
Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should 
be avoided. 
4.9 
Patient Replacement 
If a patient drops out of the study prior to progression, they may be replaced after 
consultation with the manufacturer of trametinib and dabrafenib, GSK.  We 
anticipate that ≤3 patients will fall into this category. 
4.10 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments as 
thoroughly as possible. The investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as 
completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the patient’s study withdrawal should be made with an 
explanation of why the patient is withdrawing from the study. If the reason for 
removal of a patient from the study is an adverse event, the principal specific 
event will be recorded on the eCRF. 
 
5.0 
DRUG INFORMATION 
5.1 
Trametinib Description and Management 
Details on this product may be found in the prescribing information (see 
www.accessdata.fda.gov)  and the Investigator’s Brochure.[4]  Please also see 
sections 1.5 and the appendices (section 11.3) for additional information on  
safety when dabrafenib is combined with trametinib. 
5.1.1 Supplier/How Supplied 
Trametinib commercially available product with auxiliary labeling will be 
provided by Novartis.  The study drug should be administered and stored as per 
the instructions specified on the label (refer to the label, the PI or the IB for more 
detailed information) 
 
The drug substance (tablet) is blended with inert ingredients. It comes as 0.25, 
0.5mg, 1 mg and 2 mg film coated tablets.  For this trial it will be provided in 0.5 
and 2.0 mg strengths.  


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5.1.2 Handling and Dispensing 
A Material Safety Data Sheet (MSDS) describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by 
local laws or will otherwise be available from Novartis upon request. 
5.1.3 Dosage and Administration 
See Section 4.3. 
5.1.4 Return and Retention of Study Drug 
Unused study drug returned by the subjects will be accounted for on site and will 
then be destroyed per UNC IDS drug destruction policy or per Affiliate 
institutional guidelines. Any study drug remaining after trial is complete will be 
destroyed per UNC IDS drug destruction policy or per Affiliate institutional 
guidelines.    
5.1.5 Adverse Events (AEs) Associated with Trametinib 
The data and guidance presented in this section is based on the nonclinical data 
and the safety profile seen in clinical studies involving trametinib to date, 
described in the trametinib Investigator’s Brochures.[4]   
 
Based on available AE data from the clinical studies to date, the most common 
toxicities ≥ 20% at the 2.0 mg/day dose are rash, diarrhea, fatigue, peripheral 
edema, nausea, vomiting, constipation, anemia, decreased appetite, dyspnea, 
pruritus, and abdominal pain. Rash and diarrhea are common, class-effect 
toxicities for MEK inhibitors. In addition, visual impairment and left ventricular 
ejection fraction (LVEF) reduction, although observed at lower frequencies, are 
also considered class effect toxicities as they have been observed with trametinib 
as well as other MEK inhibitors. Other very common toxicities (≥10% up to 19%) 
include alopecia, dermatitis acneiform, dry skin, pyrexia, hypertension, cough, 
and dry mouth; common toxicities (≥1% to <10%) include pneumonitis, 
dehydration, periorbital edema, blurred vision, vision impairment, left ventricular 
dysfunction, lymphedema, epistaxis, stomatitis, erythema, palmar-plantar 
erythrodysaesthesia syndrome, chapped skin, skin fissures, asthenia, facial edema, 
mucosal inflammation, cellulitis, folliculitis, paronychia, pustular rash, increases 
in ALT, AST, alkaline phosphatase, and serum creatinine, and decreased ejection 
fraction. Uncommon toxicities include hypersensitivity (which may present with 
symptoms such as fever, rash, increased LFTs, and visual disturbances), 
chorioretinopathy, papilloedema, retinal detachment, retinal vein occlusion, 
cardiac failure, pneumonitis, and interstitial lung disease. 
 
The following Contraindications, Warnings and Precautions apply: 
 
Contraindications: 
Pregnancy:  
There are no adequate and well-controlled studies of GSK1120212 in pregnant 
women. Animal studies have shown reproductive toxicity. In repeat dose studies 


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in rats given trametinib, there were ovarian effects that could likely affect female 
fertility. Therefore, the compound must not be administered to pregnant women 
or nursing mothers. Women of childbearing potential should use effective 
methods of contraception during therapy and for 4 months following 
discontinuation. If GSK1120212 is used during pregnancy, or if the subject 
becomes pregnant while taking GSK1120212, the subject should be informed of 
the potential hazard to the fetus. 
 
There are no adequate and well-controlled studies of GSK1120212 in pregnant 
women. Animal studies have shown embryofetal development toxicities, 
including teratogenic effects.  Therefore, the study drug must not be administered 
to pregnant women or nursing mothers. Women of childbearing potential should 
be advised to avoid pregnancy and use effective methods of contraception during 
therapy and for 4 months following discontinuation. Men with a female partner of 
childbearing potential must have either had a prior vasectomy or agree to use 
effective contraception. If a female patient or a female partner of a patient 
becomes pregnant while the patient receives trametinib, the potential hazard to the 
fetus should be explained to the patient and partner (as applicable). Safety and 
efficacy in the elderly or pediatric populations have not been investigated. 
 
Lactation 
It is not known whether trametinib is excreted in human milk. Because many 
medicinal products are excreted in human milk, a risk to the nursing infant cannot 
be excluded. A decision should be made whether to discontinue nursing or to 
discontinue 
 
Hypersensitivity 
Any known hypersensitivity to the constituents of the vehicle would 
contraindicate trametinib use. Hypersensitivity to trametinib was reported by one 
subject 7 days after starting trametinib who experienced fever, asthenia, visual 
disturbance, and symptoms suggestive of a hypersensitivity reaction described by 
the investigator as “vascularity.” This subject also developed LFT elevations, 
lower limb nodules that by biopsy showed “dermo-hypodermatitis with 
plasmocyte and lymphocyte infiltrate.” 
 
Precautions: 
Pediatric Use 
Trametinib should not be administered to pediatric populations and should be 
administered to elderly populations with caution. 
 
Skin toxicities: Rash was a common toxicity in the FTIH study, and occurred at 
doses as low as 0.5 mg. At the 2.0 mg dose level in the FTIH study, 87% of the 
subjects experienced rash; most cases were Grade 1 or Grade 2 in severity; rash 
occurred as early as the first week of dosing, with the median onset on Day 15 of 
study treatment. In clinical studies overall, rash has been observed in about 60% 
of subjects. The majority of these cases was Grade 1 or 2 and did not require any 
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Gastrointestinal toxicities: Diarrhea was a common toxicity, and occurred 
throughout the dose range. At the 2.0 mg dose level in the FTIH study, 56% of the 
subjects experienced diarrhea; most events were either Grade 1 or Grade 2 in 
severity.  
 
Visual impairment:  
Visual impairments, including chorioretinopathy, retinal vein occlusion (RVO), 
retinal pigment epithelial detachment (RPED) and papilledema have been 
reported with trametinib. 
 
Subjects with a history of RVO or risk factors of RVO should not receive 
trametinib. Exclusion criteria based on these risk factors, comprehensive stopping 
criteria, dose modifications, and ocular effects management guidelines have been 
incorporated into this protocol.[4] 
 
Cardiomyopathy:  
Cardiomyopathy, defined as cardiac failure, left ventricular dysfunction, or 
decreased left ventricular ejection fraction (LVEF) has been reported with 
trametinib as well as with other MEK inhibitors in clinical development. Subjects 
with a history or evidence of cardiovascular risk including current ≥ Class II 
congestive heart failure as defined by New York Heart Association are not being 
enrolled in current studies. Subjects must have a normal LVEF on screening 
assessment. Comprehensive stopping criteria, dose modifications, and left 
ventricular dysfunction management guidelines have been incorporated into this 
study. In addition, there have been 9 cases of sudden death or cardiac arrest 
reported across the trametinib program.  See the trametinib IB.[4] 
 
Pneumonitis: Pneumonitis was seen in 6 out of 31 subjects (19%) treated with 
trametinib plus gemcitabine in Study MEK112111. Four of the 6 subjects were 
rechallenged with study drug, and while a relationship to trametinib could not be 
ruled out, all 4 subjects had no further pulmonary symptoms or evidence of 
pneumonitis on imaging studies. Investigators must use caution when using 
trametinib in combination with drugs that have been associated with or induced 
pneumonitis.   
 
Drug Interactions 
As trametinib is metabolized predominantly via deacetylation likely mediated by 
hydrolytic esterases, its pharmacokinetics are unlikely to be affected by other 
agents through metabolic interactions. Based on in vitro and in vivo data, 
trametinib is unlikely to significantly affect the pharmacokinetics of other 
medicinal products via interactions with CYP enzymes or transporters. 
 
Drug-Food Interactions  
Administration of a single dose of trametinib with a highfat, high-calorie meal 
resulted in a 70% and 10% decrease in Cmax and AUC(0-∞), respectively 


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compared to fasted conditions. The recommendation is to administer trametinib 
on an empty stomach.  
 
Renal Impairment 
No dosage adjustment is required in subjects with mild or moderate renal 
impairment. There are no data in subjects with severe renal impairment; therefore, 
trametinib should be used with caution in subjects with severe renal impairment. 
 
Hepatic Impairment 
No dosage adjustment is required in subjects with mild hepatic impairment. There 
are no clinical data in subjects with moderate or severe hepatic impairment; 
therefore, trametinib should be used with caution in subjects with moderate or  
severe hepatic impairment. 
 
 
Potential for Abuse and Dependence: Not known. 
 
Overdose:  
 
In BRF113220 study, 12 subjects experienced fourteen events of trametinib  
overdose as defined by the protocol (trametinib doses > 2mg in a day). All 
overdoses lasted for one day only. Five of these subjects took 2 tablets (4mg) 
trametinib and experienced 12 AEs, all within 3 days of taking the overdose. The 
adverse events were primarily grade 1 (chills, hot flash, diarrhea, low back pain, 
changes in hair texture, vomiting, weakness, and cough), with grade 2 pyrexia and 
chills, and grade 3 hyponatremia. One subject experienced mesenteric artery 
thrombosis identified as due to disease progression. No subjects required dose 
reduction or discontinuation. All subjects resumed trametinib treatment at the 
assigned dose. 
 
In the event of a trametinib overdose, defined as administration of more than 3mg 
once daily (the maximum tolerated dose defined in the MEK111054 study), the 
investigator should contact the study PI immediately and closely monitor the 
subject for AEs/SAEs and laboratory abnormalities. The investigator will use 
clinical judgment to treat any overdose.  
 
Decisions regarding dose interruptions or modifications will be made by the 
investigator in consultation with the study PI based on the clinical evaluation of 
the subject. 
 
There is no specific antidote for an overdose with trametinib. In the event of a 
suspected overdose, it is recommended that the appropriate supportive clinical 
care should be instituted, as dictated by the subject’s clinical status. Hemodialysis 
is not expected to enhance the elimination of trametinib as it is highly bound to 
plasma proteins. The most likely results of acute overdose with trametinib may 
include rash, nausea, vomiting, or diarrhea. 


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5.2 
Dabrafenib Description and Management 
Details on this product may be found in the prescribing information (see 
www.accessdata.fda.gov) and the Investigator’s Brochure for dabrafenib.[5] 
Please also see sections 1.5 and the appendices (section 11.3) for additional 
information on the safety seen when dabrafenib is combined with trametinib. 
5.2.1 Supplier/How Supplied 
Dabrafenib commercially available product with auxiliary labeling will be 
provided by Novartis.  The study drug should be administered and stored as per 
the instructions specified on the label (refer to the label, the PI or the IB for more 
detailed information). 
 
Each capsule contains 25, 50 mg or 75 mg of dabrafenib. For this trial it will be 
provided in 50 and 75 mg strengths. 
5.2.2 Handling and Dispensing 
A Material Safety Data Sheet (MSDS) describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by 
local laws or will otherwise be available from Novartis upon request. 
5.2.3 Dosage and Administration 
See Section 4.3. 
5.2.4 Return and Retention of Study Drug 
Unused study drug returned by the subjects will be accounted for on site and will 
then be destroyed per UNC IDS drug destruction policy or per Affiliate 
institutional guidelines.  Any study drug remaining after trial is complete will be 
destroyed per UNC IDS drug destruction policy or per Affiliate institutional 
guidelines.    
5.2.5 AEs Associated with Dabrafenib 
As summarized in the table below (from the dabrafenib 2014 IB)[5] the following 
adverse events were considered related to dabrafenib when administered as 
monotherapy across company-sponsored clinical trials (n=578).   
Adverse reactions are listed below by MedDRA body system organ class and by 
frequency. The frequency categories used are: 
 
Very common: ≥ 1/10 (≥ 10%) 
Common: ≥1/100 and <1/10 (≥ 1% and <10%) 
Uncommon: ≥1/1,000 and <1/100 (≥0.1% and <1%) 
Rare: ≥1/10,000 and <1/1,000 (≥0.01% and <0.1%) 
 
Eye Disorders 
Uncommon 


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• Uveitis (including chorioretinitis, choroiditis, retinitis, vitritis, cyclitis, 
iridocyclitis, iritis, and uveitis) 
 
Neoplasms benign and malignant (including cysts and polyps) 
Very Common 
• Skin papilloma, papilloma 
 
Common  
• Cutaneous squamous cell carcinoma (SCC), including SCC of the skin, 
SCC in situ (Bowen’s disease) and keratoacanthoma 
• Acrochordon (skin tags) 
• Seborrheic keratosis 
 
 
Uncommon 
• New primary malignant melanoma 
 
Immune System Disorders 
Uncommon  
• Hypersensitivity 
 
Renal and urinary disorders 
Uncommon  
• Renal failure, acute renal failure 
 
Respiratory, thoracic and mediastinal disorders 
Very Common  
• Cough 
 
Metabolism and nutrition disorders 
Very Common  
• Decreased appetite 
Common  
• Hypophosphataemia 
 
Nervous system disorders 
Very Common 
• Headache 
 
Gastrointestinal disorders 
Very Common  
• Nausea 
• Vomiting 
• Diarrhea 
Common  
• Constipation 


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Uncommon 
• Pancreatitis 
 
Skin and subcutaneous tissue disorders 
Very Common  
• Skin effects (Rash, Hyperkeratosis) 
• Alopecia 
• Palmar-plantar erythrodysaesthesia syndrome 
Common  
• Skin effects (Actinic keratosis, skin lesion, dry skin, erythema) 
 
Musculoskeletal, connective tissue and bone disorders 
Very Common  
• Arthralgia 
• Myalgia 
• Pain in extremity 
 
General disorders and administration site conditions 
Very Common  
• Asthenia 
• Fatigue 
• Pyrexia  
• Chills 
 
Common  
• Influenza-like illness 
5.2.6 Contraindications 
Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, Pgp or BCRP 
transporters, are contraindicated.  See appendices and sections 4.5 and 11.2.1.  
Any known hypersensitivity to the constituents of the vehicle would 
contraindicate dabrafenib use. 
5.2.7 Special Warnings and Special Precautions for Use 
Dermatological effects: 
Epidermal hyperplasia (acanthosis) and hyperkeratosis of the skin was seen in 
dogs and in rats. In clinical trials rashes have been observed, and in the 
monotherapy studies hyperkeratosis (29%), skin lesions including actinic 
keratosis (7%) and seborrheic keratosis (7%), hand-foot skin reactions (13%), 
rash (18%) and cutaneous SCC including keratoacanthomas (KA) (9%) have been 
observed. Approximately 70% of events occurred within the first 12 weeks of 
treatment with a median time to onset of 8 weeks. More than 90% of patients who 
developed cutaneous SCC continued on dabrafenib treatment without dose 
modification. Most events were Grade 1 with the exception of cutaneous squamous 
cell carcinomas, which were predominantly Grade 3. Dermatological changes are 


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being monitored in subjects through interim medical history, assessment of 
adverse events and physical examination including examination of the skin. 
Guidelines on management of HFSR and skin rashes have been provided in the 
protocol.  
 
Non-cutaneous secondary/recurrent malignancy 
Cases of RAS-driven malignancies have been seen with BRAF inhibitors. 
One case of RAS-mutation positive non-cutaneous malignancy (bile duct 
adenocarcinoma) has been identified to date in a subject receiving dabrafenib 
monotherapy. Patients should be monitored as clinically appropriate. 
 
Ophthalmology effects: 
Eye effects including blurred vision (2), uveitis/iritis (<1%), eye pain (<1%), 
visual impairment (<1%) and reduced visual acuity (<1%) have been infrequently 
observed in clinical studies to date, with events generally grade 1 or 2. An 
ophthalmologic consult is required for subjects developing symptoms associated 
with uveitis including blurry vision, eye pain or erythema.  
 
Pyrexia: 
In clinical studies, pyrexia was one of the most frequently occurring AEs (27%), 
most of which (64%) were considered to be related to study treatment. Events 
were primarily Grade 1 (55%) or Grade 2 (39%) in severity. The majority of 
events occurred early during study treatment, with a median time to onset of first 
occurrence of 3 weeks, and most cases (74% of first occurrences) were of short 
duration (5 days). The majority of subjects with pyrexia were managed without dose 
interruption or dose reduction.  
 
Subjects should be evaluated for signs and symptoms of infection and work up 
considered as clinically indicated. Drug must be held for fever of 38.5°C or 
higher, and an absolute neutrophil count, serum creatinine and BUN must be 
drawn in the setting of fever. Subjects with fever should have a medical 
evaluation including measurement of blood pressure. Cases of fever with rigors or 
fever with hypotension should be reported as SAEs (regardless of whether or not 
hospitalization was required); see section 7.1.4. 
 
Glucose-6-phosphate dehydrogenase: 
Subjects with a history of known glucose-6-phosphate dehydrogenase (G6PD) 
deficiency may develop non-immune hemolytic anemia in response to dabrafenib 
which contains a sulfonamide, a potential risk factor for subjects with this 
deficiency (NOTE: patients with history of sulfa allergies do not need to be 
excluded from studies incorporating dabrafenib). 
 
Hyperglycemia: 
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral 
hypoglycemic agent therapy can occur with dabrafenib.  The incidence of grade 3 
hyperglycemia based on laboratory values was 6% in patients treated with 
dabrafenib compared to 0% in the dacarbazine group in the phase 3 randomized 


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trial that compared dabrafenib to dacarbazine.  Some patients may require more 
intensive hypoglycemic therapy while taking dabrafenib. Monitor serum glucose 
levels as clinically appropriate during treatment with dabrafenib in  
patients with pre-existing diabetes or hyperglycemia. Advise patients to report 
symptoms of severe hyperglycemia such as excessive thirst or any increase in the 
volume or frequency of urination. 
 
Acute renal failure:  
Acute renal failure/renal failure has been rarely reported (<1%) in patients 
receiving dabrafenib, and a case of granulomatous interstitial nephritis has also 
been reported in a clinical trial. In some cases complicated pyrexia may be 
associated with renal insufficiency/renal failure, possibly secondary to 
dehydration or hypotension. Renal function should be monitored carefully, 
especially in patients with pyrexia. Dabrafenib should be interrupted in patients 
with significantly elevated serum creatinine (creatinine rise > 0.5 mg/dL [44 
μmol/L] above baseline or creatinine > 2.0 mg/dL [177 μmol/L]).  
 
Pancreatitis:  
Pancreatitis (<1%) and/or increased lipase/amylase (2%) have been reported at 
low frequency with dabrafenib, typically occurring within 14 days of starting 
therapy. For adverse events of abdominal pain or suspected pancreatitis, amylase 
and lipase laboratory samples should be monitored locally.  
 
New primary melanoma: 
New primary melanomas have been reported in patients treated with dabrafenib. 
These were identified within the first 5 months of therapy and did not require 
treatment modification other than excision. Monitoring for skin lesions should 
occur as described for cuSCC. 
 
Hypersensitivity:  
There has been a report of hypersensitivity (blisters), occurring on the same day 
as the 1st dose of study drug as well as upon rechallenge. Grade 1 AEs of blisters 
on limbs (4 subjects) and drug hypersensitivity (rash, 1 subject) have been 
reported in previous studies with dabrafenib. However, the precise etiology of 
these events is unclear. 
 
Drug interactions: 
Strong inhibitors or inducers of CYP3A or CYP2C8 are prohibited since they may 
increase or decrease dabrafenib concentrations. Mild or moderate 
inhibitor/inducers of these enzymes/transporters should be used with caution. 
Dabrafenib has been shown to induce CYP3A4 and CYP2C9, and,may induce 
CYP2C8, CYP2B6, CYP2C19 and UGT. Co-administration of dabrafenib and 
medications affected by the induction of these enzymes may result in decreased 
exposure of these medications and associated loss of efficacy. If co-administration 
of these medications is necessary, investigators should monitor subjects for loss of 
efficacy or consider substitutions of these medications. 


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Drugs that affect gastric pH: 
Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, 
H2-receptor antagonists, antacids) may alter the solubility of dabrafenib 
and reduce its bioavailability. However, no formal clinical trial has been 
conducted to evaluate the effect of gastric pH-altering agents on the 
systemic exposure of dabrafenib. When dabrafenib is coadministered with 
a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic 
exposure of dabrafenib may be decreased and the effect on its efficacy is 
unknown. 
 
Drug-food interactions: 
Administration of dabrafenib with a high-fat, high-calorie meal reduced the oral 
bioavailability of dabrafenib when compared to the fasted state with a decrease in 
Cmax and AUC of 51% and 31%, respectively, and delayed its absorption.  The 
recommendation is to take dabrafenib on an empty stomach. 
 
Pediatric population: 
Safety and efficacy in the pediatric population has not been established, therefore, 
dabrafenib should not be administered to this population. 
5.2.8 Other Considerations 
Renal impairment 
There are limited clinical data for dabrafenib in subjects with renal impairment. In 
clinical studies, 3% of subjects had baseline Grade 1 renal impairment.  
Mild or moderate renal impairment is not expected to have a clinically relevant 
effect on dabrafenib pharmacokinetics given the low renal excretion of dabrafenib 
and metabolites. There are currently no data on which to base a dosing 
recommendation in subjects with severe renal impairment or end-stage renal 
disease. Dabrafenib should be administered with caution in this setting. 
 
 
Hepatic impairment 
There are limited clinical data for dabrafenib in subjects with hepatic impairment. 
In a population pharmacokinetic analysis, dabrafenib oral clearance and thus 
exposure was not significantly different in subjects with mild hepatic impairment 
compared to subjects with normal hepatic function. There are no PK data in 
subjects with moderate or severe hepatic impairment; therefore, the potential need 
for starting dose adjustment cannot be determined. In clinical studies, mild 
elevations in AST or ALT were observed in 9% and 13% of subjects, respectively, at 
baseline. Based on preclinical and in vitro studies, hepatic metabolism and biliary 
secretion are likely to be the primary route of elimination. Dabrafenib 
concentrations may be increased in subjects with moderate and severe hepatic 
impairment. Dosage adjustment may be required, particularly in subjects with 
severe hepatic impairment. 
 


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Cardiovascular effects 
Data from preclinical studies with dabrafenib suggest the potential for 
cardiovascular effects, including cardiac valve effects in the 28 day dog study, 
coronary vascular effects in the 7 day dog study, hepatic vascular effects in a 10 
day rat study, increased incidence of minimal cardiomyopathy in male rats and 
mild increases in heart rate in single dose studies in dogs and rats. In addition, 
preliminary histological assessment of hearts from a 13-week oral toxicity study 
in dogs with dabrafenib revealed treatment-related right atrial wall thickening 
characterized microscopically by fibrovascular proliferation (transmural 
granulation tissue) associated with the right atrium/appendage. 
 
Dabrafenib clinical protocols did not exclude subjects with risk factors for or 
known atherosclerotic coronary artery disease if cardiac function was stable, thus 
these conditions were frequently present at study entry, consistent with the 
expected incidence in the general population. Subjects with clinically significant 
baseline cardiac abnormalities were excluded from the studies. In the Phase III 
study BREAK-3 in which subjects with unresectable BRAFV600E mutation-
positive melanoma received either dabrafenib or dacarbazine (DTIC) 
chemotherapy, none of the individual cardiac AEs of potential concern including 
decreased LVEF, valvular abnormalities, conduction abnormailities, or 
myocardial effects was seen at a higher incidence relative to DTIC than 
expected, when viewed in context of the 3:1 randomization and the longer 
exposure of dabrafenib treated patients (4.9 vs 2.8 months). Therefore, the 
preclinical findings regarding potential cardiovascular AEs have not been 
confirmed by clinical data.  
 
Reproductive effects 
In embryofetal development studies in rats, developmental toxicities including 
reduced fetal body weight, embryo-lethality, cardiac ventricular septal defect 
malformations, delayed skeletal development and variation in thymic shape have 
been observed. In pregnant rats given dabrafenib, dose-dependent reductions in 
ovarian corpora lutea have been observed. Animal studies with dabrafenib have 
shown embryofetal developmental toxicities, including teratogenic effects. 
Dabrafenib must not be administrated to pregnant women or nursing mothers. 
Female subjects of childbearing potential are required to use effective methods of 
contraception from the time of a negative serum pregnancy test within 14 days 
prior to the first dose of study medication, until 4 weeks after the last dose of 
study medication. 
 
In dogs and in rats, testicular degeneration/depletion has been observed in repeat 
dose studies (up to 13 weeks duration) with no clear evidence of recovery 
following off treatment periods of up to 4 weeks duration. Spermatid retention 
was observed in mice in a 14 day study. Male subjects enrolled or in follow-up in 
clinical trials are informed of the potential risk for impaired spermatogenesis, 
which may be irreversible. Male subjects must agree to use one of the 


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contraception methods in clinical protocols from the time of first dose of study 
medication until 16 weeks after the last dose of study medication. 
 
Respiratory effects 
Lobar bronchoalveolar inflammation has been observed in dogs, with shallow 
and/or labored breathing noted during the treatment phase in 2 dogs given 
dabrafenib for 13 weeks. Respiratory changes are being monitored through 
medical history and physical examination. Clinical trial investigators will be 
requested to consider performing a lung CT scan for cases of clinically significant 
respiratory symptoms. Adverse events classified as respiratory, thoracic or 
mediastinal disorders have been reported in studies of dabrafenib in subjects both 
with and without pulmonary metastases.The majority of these events were low 
grade and a consistent relationship to treatment was not observed. No pattern of 
specific events was observed; all adverse events in the integrated safety 
population (ISP) occurred at a frequency of <1% with the exceptions of cough 
(11%), dyspnoea (5%), oropharyngeal pain and productive cough (1% each). 
 
Overdose 
There has been a single report of dabrafenib overdose in study BRF112680 in 
which the patient ingested 300 mg three times daily (TID) (900 mg cumulative 
daily dose) instead of the intended dose of 100 mg TID (300 mg cumulative daily 
dose), for a period of 49 days. The patient did not experience any known adverse 
events related to the study medication. 
 
There was one additional subject in BRF112680 who mistakenly took 225mg BID 
of dabrafenib for 11 days (22 doses) along with trametinib 2mg from study day 58 
through day 68; this event was identified as an overdose by the site. On study day 
58 the subject reported AEs of grade 1 blurred vision, grade 1 increase in GGT 
and grade 2 increase in alkaline phosphatase. The event of blurred vision did not 
resolve, the increased GGT and alkaline phosphatase both resolved. Only the 
increased GGT was considered related to study treatment. On study day 73 the 
subject reported AEs of Grade 1 diarrhea and Grade 1 seasonal allergies; neither 
resolved, the diarrhea was considered related to study treatment. There were no 
vital signs, laboratory studies, or cardiac assessments obtained during the event of 
overdose. The subject discontinued treatment on study day 226 due to disease 
progression. 
 
In the event of a dabrafenib overdose, defined as administration of more than 300 
mg as a single dose or 600 mg daily (the highest dose tested in clinical studies to 
date), the investigator should contact the overall PI of the study immediately and 
closely monitor the subject for AEs/SAEs and laboratory abnormalities. 
Hemodialysis is not expected to enhance the elimination of dabrafenib as it is 
highly bound to plasma proteins. The investigator will use clinical judgment to 
treat any overdose.  
 


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Decisions regarding dose interruptions or modifications will be made by the 
investigator in consultation with the study PI based on the clinical evaluation of 
the subject. 
 
Information regarding the quantity of the excess dose as well as the duration of 
the overdosing should be documented in the eCRF. 
 
5.2.9 Adverse Events (AEs) Associated with Dabrafenib in Combination with 
Trametinib 
Per the dabrafenib (Tafinlar®) prescribing information January 2014, the most 
common adverse reactions (≥20%) reported when the two therapies are used in 
combination are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, 
abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, 
decreased appetite, constipation, and myalgia. Based on the safety summary in the 
June 2014 IB of the combination, of the 420 patients enrolled in MEK115306, the 
most common adverse reactions (≥20%) when the two therapies are used in 
combination are pyrexia, fatigue, headache, nausea, chills, arthralgia, diarrhea, 
rash, hypertension and vomiting. See sections 1.5, 11.8, and the Investigator 
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6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table  
Assessment 
Pre-Study1 
(≤ 21 days 
except 
where 
noted) 
D1 
Cycle 
1 
D1 
Cycle 
2 
(+/- 3 
days) 
D1 
Cycle 
3 
(+/- 3 
days) 
D1 
Cycle 
4 
(+/- 3 
days) 
D1 
Cycle 
5 
(+/- 3 
days) 
D1 
Cycle 
6 
(+/- 3 
days) 
D1 
Cycle 
7 
(+/- 3 
days) 
D1 
Cycle 
8 
(+/- 3 
days) 
D1 Cycle 
9 and 
every  
other 
cycle2 
(+/- 5 
days) 
 
D1  
  Cycle 9, 
and every 
4th cycle2 
 (+/- 5 days) 
 
 
Yrly3 
End of 
Treatment 
(+/- 7 days) 4 
Follow –up4 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History, PE5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Dermatologic exam 
X 
 
 
X 
 
X 
 
X 
 
X 6 
 
 
X6 
X6 
Ophthalmic exam 
X3 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Pregnancy Test7 
X 
 
Only if clinically appropriate7 
 
Hematology, serum 
chemistries, and LFTs8 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Coagulation studies9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
ECHO 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Patient Diary 
 
 
Review throughout study 
 
Concomitant Meds  
X 
Review throughout study 
 
X4 
 
Toxicity Assessment10 
X 
Review throughout study10 
 
X4 
X10 
Tumor measurement11 
X 
 
 
X 
 
X 
 
X 
 
X12 
 
 
 
 
Brain Scan11 
X 
 
Only if clinically indicated 
 
Tumor biopsy13 
X13 
At time of  or after  progression13 
 
 
 
LCCC1108 enrollment14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample15 
 
See footnote #15 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Key to Time and Events Table 6.1 Footnotes  
 
1Radiological assessments, physical, dermatologic and ophthalmic exams, EKG and ECHO, as well as laboratory evaluations including 
hematology, serum chemistries, and LFTs may be performed up to 3 weeks prior to day 1 of treatment.  Screening labs performed within 48 hours 
prior to Cycle 1 Day 1 do not need to be repeated on C1D1.  
 
2Treatment cycles are defined as every 21 days; study site visits are every other cycle after cycle 9. The study window for cycle 9 and beyond is 
+/-5 days. Please note: patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still 
experiencing clinical benefit (see section 4.1). Patients may continue on study and receive treatment for up to 3 years or death (whichever occurs 
first) with clinic visits and tumor evaluations as noted in table. 
 
3 a Repeat ophthalmic exams annually while on treatment and if clinically-indicated due to the presence of ocular symptoms. The exams will be 
performed one year after the day 1 cycle 8 visit +/- 2 months and every year thereafter until the patient is off treatment. See Appendix G (section 
11.7) for Ophthalmic Exam Worksheet.   
 
4The end of treatment visit should only occur when patients permanently stop study treatment and should be performed 30 days (+/-7 days) after 
the last dose of study medication. All adverse events and concomitant medications should be followed up until the 30-day End of Treatment (EOT) 
visit. Patients who have an ongoing ≥grade 2 or serious AE (SAE) at the EOT will continue to be followed until the event is resolved or deemed 
irreversible by the investigator. See section 6.5 for follow-up schedule for patients who discontinue study treatment due to progression or for other 
reasons.  
 
5Complete history at baseline only, thereafter focused history on symptoms/toxicity; physical exam to include height (baseline only), weight, and 
vital signs  
 
6Dermatologic exams will continue every 3 months for the first 6 months following discontinuation from dabrafenib, and should include 
monitoring for cutaneous and non-cutaneous secondary/recurrent malignancies.  
 
7Serum B-HCG within 48 hours prior to first dose of study medication for WOCBP; serum B-HCG will be repeated only if clinically appropriate. 
 
8Hematology: CBC with differential, Hgb, and platelet count; Serum chemistries: creatinine, sodium, potassium, calcium, magnesium, 
phosphorus, LDH and albumin. Liver function tests: total bilirubin, AST (SGOT) and ALT (SGPT). Also see sections 4.4.9.3 and 11.4 4 for 
required monitoring in event of liver toxicities, including possibility of blood draw for pharmacokinetics.  If screening evaluations of these tests 
are performed within 48 hours prior to Day 1 of treatment, they do not need to be repeated. 
 


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9Coagulation profile includes prothrombin time or INR, and activated partial thromboplastin time.  
 
10Toxicity assessment should include interrogation of the patient related to any visual changes they may be experiencing. Patients who have an 
ongoing ≥grade 2 or serious AE (SAE) at the time of discontinuation from treatment will continue to be followed until the event is resolved or 
deemed irreversible by the investigator.  
 
11Tumor imaging should remain consistent throughout study, and will include contrasted computed tomography (CT) scan of chest, abdomen and 
pelvis. These tests may be performed within 7 days prior to the study visit. At screening, a scan of the brain is required; MRI unless 
contraindicated, in which case a CT scan with contrast may be substituted. Beyond screening, a scan of the brain is not required but should be 
repeated if clinically indicated. For patients removed from treatment for reasons other than disease progression, follow-up tumor assessments (if 
available) should be documented until PD is confirmed. 
 
12  The frequency of tumor assessment scans reduced to every 12 weeks for subjects responding to combination therapy after cycle 9 
AND 
For subjects responding to combination therapy for > 2 years, reduce the frequency of disease assessment scans to every 6 months. 
 
 
13At baseline, if frozen tissue is unavailable from any site of disease, fresh tissue must be obtained. If possible, the pre-treatment biopsy should be 
performed after all other eligibility criteria are confirmed. Fresh tissue collection of accessible tumor will be repeated at progression whether 
patient continues treatment post progression or not. If possible, biopsies at progression should be performed within 7 business days of documented 
disease progression, and optimally within 4 hours of taking that day’s study medication. If treating physician decides to continue treatment 
because the patient exhibits continued clinical benefit from therapy (and the patient agrees) then the biopsy can be delayed until the investigator 
deems the biopsy feasible as long as patient safety is not compromised. Post-treatment biopsies will not be required for patients removed for 
reasons other than disease progression. See section 6.7 and laboratory manual. Please also see the note in section 6.9.3 regarding assessment of 
biopsied lesions per RECIST v1.1. NOTE: For subjects who are withdrawn from study treatment, but are later placed back on the 
trametinib/dabrafenib combination therapy, a biopsy may be collected from the former study subject at the time of progression from the standard 
of care trametinib/dabrafenib therapy.   These subjects must be re-consented and placed back on study to allow for attainment of a biopsy at 
progression. These subjects will then remain on study for safety monitoring, in relation to the biopsy procedure, for 30 days. Subjects who have an 
ongoing ≥grade 2 or serious AE (SAE) related to the study procedure at 30 days will continue to be followed until the event is resolved or deemed 
irreversible by the investigator. 
 
 
 


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14Document status of LCCC1108--if patients consent to co-enroll into LCCC1108, the Study Coordinator of LCCC1128 should coordinate tissue 
collection during biopsies with Study Coordinator of LCCC1108. See section 6.6 for additional information.   
 
15 For those patients who do and do not co-enroll into LCCC1108, we will ask for a blood sample (~8mLs) to ensure sufficient germline DNA in 
the event tissue samples are insufficient or request blood samples collected under LCCC9001 with IRB # 90-0573. . This request and collection 
may take place at any point during the study, including during follow-up. 
 
 
 


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6.2 
Pre-Study Assessments 
Please see section 6.7 regarding collection of a single blood sample at some point 
over course of study for germline DNA. 
 
Clinical evaluation:  complete history, physical examination (to also include vital 
signs, height, and weight), dermatologic exam (including full body skin exam), 
ophthalmic exam (See Appendix G (section 11.7) for Ophthalmic Exam Worksheet), 
and ECOG performance status.  
Laboratory studies:   
 Pregnancy Test: A serum pregnancy test (β-HCG) is required for all 
women of childbearing potential at screening within 48 hours prior to 
the first dose of study treatment.  Note: Postmenopausal women must 
have had amenorrhea for ≥12 months in order to be considered “of 
non-childbearing potential.”  This should be documented 
appropriately in the patient’s medical history. 
 Hematology: Hematology includes the following parameters: 
complete blood count (CBC) with differential, hemoglobin (Hgb), 
and platelet count. 
 Coagulation Profile: The coagulation profile includes prothrombin 
time or INR, and activated partial thromboplastin time.  
 Serum Chemistries and LFTs: These include the following 
parameters: creatinine, sodium, potassium, calcium, magnesium, 
phosphorus, LDH, albumin, total bilirubin, AST (SGOT) and ALT 
(SGPT) 
Cardiac monitoring:  12-lead ECG, ECHO (preferred) or MUGA 
Concomitant medications: Documentation of all concomitant medications, and in 
particular any prohibited drugs and drugs to be used with caution as listed in the 
appendices (see section 11.2).  NOTE: Patients will be given a list of medications 
that are prohibited and/or should be used with caution as a separate document.  
Patients will be informed that these drugs may interact with trametinib or 
dabrafenib, and may increase or decrease their toxicity.   
Patient Diary: Patients will be provided diary (as separate document) and 
instructed to record the time and date of each dose of study medication.  Diary 
will be reviewed during study visits. See Appendices, section 11.6, for a model 
diary. 
Toxicity assessment: Using NCI CTCAEv4 for baseline documentation 
Tissue acquisition: Sufficient frozen tissue remaining from diagnostic biopsy or willing 
to undergo biopsy for research purposes.  See section 6.7 and laboratory manual. 
Tumor measurement: Tumor measurement or imaging should remain consistent 
throughout study, and will include contrasted computed tomography (CT) scan of 
chest, abdomen and pelvis.  These tests may be performed ±7 days of the 
scheduled day.  At screening, an MRI of the brain is required. 
Brain scan: At screening, a scan of the brain is required; MRI unless 
contraindicated, in which case a CT scan with contrast may be substituted. 


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6.3 
Treatment Assessments  
6.3.1 Day 1 of each 3-week cycle until cycle 9, and then D1 of every odd numbered 
cycle thereafter 
Clinical evaluation: focused history, physical examination (to also include vital 
signs, and weight), and ECOG performance status.  
 
Laboratory studies:   
 Hematology: Hematology includes the following parameters: 
complete blood count (CBC) with differential, hemoglobin (Hgb), 
and platelet count. 
 Serum Chemistries and LFTs: These include the following 
parameters: creatinine, sodium, potassium, calcium, magnesium, 
phosphorus, LDH, albumin, total bilirubin, AST (SGOT) and ALT 
(SGPT). 
Concomitant medications: Review any additions or deletions   
Patient Diary: Review Diary 
Toxicity Assessment: Using NCI CTCAEv4; toxicity assessment should include 
interrogation of the patient related to any visual changes they may be experiencing.   
6.3.2 Day 1 of every other 3-week cycle starting with Cycle 3 until end of treatment 
Clinical evaluation: Dermatologic exam  
Tumor measurement: Tumor measurement or imaging should remain consistent 
throughout study, and will include contrasted computed tomography (CT) scan of 
chest, abdomen and pelvis.  These tests may be performed ±7 days of the 
scheduled day.  
 
Note: The frequency of tumor assessment scans reduced to every 12 weeks for 
subjects responding to combination therapy after cycle 9; For subjects responding 
to combination therapy for > 2 years, the frequency of disease assessment scans 
should be reduced to every 6 months.  
6.3.3 Day 1 of Cycles 3, 5, 9, 13 and every 4th cycle thereafter 
Cardiac monitoring:  12-lead ECG and ECHO  
 
6.3.4 At screening, annually and as clinically indicated 
Ophthalmic exam (See Appendix G (section 11.7) for Ophthalmic Exam Worksheet). The 
exams will be performed one year after the day 1 cycle 8 visit +/- 2 months and every year 
thereafter until the patient is off treatment. 
.  
6.4 
Continued Treatment after Disease Progression  
See section 6.8, correlative study procedures for more information.   


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6.5 
End of Treatment 
This visit should occur in patients when they permanently stop treatment for any 
reason, and should be performed 30 days (+/-7 days) after the last dose of study 
medication. 
 
Clinical evaluation:  complete history, physical examination (to also include vital 
signs and weight), and ECOG performance status.  
Laboratory studies:   
 Hematology: Hematology includes the following parameters: CBC 
with differential, Hgb, and platelet count. 
 Serum Chemistries: These include the following parameters: 
creatinine, sodium, potassium, calcium, magnesium, phosphorus, 
albumin, total bilirubin, AST (SGOT) and ALT (SGPT). 
Concomitant medications: Review any additions or deletions   
Patient Diary: Review Diary 
Toxicity Assessment: Using NCI CTCAEv4; Patients who have an ongoing grade 
4 or serious AE (SAE) at the time of discontinuation from treatment will continue 
to be followed until the event is resolved or deemed irreversible by the 
investigator, and will then be followed-up per protocol. Toxicity assessment 
should include interrogation of the patient related to any visual changes they may 
be experiencing.   
Tissue acquisition: Biopsy of accessible tumor will be done in patients who stop 
treatment due to progression, if possible within 7 business days of documented 
disease progression, and optimally within 4 hours of taking that day’s study 
medication.  Post-treatment biopsies will not be required for patients removed for 
reasons other than disease progression. See section 6.7 and laboratory manual. 
6.6 
Follow-up Assessments 
Patients who come off therapy due to progression will enter the follow-up phase 
every 3 months for up to 1 year from study entry to document survival (no tumor 
measurement per study protocol will be necessary after progression). Patients who 
come off therapy for reasons other than progression will enter the follow-up phase 
every 3 months for up to 1 year from study entry to document survival.  If tumor 
assessments are available for patients who have not yet experienced progressive 
disease (PD), enter the follow-up tumor evaluations in the eCRF until PD is 
confirmed.  Regardless, of the reason that a patient comes off treatment, 
dermatologic exams will continue every 3 months for the first 6 months following 
discontinuation from dabrafenib, and may be done by a physician local to the 
patient. Only after these dermatologic exams are complete is the patient 
considered off follow-up, even if they do not require survival follow-up for this 
entire 6 month period. 
 
Patients who have an ongoing ≥Grade 2 AE or SAE at the time of discontinuation 
from treatment will continue to be followed in clinic until the event is resolved or 
deemed irreversible by the investigator.   
 


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For subjects who are withdrawn from study treatment, but are later placed back on 
the trametinib/dabrafenib combination therapy, a biopsy may be collected from 
the former study subject at the time of progression from the standard of care 
trametinib/dabrafenib therapy.   These subjects will then remain on study for 
safety monitoring, in relation to the biopsy procedure, for 30 days. Subjects who 
have an ongoing ≥grade 2 or serious AE (SAE) related to the study procedure at 
30 days will continue to be followed until the event is resolved or deemed 
irreversible by the investigator. 
6.7 
Correlative Study Procedures 
For both those patients who do and do not co-enroll into LCCC1108, we will ask 
for a blood sample (~8mLs in a yellow-top ACD tube) to ensure sufficient 
germline DNA in the event tissue samples are insufficient. This request and 
collection may take place at any point during the study, including during follow-
up. 
 
At baseline, if patient does not have frozen tissue available, fresh tissue must be 
obtained by biopsy.  Biopsy of tumor will be repeated at or after progression 
(clinical or radiological) whether patient continues treatment post progression or 
not.  If possible, biopsies at progression should be performed within 7 business 
days of documented disease progression, and optimally within 4 hours of taking 
that day’s study medication. Please note that drug may be extended post 
progression (see section 4.1), and there is no need to hold drug for any length of 
time prior to the biopsy.  In fact, patients will be requested to remain on study 
medication until the biopsy at progression is performed. If the treating physician 
decides to continue treatment at progression because the patient exhibits 
continued clinical benefit from therapy, the biopsy may be delayed until the 
investigator deems the biopsy feasible as long as patient safety is not 
compromised Post-treatment biopsies will not be required for patients removed 
for reasons other than disease progression. See laboratory manual.  
 
Note: For subjects who are withdrawn from study treatment, but are later placed 
back on the trametinib/dabrafenib combination therapy, a biopsy may be collected 
from the former study subject at the time of progression from the standard of care 
trametinib/dabrafenib therapy.   These subjects must be re-consented and placed 
back on study to allow for attainment of a biopsy at progression.  
 
 
Biopsies may be obtained by punch biopsy, core biopsy, or surgical excision, and 
may be performed by clinical personnel trained to do biopsies for standard of care 
collections.  The number of - passes made through tumor per biopsy will be 
determined by the treating physician and the physician performing the biopsy 
procedure with primary consideration being safety.  The tissue collected will be 
divided into aliquots (depending on size of collection, up to 4 aliquots per 
collection).  For patients who co-enroll into LCCC1108 for NextGen sequencing, 
enough tissue will be collected for both kinomining and NextGen sequencing by 


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coordinating with the Study Coordinator of LCCC1108.   When insufficient tissue 
samples are available to achieve both kinomining and NextGen sequencing, 
priority will be given to kinomining.    Additional details regarding processing, 
storing and handling tissue will be provided in a separate laboratory manual.    
 
Biological samples collected for the study will be stored at the research 
laboratories at the Lineberger Comprehensive Cancer Center (LCCC), University 
of North Carolina at Chapel Hill, NC until the completion of the study.  With 
patient consent, any remaining tumor tissue after protocol specific studies are 
complete will be stored for future research concerning melanoma.  
6.7.1 Biopsy Risks 
The risks of these procedures are associated with a small risk of pain, bleeding, 
infection, and damage to adjacent organs.  The magnitude of this risk depends 
somewhat upon the site of the procedure.   
 
Potential risks according to site are: 
Skin/chest wall (punch biopsy or surgical excision):  
Likely: local discomfort and minor bleeding.  
Less likely: moderate or major bleeding, or infection 
 
 
Lymph node or soft tissue (punch biopsy or surgical excision): 
Likely: local discomfort and minor bleeding.  
Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, pneumothorax, 
damage to adjacent organs. Additional risks may be present if intravenous 
conscious sedation (IVCS) is required (see below). 
 
Liver (core needle biopsy): 
Likely: local discomfort and minor bleeding 
Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, bowel 
perforation or damage to adjacent organs 
Additional risks may be present if IVCS is required (see below). 
 
Breast (core biopsy): punch biopsy or surgical excision 
Likely: local discomfort and minor bleeding.  
Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, pneumothorax, 
damage to adjacent organs. 
 
In order to minimize the risk of a biopsy, only qualified personnel will perform 
these procedures.  Prior to the procedure, the physician performing the procedure 
will discuss the risks with each study participant, answer any questions, and 
obtain a separate procedure consent.  For biopsies of lesions that are not 
superficial and clearly palpable, imaging studies such as CT or ultrasound will be 


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used to guide the biopsy in order to minimize the risk of damage to adjacent 
structures.  Patients receiving therapeutic anticoagulation, and patients with 
abnormal coagulation studies, neutropenia, or thrombocytopenia will not undergo 
biopsy until and unless these resolve because of the increased risk of potential 
complications under these circumstances.  After lymph node biopsies, patients 
will be observed for approximately 2 hours (range 2-4 hours) after the procedure, 
or per institutional standard guidelines.  After liver biopsies, patients will be 
observed for approximately 4 hours (range 4-6 hours) after the procedure, or per 
institutional standard guidelines.  Less than the goal quantity of tissue is 
acceptable for each type of biopsy, and will be left to the clinical judgment of the 
physician performing the procedure.   
6.7.2 Risks of Anesthesia 
Local Anesthesia 
All biopsy procedures require local anesthesia using lidocaine or related 
compounds.  There is a small risk of an allergic reaction associated with these 
drugs. 
 
In order to minimize the risk of local anesthesia, only qualified personnel will 
perform the biopsy procedure.  Patients will be queried if they have had previous 
allergic reactions to local anesthetics.   
 
Intravenous Conscious Sedation (IVCS) 
Certain biopsy procedures, such as lymph node or liver biopsies, may require 
IVCS.  IVCS is a minimally depressed level of consciousness that retains the 
patient’s ability to maintain a patent airway independently and continuously and 
respond appropriately to physical stimulation and verbal commands.  The 
medications used to induce conscious sedation include the benzodiazepine 
midazolam and the opioid agonist fentanyl, as per standard of care.  IVCS is 
performed once over a 30-60 minute period, and may require administration of 
multiple doses of each agent over this time-frame.  Rarely, IVCS will last longer 
than 60 minutes.   
 
Midazolam: 
See http://www.drugs.com/pro/midazolam-injection.html for complete prescribing 
information on midazolam, including complete information on risks associated 
with its use.   
 
The risks of midazolam include respiratory depression and respiratory arrest, 
especially when used for sedation in non-critical settings.  Respiratory arrest 
could require intubation.  In very rare cases, when this was not recognized 
promptly and treated effectively, death or hypoxic encephalopathy has resulted.  
Other serious cardiorespiratory adverse events have occurred after administration 
of midazolam, including airway obstruction, oxygen desaturation, apnea, and 
cardiac arrest, rarely resulting in death or permanent neurologic injury.  There 
have also been rare reports of hypotensive episodes requiring treatment, 


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particularly in patients with hemodynamic instability.  Agitation, involuntary 
movements, hyperactivity and combativeness have been reported in adults 
patients treated with midazolam.   
 
Concomitant use of midazolam with other respiratory depressants like fentanyl 
may increase the risk of hypoventilation, airway obstruction, desaturation or 
apnea, and may contribute to profound and/or prolonged drug effect.    Prolonged 
sedation may also be seen midazolam is administered concomitantly with drugs 
known to inhibit the P450 3A4 enzyme system such as cimetidine, erythromycin, 
diltiazem, verapamil, ketoconazole and itraconazole.   
 
Adverse effects reported after intravenous administration of a single dose when 
used as a sedative include the following (percentage is percentage of adult 
patients with adverse events): hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), 
coughing (1.3%), “oversedation” (1.6%), headache (1.5%), and drowsiness 
(1.2%).  In addition, the following local effects at the site of the injection have 
been reported: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), 
induration (1.7%), and phlebitis (0.4%).   Additional rare (<1.0%) adverse events 
occurring when midazolam is used as a sedative include: 
Respiratory (laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, 
shallow respirations, airway obstruction, tachypnea); 
Cardiovascular (bigeminy, premature ventricular contractions, vasovagal episode, 
bradycardia, tachycardia, nodal rhythm); 
Gastrointestinal (acid taste, excessive salivation, retching); 
CNS/Neuromuscular (retrograde amnesia, euphoria, hallucination, confusion, 
argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence 
delirium or agitation, prolonged emergence from anesthesia, dreaming during 
emergence, sleep disturbance, insomnia, nightmares, athetoid movements, 
seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, 
paresthesia); 
Special Senses (blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic 
movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, 
loss of balance, light-headedness); 
Integumentary (hive-like elevation at injection site, swelling or feeling of burning, 
warmth or coldness at injection site); 
Hypersensitivity (allergic reactions including anaphylactoid reactions, hives, rash, 
pruritus); 
Miscellaneous (yawning, lethargy, chills, weakness, toothache, faint feeling, 
hematoma) 
 
Fentanyl  
See http://www.drugs.com/pro/fentanyl-injection.html for complete prescribing 
information on fentanyl (Duragesic®), including complete information on risks 
associated with its use.   
 


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Fentanyl may cause muscle rigidity, particularly involving the muscles of 
respiration.  Skeletal muscle movements in the extremities, neck and external eye 
have also been reported with fentanyl; rarely, these have been strong enough to 
pose patient management problems.  Fentanyl may also produce euphoria, miosis, 
bradycardia and bronchoconstriction, as seen with other narcotic analgesics.  The 
most common serious adverse reactions reported with fentanyl include respiratory 
depression, apnea, rigidity, and bradycardia.  If these remain untreated, 
respiratory arrest, circulatory depression or cardiac arrest could occur.  Other 
adverse reactions that have been reported are hypertension, hypotension, 
dizziness, blurred vision, nausea, emesis, laryngospasm and diaphoresis.   
 
The risks of IVCS also include inhibition of the gag reflex and concomitant risk 
of aspiration and allergic reactions to the sedative or analgesic medications.  The 
chances of serious risks from IVCS are small but real; for example, in a 
prospective study of 14,149 patients undergoing IVCS during upper 
gastrointestinal endoscopies, the rate of immediate cardiopulmonary events was 2 
in 1000.  The 30-day mortality was 1 per 2,000 cases.  In this study, there was a 
strong association between lack of monitoring and use of high-dose 
benzodiazepines with adverse outcomes.  There was also an association between 
the use of local anesthetic sprays to the oropharynx and the development of 
pneumonia. 
 
In order to minimize the risk of IVCS, only qualified personnel (M.D. and R.N) 
will be responsible for conscious sedation.  A minimum of two individuals will be 
involved in the care of patients undergoing conscious sedation—the physician 
performing the biopsy procedure, and the individual (R.N.) who monitors the 
patients and his/her response to both the sedation and the procedure, and who is 
capable of assisting with any supportive or resuscitative measures.  The room 
where the procedure utilizing IVCS takes place in the interventional radiology 
suite will have adequate equipment to provide supplemental oxygen, monitor vital 
signs, and maintain an airway should this be necessary.  An emergency cart will 
also be immediately accessible to the room where the procedure is to take place, 
and emergency support services will be available on page.  Patients will be 
screened and evaluated for their fitness to undergo conscious sedation by a trained 
physician.  Patients with active cardiac disease are excluded from this study.  No 
local anesthetic spray to the oropharynx will be necessary, given that endoscopy 
is not a planned procedure.  Following the procedure, patients will be observed 
closely in the recovery room according to standard institutional guidelines.  
 
 
Risks of Imaging Studies 
Some biopsy procedures require imaging studies, either to plan or guide the 
procedure.  Imaging studies that may be used in obtaining tissue samples include 
CT scans and ultrasound.  CT scans will expose study participants to controlled 
amounts of radiation.  The total dose of radiation from these tests is not 
anticipated to cause any adverse effects.  There is also a risk of an allergic 
reaction to the intravenous contrast dye used during CT imaging, as well as a risk 


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of experiencing feelings of anxiety or claustrophobia while undergoing a CT scan.  
There are no anticipated risks with the use of ultrasound. 
 
In order to minimize these risks, patients will be queried, as per standard 
institutional practice, regarding their history of reactions to intravenous contrast 
dye.  If a patient has had such a reaction, she/he will be premedicated, or dye will 
not be used, as per standard institutional practice.  If a patient has previously 
experienced anxiety or claustrophobia while undergoing a CT scan, she/he will be 
encouraged to discuss this with her primary oncologist.  Anxiolytics may be 
considered by the patient’s primary oncologist as indicated. 
6.8 
Assessment of Safety  
Any patient who receives at least one dose of study medication on this protocol 
will be evaluable for toxicity, with toxicity evaluated using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.0 available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
6.9 
Assessment of Primary Endpoint and Efficacy 
Provided sufficient tumor tissue is available pre and post treatment (specifically at 
progression) to perform kinomining, data from the patient will be utilized to 
inform the primary objective.  If a patient drops out of the study prior to 
progression, they may be replaced. See section 4.9 for additional information. For 
subjects who are withdrawn from study treatment, but are later placed back on the 
trametinib/dabrafenib combination therapy, a biopsy may be collected from the 
former study subject at the time of progression from the standard of care 
trametinib/dabrafenib therapy.   Information from these biopsies will be included 
in the analysis of the primary objective and the correlative secondary objective.  
 
 
Patients who have received at least 2 cycles of therapy and have their disease re-
evaluated after 2 cycles will be evaluable for assessment of objective response.   
Patients who drop out of the study prior to this point will not be evaluable for 
response unless their disease progressed prior to this point.     
6.9.1 Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
See the international criteria proposed by the Response Evaluation Criteria in 
Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) 
for additional details on RECIST1.1. 
 
Measurable disease will be defined as the presence of at least one measurable 
lesion that can be accurately measured in at least one dimension with the longest 
diameter a minimum size of: 
• >10mm by CT scan (CT scan slice thickness no greater than 5 mm) 


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• 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
• 20 mm by chest x-ray. 
 
For malignant lymph nodes to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5mm).  At 
baseline and in follow-up, only the short axis will be measured and followed.   
 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-
measurable lesions, will be considered non-measurable.  Lesions considered truly 
non-measurable include leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start 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 should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  Clinical lesions will only be considered measurable 
when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
6.9.2 Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline.   
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of 
the disease. 
 


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All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as “present” 
or “absent”, or in rare cases “unequivocal progression”.   
6.9.3 Evaluation of Target Lesions using RECIST 1.1 Criteria 
NOTE: Whenever possible, a biopsied lesion should not be considered a target 
lesion for RECIST tumor assessments.  If the biopsied lesion is the only site of 
measurable disease, it may only be followed as a target lesion if a core biopsy was 
performed.  Lesions that have been completely removed or subjected to excisional 
biopsy should not be followed as target lesions.   
 
NOTE: In addition to the information below, also see section 4.3.2 in the 
international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) for 
special notes on the assessment of target lesions.  
 
Complete response (CR)−Disappearance of all target lesions.  Any pathological 
lymph node (LN) target or no must have decreased in short axis to <10mm. 
 
Partial response (PR)−At least a 30% decrease in the sum of the LD of the target 
lesions taking as reference the baseline sum LD. 
 
Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the 
target lesions taking as reference the smallest sum LD recorded since the 
treatment started including baseline if that is the smallest on study.  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5mm.  The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD)−Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
6.9.4 Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target lesions and 
normalization of tumor marker levels.  All LN must be non-pathological in size 
(<10mm short axis).   
 
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one 
or more non-target lesion(s) or/and maintenance of tumor marker level above the 
normal limits. 
 
Progressive disease (PD)−Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 


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6.9.5 Evaluation of Best Overall Response using RECIST 1.1 Criteria 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment.    The best overall response will be defined 
according to the following table. 
 
Overall 
Response First 
Time Point 
Overall Response 
Subsequent Time 
Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
NE 
NE2 
NE2 
 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  Best 
response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
time point.  Under these circumstances, the original CR should be changed to PR and the best response is PR.  
2  NE=inevaluable  
 
7.0 
ADVERSE EVENTS 
7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 


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7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
77 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event.  
• All events of possible drug-induced liver injury with 
hyperbilirubinaemia defined as ALT ≥3xULN and bilirubin ≥ 2xULN 
(>35% direct) (or ALT ≥ 3xULN and INR>1.5, if INR measured) or 
termed ‘Hy’s Law’ events (INR measurement is not required and the 
threshold value stated will not apply to patients receiving 
anticoagulants).NOTE: bilirubin fractionation is performed if testing 
is available. If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick indicating direct bilirubin elevations and 
suggesting liver injury. If testing is unavailable and a subject meets the 
criterion of total bilirubin ≥ 2xULN, then the event is still reported as 
an SAE. If INR is obtained, include values on the SAE form. INR 
elevations >1.5 suggest severe liver injury. 
• Any new primary cancers and treatment emergent malignancies 
(including squamous cell carcinoma and new primary melanoma) with 
the exception of basal cell carcinoma (BCC).  BCC should be reported 
as an AE or SAE based on the discretion of the investigator. 
• Symptomatic LVEF decrease that meets stopping criteria or 
asymptomatic LVEF decrease that does not recover, as outlined as 
LVEF guidance (Section4.4.3.3) 
• Retinal pigment epithelial detachment (RPED) or retinal vein 
occlusion (RVO) 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
In addition to the above, cases of fever with rigors or fever with hypotension 
should be reported as SAEs (regardless of whether or not hospitalization was 
required). 
7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is 
discontinued.   
 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
78 
Collected information should be recorded in the Electronic Case Report Forms 
(eCRF) for that patient.  Please include a description of the event, its severity or 
toxicity grade, onset and resolved dates (if applicable), and the relationship to the 
study drug.    Documentation should occur at least monthly.  
7.3 
SAEs or Serious SARs  
7.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout, or no treatment run-
in).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30 day follow-up period after treatment is discontinued.  
7.3.2 Documentation and Notification 
These events (SAEs or Serious SARs) must be recorded in the SAE console 
within Oncore™ for that patient within 24 hours of learning of its occurrence.  
For Affiliate sites, an email must also be sent to the NCCN Study Coordinator 
indicating that an SAE or Serious SAR has been entered into Oncore (email 
contact will be provided at study start-up).  
7.3.3 Reporting  
IRB Reporting Requirements: 
UNC: 
The UNC IRB will be notified of all SAEs that qualify as an Unanticipated 
Problem as per the UNC IRB Policies using the IRB’s web-based reporting 
system within 7 days of the Investigator becoming aware of the problem. Please 
note, these events must be reported to the sponsor within 24 hours of learning of 
the occurrence.  
Affiliate sites:   
• For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 
• For affiliate sites relying on the UNC-IRB, the UNC IRB will be notified 
of all SAEs that qualify as an Unanticipated Problem as per the UNC IRB 
Policies using the IRB’s web-based reporting system within 7 days of the 
Investigator becoming aware of the problem. Please note, these events 
must be reported to the sponsor within 24 hours of learning of the 
occurrence. 
 
 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
79 
Novartis Reporting Requirements: 
The principal investigator has the obligation to report all serious adverse events to 
the FDA (if applicable), IRB, and Novartis Pharmaceuticals Drug Safety and 
Epidemiology Department (DS&E) (For patients taking Novartis drugs). 
All events reported to the FDA by the investigator are to be filed utilizing the Form 
FDA 3500A (MedWatch Form), if applicable 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment must be reported to Novartis within 24 hours 
of learning of its occurrence. Information about all SAEs is collected and recorded 
on a Serious Adverse Event Report Form.  The investigator must assess and record 
the relationship of each SAE to each specific study treatment (if there is more than 
one study treatment), complete the SAE Report Form in English, and send the 
completed, signed form along with the Novartis provided fax cover sheet to the 
Novartis Oncology Drug Safety and Epidemiology (DS&E) department by fax 
(fax: 877-778-9739) within 24 hours. 
Any additional information for the SAE including complications, progression of 
the initial SAE, and recurrent episodes must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An 
SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
Any SAEs experienced after the 30 day safety evaluation follow-up period should 
only be reported to Novartis if the investigator suspects a causal relationship to the 
study treatment.   
Follow-up information is submitted in the same way as the original SAE Report.  
Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study treatment, 
an oncology Novartis Drug Safety and Epidemiology (DS&E) department associate 
may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform 
all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees 
in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
 
 


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CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
80 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be reported by the investigator to the Novartis Oncology Drug 
Safety and Epidemiology Department (DS&E) by fax (fax: 877-778-9739). 
Pregnancy follow-up should include an assessment of the possible relationship to 
the study treatment and any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who 
took study treatment in this study. Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother. 
 
 
 
FDA Expedited Reporting requirements for studies conducted under an IND: 
A sponsor must report any suspected adverse reaction that is both serious and 
unexpected and related to the cellular product to the FDA. The sponsor must report 
an adverse event as a suspected adverse reaction only if there is evidence to suggest 
a causal relationship between the cellular product and the adverse event, such as: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with cell infusion exposure (e.g., angioedema, hepatic injury, 
Stevens-Johnson Syndrome); 
• One or more occurrences of an event that is not commonly associated with 
cellular product exposure, but is otherwise uncommon in the population 
exposed to the cellular product (e.g. tendon rupture); 
• An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of cellular product therapy) that indicates those events occur 
more frequently in the cell infusion treatment group than in a concurrent or 
historical control group. 
 
The sponsor must submit each IND safety report on a MedWatch form. Each 
notification to FDA must bear prominent identification of its contents, i.e., “IND 
Safety Report,” and must be transmitted to the review division that has the 
responsibility for review of the IND. For this study, the review division is the 
Center for Drug Evaluation and Research. In each IND safety report, the sponsor 
must identify all IND safety reports previously submitted to FDA concerning a 
similar suspected adverse reaction, and must analyze the significance of the 
suspected adverse reaction in light of previous, similar reports or any other relevant 
information.  
 
Timing 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
81 
FDA must be notified of potential serious risks within 15 calendar days after the 
sponsor determines the event requires reporting. FDA must be notified of 
unexpected fatal or life-threatening suspected adverse reactions as soon as possible 
but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information. The sponsor must be notified of the SAE by the investigator within 24 
hours of the event. If the results of a sponsor’s investigation show that an adverse 
event not initially determined to be reportable is reportable, the sponsor must report 
such suspected adverse reaction in an IND safety report as soon as possible, but in 
no case later than 15 calendar days after the determination is made. 
 
Follow-up 
The sponsor must promptly investigate all safety information it receives. Relevant 
follow-up  information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., “Follow-up IND Safety 
Report.” Additionally, upon request from FDA, the sponsor must submit to FDA 
any additional data or information that the agency deems necessary, as soon as 
possible, but in no case later than 15 calendar days after receiving the request.  
 
Notification of Investigators 
The sponsor must notify all participating investigators (i.e., all investigators to 
whom the sponsor is providing cell infusion under its INDs or under any 
investigator’s IND) in an IND safety report of potential serious risks, from clinical 
trials or any other source, as soon as possible, but in no case later than 15 calendar 
days after the sponsor determines that the information qualifies for reporting.  
 
Process 
If the sponsor deems that an event is both a serious adverse reaction (SAR) AND 
unexpected, it must also (in addition to Oncore) be recorded on the MedWatch Form 
3500A as per 21 CFR 312.32. Unexpected adverse events or adverse reaction refers 
to an event or reaction that is not listed in the Investigator’s Brochure or is not listed 
at the specificity or severity that has been observed; or if an investigator’s brochure 
is not required or available, is not consistent with the risk information described in 
the general investigation plan or elsewhere in the current IND application.   
 
The MedWatch form should be submitted on MedWatch by the study coordinator.  
 
The 
MedWatch 
3500a 
form 
can 
be 
accessed 
at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.  
 
(Please be sure and access form 3500a, and not form 3500).  
 
The MedWatch form should also be sent to the UNC Regulatory Associate and the 
IND Specialist within 48 hours of the sponsor being aware of the event.  The 
Regulatory Associate with the aid of the IND Specialist will submit the IND Safety 
Report via IND serial submission to the FDA review division. 
 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
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Additional Reporting Requirements 
The following additional items must be reported via IND safety report: 
• Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor, that suggest a significant risk to humans 
exposed to the cell infusion.  
• Findings from animal or in vitro testing. The sponsor must report any 
findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the cell 
infusion, such as reports of mutagenicity, teratogenicity, or 
carcinogenicity, or reports of significant organ toxicity t or near the 
expected human exposure. 
• Increased rate of occurrence of serious suspected adverse reactions. 
 
Additional Guidance 
Please refer to 21CFR312.32 and “Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies” for additional information 
and reporting requirements. All IND Safety Reports will be submitted in accordance 
with these regulations/guidances.  
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as study coordinators, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight of the Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
83 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size and Data Analysis Plans 
Our sample size justification is based on the primary objective to identify kinases 
which are differentially expressed between pre (just prior to treatment initiation) 
and post treatment (patients who developed resistance) after treatment with 
BRAF+MEK inhibition in melanoma patients.  
 
The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled 
with mass spectrometry. We anticipate this technique to capture between 50 – 100 
kinases in melanoma patients. The kinase activity is reported as a quant ratio 
between the experimental and control samples. The Paragon algorithm[10] 
automatically identifies high confidence peptides that will contribute to the 
average quant ratio of a kinase. Our sample size justification is based on our 
ability to detect a meaningful difference in the kinase activity between pre and 
post treatment.  The inherent matching of tumor by patient source pre and post 
treatment will provide a potential source of positive correlation that may be 
exploited to improve statistical power (e.g., using a paired t-test).  However, in 
order to be conservative, we compute our statistical power using a two-tailed 
independent Mann-Whitney test in which the kinase activity is compared in the 
two groups. Based on preliminary data, we assume that 100 kinases are captured, 
of which 10% of them are truly differentially expressed between pre and post 
treatment and a common standard deviation of 0.95 (in log2 scale).   
 
Table 1 summarizes the power to detect a true difference of D with a sample size 
of 20 tumors in each group (pre and post treatment) at FDR of 0.05 to account for 
multiple testings. For example, we achieve a power of 0.92 to detect a log2 
difference of 1.32 (or a fold change of 2.5) for each kinase between pre and post 
treatment.   
 
Table 1: Power calculation to detect kinase difference 
D=Difference in 
log2 scale 
1.00 
1.32 
1.58 
1.81 
Fold change (2D) 
2 
2.5 
3 
3.5 
Power 
0.59 
0.92 
0.99 
1.00 
 
Data Analysis Plans 
Exploratory tools such as heatmaps and two-way unsupervised hierarchical 
clustering will be utilized as visual representation of overall kinome activity. The 


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UNIVERSITY OF NORTH CAROLINA 
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univariate analysis of kinase expression will be carried out to identify 
differentially expressed kinases after FDR adjustment. Since multiple kinases 
work in concert to regulate their functions, prediction analysis of microarrays 
(PAM) based on nearest shrunken centroid [9] will also be carried out to identify 
a subset of kinases that predicts resistance to BRAF+MEK inhibition. We also 
plan to utilize the kinome pathway as prior information in the analysis for 
identifying functionally related kinase sets to improve statistical power. Focusing 
on kinase sets may yield more reproducible and interpretable results. 
 
Fisher’s exact test will be carried out to test for association between the mutations 
at baseline to mutations upon the development of resistance to BRAF + MEK 
inhibition in each oncogene/tumor suppressor gene. Tumor samples from patients 
who progress while on study and those who are removed from study and who 
later progress on the combination treatment will be analyzed as one data set. The 
p-values will be adjusted via FDR to account for multiple comparisons.  
 
The response rate will be estimated and 95% confidence interval will be 
computed. Progression-free survival will be evaluated using the Kaplan-Meier 
method.  All demographic and analytic data will be summarized by descriptive 
statistics.  Categorical data will be summarized using frequency tables whereas 
summary statistics such as means, medians, standard deviation and range will be 
provided for continuous data.   
 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
85 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation  
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Financial Disclosures 
• Executed clinical research contract 
9.3 
Registration Procedures 
All patients must be registered with the CPO at the University of North Carolina 
before enrollment to study.  For UNC patients, prior to registration, eligibility 
criteria must be confirmed with the UNC Study Coordinator. To register a patient, 
call the Oncology Protocol Office at 919-966-4432 Monday through Friday, 
9:00AM-5:00PM.  
 
For Affiliate patients, please contact the UNCCN Study Coordinator to ensure 
there is an opening available on the study for the potential subject (direct line 919-
966-7359), Monday through Friday, 9:00AM-5:00PM. To register a patient, 
please fax registration forms and eligibility documents to 919-966-4300.  
9.4 
Data Management and Monitoring/Auditing 
The CPO UNCCN of the UNC LCCC will serve as the coordinating center for 
this trial. Data will be collected through a web based clinical research platform, 
OnCore®.  Other study institutions will be given a password to directly enter their 
own data onto the web site via electronic case report forms (eCRFs).  UNCCN 
personnel will coordinate and manage data for quality control assurance and 
integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC and participating institutions.  The 
investigators at each site will allow monitors to review all source documents 
supporting data entered into OnCore®.   The UNCCN Data Coordinator can be 
reached at 919-843-2742 or 1-877-668-0683. 


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UNIVERSITY OF NORTH CAROLINA 
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                            November 22, 2017 
86 
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center compliance committee every six to twelve months depending on 
Affiliate site participation.  
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.5.1 Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior 
UNC or their respective institution’s IRB/IEC approval/favorable opinion.   
 
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.  
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
• To UNC Principal Investigator for agreement  
• The Affiliate institution’s IRB for review and approval.  (Once 
IRB’s response is received, this should be forwarded to the 
UNCCN Regulatory Associate). 
9.5.2 Single Patient/Subject Exceptions 
9.5.3 Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if 
proper regulatory review has been completed in accordance with Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy. .Other 
Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  


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UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
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• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the UNCCN Study Coordinator 
within 5 days. UNC-CH will determine if the violation affects the safety of the 
patient and integrity of the data.  Once your institution’s IRB response is received, 
please forward to the UNCCN Regulatory Associate. 
 
Unanticipated Problems: 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the UNCCN Study Coordinator.   The 
UNCCN Study Coordinator will report the event to the UNC IRB using the IRB’s 
web-based reporting system.  Examples of such UPs include a lost or stolen 
laptop computer that contains sensitive study information. 
 


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UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
88 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their 
institution’s IRB for approval.  For multi-center studies, any affiliate site must 
submit their informed consent revisions to the UNCCN Regulatory Associate 
prior to submission to their IRB.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 


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CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
89 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all eCRFs will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
10.0 REFERENCES  
 
1. 
Jemal, A., et al., Cancer statistics, 2010. CA Cancer J Clin, 2010. 60(5): p. 277-
300. 
2. 
NCCN. NCCN Practice Guidelines in Oncology for Melanoma. 2012; Version 
4.0:[ 
3. 
Flaherty, K.T., et al., Inhibition of mutated, activated BRAF in metastatic 
melanoma. N Engl J Med, 2010. 363(9): p. 809-19. 
4. 
GlaxoSmithKline, GSK1120212 (Trametinib)  Investigator's Brochure. 2013. 
Version 05. 
5. 
GlaxoSmithKline, Dabrafenib (GSK2118436) Investigators Brochure. 2014. 
6. 
GlaxoSmithKline, GSK1120212 + GSK2118436 Investigator's Brochure. 2014. 
7. 
Duncan, J.S., et al., Dynamic Reprogramming of the Kinome in Response to 
Targeted MEK Inhibition in Triple-Negative Breast Cancer. Cell, 2012. 149(2): p. 
307-21. 
8. 
Infante JR, F.G., Lawrence JS et al., Phase I/II study to assess safety, 
pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 
(GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 
(GSK436). J Clin Oncol, 2011. 29(suppl; abst CRA8503). 
9. 
Chan M, H.L., Menzies A et al., Clinical characteristics and survival of BRAF-
mutant (BRAF+) metastatic melanoma patients (pts) treated with BRAF inhibitor 
(BRAFi) dabrafenib or vemurafenib beyond disease progression (PD). J Clin 
Oncol, 2013. 31(suppl): p. abstract 9062. 
10. 
Shilov, I.V., et al., The Paragon Algorithm, a next generation search engine that 
uses sequence temperature values and feature probabilities to identify peptides 
from tandem mass spectra. Mol Cell Proteomics, 2007. 6(9): p. 1638-55. 
 
 
 
 
 
 
 


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CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
90 
11.0  APPENDICES 
11.1 
Appendix A Grading of Visual Changes 
 
Grade* 
Description 
1 
Asymptomatic or symptomatic but not limiting activities of daily living 
(ADL); clinical or diagnostic observations only; intervention not indicated 
2 
Symptomatic with moderate decrease in visual acuity (20/40 or 
better);  limiting instrumental ADL;  local or noninvasive intervention 
indicated (e.g., topical or oral agents) 
3 
Symptomatic with marked decrease in visual acuity  or marked visual field 
defect (worse than 20/40 but better than 20/200 in the affected eye); Severe 
pain or medically significant but not immediately sight-threatening; operative 
intervention indicated; disabling; limiting self-care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness 
(20/200 or worse) in the affected eye 
*based on NCI CTCAE v4 
 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
91 
11.2 
Appendix B Prohibited Drugs, and Drugs to be used with Caution  
11.2.1 PROHIBITED MEDICATIONS (also see section 4.5.1) 
• Anti-retroviral drugs (e.g., ritonavir, saquinavir, atazanavir) 
• All herbal supplements including but not limited to St. John’s wort, 
kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, or ginseng.  Grapefruit juice must 
also be avoided. 
 
OTHER PROHIBITED MEDICATIONS1 
Strong CYP2C8/3A/Pgp/Bcrp 
Inhibitor/Inducer 
Therapeutic Area 
clarithromycin, telithromycin, rifamycin class 
agents (e.g.  rifampin, rifabutin, rifapentine), 
troleandomycin 
Antibiotics 
itraconazole, ketoconazole, posaconazole, 
voriconazole 
Antifungals 
nefazodone 
Antidepressants 
gemfibrozil  
Hyperlipidemia 
carbamazepine, oxcarbamazepine, 
phenobarbital, amiodarone,  phenytoin, s-
mephenytoin, bosentan, mibefradil, modafinil, 
conivaptan, topiramate 
Miscellaneous 
pioglitazone, troglitazone 
Antidiabetics 
cyclosporine 
Immunosuppressive 
agents 
1This list may be modified based on emerging data. 
 
 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
92 
11.2.2 MEDICATIONS TO BE USED WITH CAUTION (also see section 4.5.2) 
USE WITH CAUTION: since concentrations of dabrafenib may be increased 
Class/Therapeutic Area 
Mild/Moderate CYP3A, CYP2C8, Pgp or BCRP Inhibitors 
Antiarrhythmics 
Diltiazem, verapamil 
Antibiotic 
Erythromycin, trimethoprim 
Antifungal 
Fluconazole 
Miscellaneous 
Aprepitant, cimetidine, montelukast, glitazones, quercetin 
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy.  Monitor subjects for loss of efficacy or substitute with another medication. 
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19 Substrates that May 
be Affected by Induction  
Analgesics 
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, oxycodone 
Antiarrhythmics 
Disopyramide, dronedarone, mexiletine, propafenone, quinidine 
Antibiotics 
Chloramphenicol, doxycycline, erythromycin, moxifloxacin  
Anticoagulants/ Antiplatelets 
Cilostazole, warfarin 
Anticonvulsants 
Divalproex, lamotrigine, valproate, zonisamide 
Antidepressants and Antipsychotics 
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone, amitriptyline, clomipramine, imipramine 
Antidiabetics 
Glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, repaglinide, 
rosiglitazone 
Antifungals 
Caspofungin, fluconazole, terbinafine 
Antihistamines 
Astemizole, chlorpheniramine, ebastine 
Antihypertensives 
Amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, nilvadipine, nisoldipine, 
nitrendipine, propanalol, verapamil 
Antimigraine Agents 
Cafergot, diergotamine, eletriptan, ergotamine 
Corticosteroids 
Dexamethasone, hydrocortisone, methylprednisolone, oral budesonide 
Erectile Dysfunction Agents 
Sildenafil, tadalafil, vardenafil 
HMG-CoA Reductase Inhibitors 
Atorvastatin, cerivastatin, lovastatin, simvastatin 
Hypnotics and Sedatives 
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, zolpidem, 
zopiclone 
Immunosuppressants 
Everolimus, sirolimus, tacrolimus 
Miscellaneous 
Aprepitant, cisapride, chloraquine, darifenacin, dextromethorphan, domperidone, 
disopyramide, finasteride, leflunomide, methohexital, nateglinide, ondansetron, 
oral contraceptives, pimoide, quinine, ranitidine, risperidone, salmetrol, solifenacin, 
sulfasalazine, testosterone, torisel, tramadol, tolvaptan, zaleplon, ziprasidone, 
Selective Aldosterone Blockers 
Eplerenone 
Abbreviations: BCRP = breast cancer resistance protein; CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme 
A; Pgp = p-glycoprotein. 
 
 
 
 
 


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CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
93 
11.3 
Appendix C AEs of Special Interest in Study BRF113220 
 
 
Combination Therapy 
Monotherapy 
Dabrafenib + Trametinib 
Trametinib 
Dabrafenib 
Part C 
Pooled 
ISS 
ISS 
Part C 
Dabrafenib 
150mg PO BID 
150mg PO 
BID 
 
150mg PO 
BID 
150mg PO 
BID 
Trametinib 
2mg PO QD 
2mg PO QD 
2mg PO QD 
 
 
N 
55 
202 
329 
586 
53 
Trametinib 
category, n (%) 
50 (91) 
146 (72) 
308 (94) 
323 (55) 
40 (75) 
Skin-related 
toxicities 
36 (65) 
107 (53) 
288 (88) 
262 (45) 
36 (68) 
Diarrhea 
20 (36) 
54 (27) 
162 (49) 
91 (16) 
15 (28) 
Ocular events 
14 (25) 
40 (20) 
42 (13) 
46 (8) 
8 (15) 
Hepatic events 
8 (15) 
29 (14) 
42 (13) 
36 (6) 
2 (4) 
Cardiac-related 
events 
5 (9) 
15 (7) 
31 (9) 
13 (2) 
0 
Hypertension 
5 (9) 
16 (8) 
48 (15) 
11 (2) 
2 (4) 
Pneumonitis 
0 
0 
6 (2) 
0 
0 
Dabrafenib 
category, n (%) 
46 (84) 
138 (68) 
63 (19) 
287 (49) 
28 (53) 
Pyrexia 
42 (76) 
127 (63) 
48 (15) 
194 (33) 
17 (32) 
CuSCC 
4(7) 
12 (6) 
1 (<1) 
64 (11) 
10 (19) 
PPES 
4 (7) 
10 (5) 
12 (4) 
81 (14) 
0 
Renal failure 
4 (7) 
8 (4) 
6 (2) 
7 (1) 
0 
Other treatment 
emergent 
malignancies 
1 (2) 
3 (1) 
1 (<1) 
6 (1) 
0 
New primary 
malignant 
melanoma 
0 
1 (<1) 
0 
7 (1) 
1 (2) 
Uveitis 
0 
2 (<1) 
0 
6 (1) 
0 
 
 
 


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CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
94 
11.4 
Appendix D Liver Events 
11.4.1 Liver Event Follow Up Assessments  
For subjects meeting any of the liver chemistry criteria 1 – 5 listed in Section 
4.4.8, make every attempt to carry out the liver event follow up assessments 
described below: 
 
• Viral hepatitis serology including: 
o Hepatitis A IgM antibody 
o Hepatitis B surface antigen 
o Hepatitis B Core Antibody (IgM)  
o Hepatitis C RNA  
o Cytomegalovirus IgM antibody   
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing)   
o Hepatitis E IgM antibody. 
• Blood sample for pharmacokinetic (PK) analysis, obtained within 10 days 
of last dose.  Record the date/time of the PK blood sample draw and the 
date/time of the last dose of study treatment prior to blood sample draw on 
the eCRF.  If the date or time of the last dose is unclear, provide the 
subject’s best approximation.  If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample.  If a PK analysis is required 
in the event of liver toxicity, GSK should be contacted immediately and 
supplies and instructions for collection will be sent as soon as possible. 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin ≥2xULN. 
• Obtain complete blood count with differential to assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia as relevant on the AE eCRF. 
Please note that treatment with trametinib often associates with rash which 
is usually acneiform and affects the scalp, face, neck, chest, and upper 
back. Discuss with study PI as needed. 
• Record use of concomitant medications, acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the 
concomitant medications report form. 
• Record alcohol use on the liver event alcohol intake eCRF 


LCCC1128 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
95 
• The following assessments are required for subjects with ALT ≥3xULN 
and bilirubin ≥2xULN (>35% direct) but are optional for other abnormal 
liver chemistries: 
o Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-
liver kidney microsomal antibodies 
o Liver imaging (ultrasound, magnetic resonance, or computerized 
tomography) to evaluate liver disease. 
11.4.2 Drug Restart/Rechallenge Following Liver Events that are Possibly Related 
to Study Treatment 
Approval by Study PI for study treatment restart can be considered where: 
• The subject is receiving compelling benefit, benefit of drug restart exceeds 
risk, and no effective alternative therapy is available.  Institutional Review 
Board approval of study treatment restart/rechallenge must be obtained. 
• If the restart/rechallenge is approved by the IRB, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver 
injury or death.   
• The subject must also provide signed informed consent specifically for the 
study treatment restart/rechallenge.  Documentation of informed consent 
must be recorded in the study chart.   
• Subjects must then return to the clinic twice a week for liver chemistry 
tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol.  
11.4.3 Drug Restart Following Transient Resolving Liver Events Not Related to 
Study Treatment  
Approval by study PI for drug restart can be considered where: 
• Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3xULN).  Institutional Review Board approval 
of study treatment restart/rechallenge must be obtained, as required. 
• If restart of study treatment is approved by the IRB, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver 
injury or death.   
• The subject must also provide signed informed consent specifically for the 
restart.  Documentation of informed consent must be recorded in the study 
chart.   
• Subjects must return to the clinic once a week for liver chemistry tests 
until stable liver chemistries have been demonstrated, and then laboratory 
monitoring may resume as per protocol. If protocol defined stopping 
criteria for liver chemistry elevations are met, study treatment must be 
stopped. 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
96 
11.5 
Appendix E Supportive Care and Preventive Measures for Rash 
 
Type of Care 
Action 
Prevention/Prophylaxisa 
 
• 
Avoid unnecessary exposure to sunlight 
• 
Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily. 
• 
Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily. 
• 
Topical steroids and antibiotics should be applied at least twice daily 
starting on Day 1 of study treatment, to body areas such as face, 
chest, and upper back.   
• 
Use mild-strength topical steroid  (hydrocortisone 1% cream)  
or 
• 
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptomatic Careb  
• 
Pruritic lesions: cool compresses and oral antihistamine therapies  
• 
Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide 
cream  
• 
Desquamation: thick emollients and mild soap  
• 
Paronychia: antiseptic bath, local potent corticosteroids in addition to 
oral antibiotics; if no improvement, consult dermatologist or surgeon  
• 
Infected lesions: appropriate bacterial/fungal culture-driven systemic 
or topical antibiotics  
Abbreviations:  BID = twice daily; SPF = skin protection factor 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management 
 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
97 
11.6 
Appendix F: Model Patient Diary for Compliance* 
NOTE: For dabrafenib, please revise model to account for twice daily dosing: 
 
Patient ID: ____________ 
 
 
 
Institution: ____________ 
 
Assigned Dose (mg): __________ 
 
 
Number of tablets per dose: _______ 
 
While you are on study, please record the date and time you take your ________ for each 
dose, and the number of tablets taken at each dose.  Please bring this diary to each 
appointment with your study doctor.   You should take your daily dose at the same time 
each day.   
 
Sunday  
Monday 
Tuesday 
Wednesday Thursday Friday 
Saturday 
 
# pills 
taken ___ 
 
 
Time: 
 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills  
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
 
Time: 
 
# pills 
taken ___ 
 
Time: 
 
 
 
# pills 
taken ___ 
 
Time: 
 
# pills 
taken ___ 
 
Time: 
 
# pills  
taken ___ 
 
Time: 
 
# pills  
taken ___ 
 
Time: 
 
# pills  
taken ___ 
 
Time: 
 
# pills 
taken ___ 
 
Time: 
 
Patient Signature:__________________________________ 
 
*This diary may be revised per institutional guidelines or standards. 
 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
98 
11.7 
Appendix G. Ophthalmic Exam Source Worksheet 
Subject Name:_________________________________________________ 
Note to examiner:  Please assess particularly for visible retinal pathology. 
* Optical coherence tomography is highly recommended  For patients in whom retinal abnormalities are 
noted, color fundus photos, and fluorescein angiography if clinically indicated, are recommended.   
 
OPHTHALMIC EXAMINATION 
1. Date of Examination: 
 
 
 
 
   
_ _/_ _ _ /_ _ _ _ 
   dd  /   mmm   /    yyyy 
VISUAL ACUITY 
Enter corrected visual acuity 
OD: 
 
OS: 
TONOMETRY 
Enter IOP (mmHg) 
 
OD: 
OS: 
INDIRECT FUNDOSCOPY 
Indirect Exam: Indicate 
normal or specify 
abnormalities 
OD: 
OS: 
CONFRONTATION VISUAL FIELD EXAM  OR AUTOMATED PERIMETRY 
(e.g., Humphrey 24-2 or 30-2 or equivalent if using a non-Humphrey instrument) 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
OPTICAL COHERENCE TOMOGRAPHY (strongly recommended) 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
COLOR FUNDUS PHOTOS (recommended if retinal abnormalities are noted)* 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
FLORESCEIN ANGIOGRAPHY (suggested if retinal abnormalities are noted 
and test clinically indicated)* 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
Were any of the following noted on ocular history or exam? 
Yes No 
History of CSR? 
 
 
Evidence of new optic disc cupping? 
 
 
Evidence of new visual field defects? 
 
 
EXCLUSION CRITERIA 
Yes No 
History of RVO? 
If yes, patient is not eligible for the study. 
 
 
Signature of Examiner: _____________________________   
Printed Name: _________________________      Date: ____________ 
 


LCCC1128 
 
CONFIDENTIAL 
PI: Carrie Lee, MD MPH 
UNIVERSITY OF NORTH CAROLINA 
Amendment 05 
                            November 22, 2017 
99 
11.8 
Appendix H AEs of Special Interest in Study MEK115306 
AEs of Special Interest 
Category 
Dabrafenib+Trametinib 
(n=209) 
Dabrafenib + Placebo (n=211) 
Subjects with Any Event 
Maximum Grade 
 
Maximum Grade 
 
Grade 3 
Grade 4 
Any Grade 
Grade 3 
Grade 4 
Any Grade 
Pyrexia 
13(6) 
0 
116(56) 
4(2) 
0 
65(31) 
Skin-related toxicities 
0 
0 
84 (40) 
4(2) 
0 
98(46) 
Diarrhea 
2(<1) 
0 
51(24) 
2(<1) 
0 
30(14) 
Hypertension 
8(4) 
0 
46(22) 
10(5) 
0 
29(14) 
Edema 
2(<1) 
0 
37(18) 
1(<1) 
0 
12(6) 
Hemorrhages 
2(<1) 
1(<1) 
35(17) 
3(1) 
 
27(13) 
Hepatic Events 
10(5) 
0 
28(13) 
2(<1) 
 
15(7) 
Ocular Events 
2(<1) 
0 
22(11) 
0 
 
23(11) 
Neutropenia 
8(4) 
1(<1) 
22(11) 
1(<1) 
  
4(2) 
Hypersensitivity 
0 
0 
12(6) 
0 
0 
6(3) 
Hyperglycemia 
4(2) 
0 
13(6) 
1(<1) 
0 
2(<1) 
Cardiac Related Events 
1(<1) 
0 
9(4) 
1(<1) 
0 
7(3) 
Renal Failure 
2(<1) 
0 
7(3) 
0 
0 
4(2) 
cuSCC 
4(2) 
0 
5(2) 
7(3) 
1(<1) 
20(9) 
Basal Cell Carcinoma 
3(1) 
0 
4(2) 
5(2) 
0 
8(4) 
Pneumonitis 
0 
0 
1(<1) 
0 
0 
0 
Non-Cutaneous Treatment 
emergent malignancies 
1(<1) 
0 
2(<1) 
2(<1) 
0 
3(1) 
New Primary melanoma 
1(<1) 
0 
1(<1) 
0 
0 
3(1) 
Pancreatitis 
0 
0 
1(<1) 
1(<1) 
0 
1(<1) 
DVT and PE 
2(<1) 
1(<1) 
4(2) 
1(<1) 
0 
2(<1)