MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and Trametinib in Patients With Tumors With BRAF V600E or V600K Mutations (Excluding Melanoma, Thyroid Cancer, Colorectal Adenocarcinoma, and Non-Small Cell Lung Cancer)
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

 
i 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 
ecog-acrin.org 
 
 
July 10, 2019 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #21 to EAY131-H, Phase II Study of Dabrafenib and Trametinib in 
Patients with Tumors with BRAF V600E or V600K Mutations (Excluding Melanoma, Thyroid 
Cancer, Colorectal Adenocarcinoma, and Non-Small Cell Lung Cancer) 
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions. 
IRB Review Requirements: 
This addendum has been reviewed and approved by the Central IRB, which is the sole 
IRB of record for this study. Local IRB review and approval is unnecessary. 
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum. 
This addendum is in response to Dr. Helen Chen’s June 19, 2019 (Updated: June 21, 2019) 
Request for Rapid Amendment for Debrafenib mesylate  
The following revisions to EAY131-H protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. 
2. 
3.3 
Updated the Debrafenib mesylate CAEPR list with version 2.4 May 7, 
2019. 
The following revisions to EAY131-H Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Page 1 
Updated Version Date. 
2. 
What possible risks 
can I expect from 
taking part in this 
study? 
Updated Debrafenib mesylate risk list with version 2.4 May 7, 2019. 

 
ii 
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900. 
We request review and approval of this addendum to EAY131-H so ECOG-ACRIN may activate 
it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development 
Enclosure 
CC: Erin Macrae, MD  
April Salama.MD  
Jong-In Park,  Ph.D  
Alice Chen, MD 
Keith Thomas Flaherty, MD 
Lyndsay N. Harris. MD 
Peter O’Dwyer, MD 
Mickey Williams, PhD 
James V. Tricoli, PhD 
Stanley Hamilton, MD 
Lisa McShane, PhD  
Larry Rubinstein, PhD 
Robert Gray, PhD 
Shuli Li, PhD 
Lalitha Shankar, MD 
Susanna Lee, MD, PhD 
Constantine Gastonis, PhD 
Paolo Caimi, MD 
Shaji Kumar, MD 
Carlos Arteaga, MD 
Edith Mitchell, MD 
John J. Wright, MD, PhD 
Bruce Giantonio, MD 
Donna Marinucci 
Kerry Higgins 
Gayle Ipock 
Jean MacDonald 
Carol Chami, R.N. 
Juanita Andrews 
Melinda Flood 
Kelly Redmond 
Becky Fillingham 
Kevin Pollard 
Abuchi Agu 
Michael T. Balco 
Lauren Lambert 
Cayden Maican 
Margaret Cavenagh 
Ben Kim 
Alexandra Sachs 
 
 
 

EAY131-H 
1 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and 
Trametinib in Patients with Tumors with BRAF V600E or V600K 
Mutations (Excluding Melanoma, Thyroid Cancer, Colorectal 
Adenocarcinoma, and Non-Small Cell Lung Cancer) 
TRAMETINIB AND DABRAFENIB 
TREATMENT SUBPROTOCOL CHAIR: Erin Macrae, MD 
TRAMETINIB AND DABRAFENIB 
SUBPROTOCOL CO-CHAIR: April Salama, MD 
TRAMETINIB AND DABRAFENIB  
TRANSLATIONAL CHAIR: 
 
Jong-In Park, Ph.D. 
Version Date:  July 10, 2019 
NCI Update Date:  August 12, 2015 
NOTE: This subprotocol (EAY131-H) should be 
used in conjunction with the MATCH 
Master Protocol (EAY131).  
NOTE: As of 11/17, all protocol changes will be 
noted by addendum number. 
SUBPROTOCOL ACTIVATION DATE 
August 12, 2015 
PRE-ACTIVATION DATE 
May 29, 2015 
Update #1 – Incorporated Prior to Activation 
Addendum #1 – 8/15 
Update #2 – 8/15 
Addendum #2 – 2/16 
Addendum #3 – 5/16 
Addendum #5 – 12/16 
Addendum #6 – 1/17 
Addendum #7 – 3/17 
Addendum #13 
Addendum #19 
Addendum #21 
Agent 
IND# 
NSC# 
Supply 
Trametinib 
NCI Supplied 
Dabrafenib 
NCI Supplied 
Rev. Add13 
Rev. Add19 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) .................................................. i 
MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and Trametinib in 
Patients with Tumors with BRAF V600E or V600K Mutations (Excluding 
Melanoma, Thyroid Cancer, Colorectal Adenocarcinoma, and Non-Small Cell 
Lung Cancer) ............................................................................................... 1 
Table of Contents .............................................................................................. 2 
Schema ............................................................................................................. 5 
1. Introduction ................................................................................................ 6 
1.1 
Dabrafenib and Trametinib ................................................................. 6 
1.2 
Supporting Preliminary Data ............................................................... 7 
1.3 
Dabrafenib Mesylate (GSK2118436B)................................................... 9 
1.4 
Mechanisms of Action and Preclinical Data with Dabrafenib ................. 9 
1.5 
Clinical Pharmacokinetics (PK) and Pharmacokinetics of Dabrafenib .... 10 
1.6 
Clinical Experience with the Combination of Dabrafenib + Trametinib . 12 
1.7 
Safety profile of Dabrafenib or Dabrafenib-Trametinib Combination ... 13 
1.8 
Clinical pharmacology of trametinib:.................................................. 21 
2. Selection of Patients .................................................................................. 23 
2.1 
Eligibility Criteria .............................................................................. 23 
3. Trametinib/Dabrafenib Treatment Plan ...................................................... 26 
3.1 
Administration Schedule ................................................................... 26 
3.2 
Adverse Event Reporting Requirements ............................................. 26 
3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) ............... 30 
3.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Dabrafenib mesylate (GSK2118436B, NSC 763760) ............................. 34 
3.5 
Dose Modifications ........................................................................... 39 
3.6 
General Concomitant Medication and Supportive Care Guidelines ...... 59 
3.7 
Duration of Agent-specific treatment................................................. 60 
3.8 
Duration of Follow-Up ...................................................................... 60 
4. Study Parameters ...................................................................................... 61 
4.1 
Therapeutic Parameters for Dabrafenib plus Trametinib Treatment .... 61 
5. Drug Formulation and Procurement ........................................................... 63 
5.1 
Trametinib (NSC 763093) .................................................................. 64 
5.2 
Dabrafenib (NSC 763760) .................................................................. 65 

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NCI Update Date: August 12, 2015 
3 
6. Translational Studies.................................................................................. 68 
7. References ................................................................................................ 68 
Appendix I  Patient Pill Calendars...................................................................... 71 
Appendix II  CYP3A4/CYP2C8 Inducers and Inhibitors ......................................... 74 
Appendix III  Trametinib Ophthalmic Exam Form ............................................... 75 
Appendix IV  BRAF Mutations Eligible for Inclusion ............................................ 76 
Appendix V  Patient Drug Information Handout and Wallet Card ........................ 77 
 
 
 
Rev. Add13 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
4 
TREATMENT SUBPROTOCOL CHAIR 
Erin R. Macrae, MD 
Columbus Oncology and Hematology 
Associates 
810 Jasonway Avenue, Suite A 
Columbus, OH 43214 
Phone: (614) 442-3130 
Fax: (614) 442-3145 
E-mail: emacrae@coainc.cc 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
April K.S Salama MD 
Duke University Medical Center 
200 Trent Drive 
 Morris Bldg, Room 25178 
DUMC 3198 
Phone: (919) 681-6932 
Fax: (919) 684-5163 
E-mail: april.salama@duke.edu  
 
TRANSLATIONAL CHAIR 
Jong-In Park, Ph.D. 
Department of Biochemistry 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: (414) 955-4098 
Fax: (414) 955-6510 
E-mail: jipark@mcw.edu  
 
 
 
 
 
 
 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
5 
Schema 
 
 
Long-Term Follow-Up
Trametinib 2 mg orally once daily in 
combination with Dabrafenib 150 mg 
orally twice daily
Until progression or unacceptable 
toxicity
Cycle = 28 days
Accrual Goal: 35
 
 

ECOG-ACRIN 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
6 
1. 
Introduction 
1.1 
Dabrafenib and Trametinib 
The RAF/MEK/ERK pathway plays a critical role in multiple cellular functions. 
Oncogenic activation of this pathway can result from deregulated activation or 
mutations of upstream receptor tyrosine kinases and RAS, or 
upregulation/mutations in RAF and MEK. BRAF is one of 3 structurally related 
RAF-kinase isoforms involved in signal transduction. Upon activation, RAF 
activates MEK1 and MEK2 (collectively referred to as MEK1/2), which in turn 
phosphorylate the activation loop of their effectors ERK1 and ERK2 (ERK1/2). 
Once activated, ERK1/2 translocate into the nucleus and phosphorylate a 
number of effector proteins, including transcription factors, while they also 
activate/inactivate a variety of cytosolic targets to regulate cell proliferation, 
motility, differentiation, and survival.1 
Somatic BRAF mutations were first identified in a screen of cancer cell lines in 
2002, where it appeared that a high percentage of melanomas had a mutation.2 
Mutations were noted in other malignancies as well, though at lower frequencies. 
All of the mutations identified in this study were within the kinase domain at 
exons 11 or 15, with the vast majority being due to a single point mutation at 
amino acid position 600, which resulted in the substitution of a glutamic acid for 
valine, V600E.3 Mutation of BRAF in melanoma and other tumors leads to a 
constitutive activation of the RAF/MEK/ERK pathway, and is now validated as a 
major oncogenic driver and viable therapeutic target. In melanoma, more than 
80% of the BRAF mutations cause a substitution of the amino acid glutamate (E) 
for valine (V) at position 600 (V600E) of the BRAF protein, whereas 
approximately 3-20% of melanoma mutations are a substitution of lysine (K) for 
valine at position 600 (V600K).4-6 In addition, a substitution of arginine or 
aspartate for valine at position 600 also occurs albeit at a relatively low 
frequency.7 BRAF V600E mutations occur at a variable frequency in cancer, 
including approximately 60% of melanoma,2 30 to 50% of papillary thyroid, 5 to 
20% of colorectal, 30% of ovarian cancer, 8 and less than 5% of non-small cell 
lung cancers.9 
Dabrafenib [4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole] is an orally 
bioavailable, potent and selective RAF kinase inhibitor of human wild type BRAF 
and CRAF enzymes as well as the mutant forms of the BRAF enzyme, BRAF 
V600E, BRAF V600K, and BRAF V600D. A recent report has also demonstrated 
the efficacy of dabrafenib for metastatic melanoma patients harboring BRAF 
V600R.10 The mode of action of dabrafenib is consistent with competitive 
inhibition of adenosine triphosphate (ATP) binding. Dabrafenib has demonstrated 
suppression of a downstream pharmacodynamic biomarker (phosphorylated 
ERK1/2 [pERK1/2]) in tumor cell lines, demonstrated anti-proliferative activity  
against multiple BRAF mutation-positive tumor cell lines, and achieved biomarker 
suppression and tumor regression in BRAF mutation-positive xenograft models 
[GSK2118496 Investigator’s Brochure version 06 09-JUL-2014]. Targeted 
inhibition of the RAF/MEK/ERK pathway with BRAF inhibitors dabrafenib or 
vemurafenib, as compared with chemotherapy, improved the progression-free 
and overall survival of patients who have metastatic melanoma with BRAF V600 
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NCI Update Date: August 12, 2015 
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mutations, leading to approval by the Food and Drug Administration (FDA) for 
both of these agents.11,12  
While the introduction of BRAF inhibitors represent a significant advance in the 
treatment of BRAF V600 mutation-positive metastatic melanoma patients,11 
limitations of this novel therapy have already been identified, including rapid 
resistance and paradoxical activation of the RAF/MEK/ERK pathway resulting in 
secondary cancers.13 Several distinct mechanisms of resistance to BRAF-
inhibition have been proposed and include alterations that restore 
RAF/MEK/ERK pathway activation that render cells susceptible to MEK-
inhibition.14 Trametinib is a highly potent non-ATP competitive allosteric inhibitor 
of MEK1/2 (IC50 of 0.7 and 0.9 nM against MEK1 and MEK2, respectively) and is 
provided as a dimethyl sulfoxide solvate.15 Trametinib inhibits not only MEK1/2 
kinase activity for ERK1/2 phosphorylation but also prevents RAF-dependent 
MEK phosphorylation, producing very effective and prolonged ERK1/2 inhibition. 
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse 
models showed significant mean tumor growth inhibition with multiple complete 
and partial tumor regressions [GSK1120212 Investigator’s Brochure version 05 
25-SEP-2013]. In a phase 3 trial, single-agent trametinib, compared to 
chemotherapy, improved the overall survival of patients with BRAF V600 
mutation–positive metastatic melanoma leading to FDA approval for this 
indication.16  
1.2 
Supporting Preliminary Data  
Given the efficacy of dabrafenib and trametinib monotherapy, preclinical work 
began to explore the anti-tumor activity of the combination. Experimental data 
generated with a BRAF- and MEK-inhibitor administered in combination in BRAF-
mutant melanoma cell lines in vitro and xenografts in vivo demonstrated the 
efficacy combination therapy in models of acquired dabrafenib resistance. More 
importantly, superior anti-tumor activity of the BRAF- and MEK-inhibitor 
combination as compared to each agent as monotherapy was also observed in 
BRAF-sensitive models [GSK1120212 and GSK2118496 Investigator’s Brochure 
version 03 23-JUN-2014]. This finding was confirmed in a randomized, phase 2 
study of a combination of dabrafenib and trametinib, as compared with 
dabrafenib alone in patients with metastatic BRAF V600E and V600K mutated 
melanoma. In this trial, the investigators demonstrated a longer progression free 
survival with the combination (9.4 vs 5.8 months), as well as less squamous skin 
carcinoma (7% vs 19%).17 Based on this study, the combination is now FDA 
approved for the treatment of V600E or V600K BRAF mutant melanoma.  
Recently, a double-blind, randomized, phase 3 study without crossover was 
published comparing the combination of dabrafenib and trametinib to dabrafenib 
plus placebo as first-line therapy in patients who had metastatic melanoma with 
BRAF V600E or V600K mutations.13 The median progression-free survival was 
9.3 months in the dabrafenib–trametinib group and 8.8 months in the dabrafenib-
only group (P=0.03). The overall response rate was 67% in the dabrafenib–
trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, 
the interim overall survival rate was 93% with dabrafenib–trametinib and 85% 
with dabrafenib alone (P=0.02). Available efficacy data of dabrafenib and 
trametinib in patients with solid tumors are listed in Table 1.  

ECOG-ACRIN 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
8 
Table 1. Efficacy data from clinical trials evaluating the combination of trametinib 
with dabrafenib in patients with cancer 
Study 
Population 
Therapy 
RR, % 
PFS 
OS 
Long et 
al; phase 
III 
(n=423)13  
Metastatic 
melanoma with 
BRAF V600E or 
V600K mutations 
Dabrafenib plus 
trametinib vs. 
dabrafenib plus 
placebo  
67% vs. 
51% 
9.3 months 
vs. 8.8 
months 
Median OS not 
yet reached at 
time of analysis  
Flaherty 
et al; 
phase I/II 
(n=162)17 
Metastatic 
melanoma with 
BRAF V600E or 
V600K mutations 
Dabrafenib 
monotherapy vs. 
Dabrafenib plus 
trametinib (1 mg 
dose) vs. Dabrafenib 
plus trametinib (2 mg 
dose) 
54% vs. 
50% vs. 
76% 
5.8 months 
vs. 9.2 
months vs. 
9.4 months 
Median OS not 
yet reached at 
time of analysis 
Phase I; 
(n=43)18 
Metastatic 
colorectal patients 
with BRAF V600 
mutations 
Dabrafenib plus 
trametinib  
7% 
3.5 months 
8.7 months 
Over 1000 subjects, primarily with BRAF V600-mutated melanoma, have 
received the combination therapy regimen of dabrafenib and trametinib 
[GSK1120212 and GSK2118496 Investigator’s Brochure version 03 23-JUN-
2014]. In the phase III study, Long et al13 report pyrexia, fatigue, headache, 
nausea, chills, arthralgias, diarrhea, rash, and hypertension as the most common 
adverse events (AEs) observed with these two agents. Grade 3 or 4 AEs occur in 
up to 35% of patients receiving combination therapy.  Grade 3 or 4 AEs occurring 
in >1% of the study population included pyrexia, hypertension, neutropenia, 
AST/ALT increase, syncope, fatigue, and hyperglycemia.  Life threatening and 
fatal AEs were observed, however, most were judged to not be related to 
treatment with dabrafenib and trametinib. Long et al13 reported 4 deaths related 
to adverse events occurred in the dabrafenib–trametinib group: 3 from cerebral 
hemorrhage (2 during receipt of study treatment and one 5 days after cessation) 
and one from pneumonia (22 days after cessation of treatment). All 4 events 
were considered by the investigator to be unrelated to study treatment. The 
incidence of squamous cell carcinoma and squamous cell carcinoma of skin 
were lower when trametinib was added to dabrafenib compared to dabrafenib 
alone (2% vs. 9% respectively). Fewer patients in the dabrafenib–trametinib 
group than in the dabrafenib-only group had cutaneous squamous-cell carcinoma 
or cutaneous hyperkeratoses (3% vs. 32%).13 Similar toxicity data were reported 
in other studies with melanoma, colorectal, and non-small cell lung cancer 
patients [GSK1120212 and GSK2118496 Investigator’s Brochure version 03 23-
JUN-2014].   
Rationale: Targeting the RAF/MEK/ERK pathway in BRAF V600-mutated 
melanoma has led to improved outcomes and new standard of care options for 
this disease. Dual MEK and BRAF inhibition has demonstrated superior 
response rates and progression free survival when compared to BRAF 
monotherapy in advanced melanoma.  This provides a strong rationale to assess 
the activity of combination therapy in other malignancies with limited treatment 
options with a BRAF V600E, V600K, V600D, or V600R mutation. 

ECOG-ACRIN 
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NCI Update Date: August 12, 2015 
9 
1.3 
Dabrafenib Mesylate (GSK2118436B) 
The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many 
human cancers.  This pathway can be constitutively activated by molecular 
alterations including BRAF activating mutations.  Approximately 90% of all 
identified BRAF mutations in human cancer consist of a T1799 transversion 
mutation in exon 15, which results in a V600 E/D/K (T1799A) amino acid 
substitution.  This mutation appears to mimic regulatory phosphorylation and 
increases BRAF activity approximately 10-fold compared to wild type (wt).  RAF 
is a validated target in BRAF V600E-containing melanoma.  In August 2011, the 
FDA approved vemurafenib (PLX4032, Zelboraf®), an ATP-competitive selective 
RAF inhibitor for the treatment of late-stage BRAFV600E melanoma.  In the pivotal 
phase III trial of vemurafenib vs. dacabazine (Chapman et al., 2011), 
vemurafenib demonstrated significant improvement in overall survival (OS) (6-
month OS of 84% vs. 64%, hazard ratio [HR]=0.37; P<0.001), progression-free 
survival (PFS) (estimated median PFS of 5.3 months vs. 1.6 months (HR=0.26; 
P<0.001]), and overall response rate (ORR) (48% vs. 5%).  However, in patients 
with colorectal cancer (CRC) bearing the BRAF V600E mutation, there was only 
one partial response (PR) among 20 patients treated (ORR 5%) and four minor 
responses (Kopetz et al., 2010). 
Dabrafenib mesylate (GSK2118436B, Tafinlar®; referred to as dabrafenib 
hereafter), a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is an ATP-
competitive, selective inhibitor of RAF kinase currently in clinical development.  
On May 29, 2013, the U.S. FDA approved dabrafenib for the treatment of 
patients with unresectable or metastatic melanoma with BRAFV600E mutation as 
detected by an FDA-approved test (FDA, 2013).  On January 10, 2014, the FDA 
granted accelerated approval to dabrafenib and MEK inhibitor trametinib for use 
in combination to treat patients with unresectable or metastatic melanoma with 
either BRAFV600E or BRAFV600K mutation as detected by an FDA-approved test 
(FDA, 2014). 
1.4 
Mechanisms of Action and Preclinical Data with Dabrafenib 
Dabrafenib potently inhibits all RAF isoforms, with the strongest potency against 
the V600 mutant, as compared to its activity against wt BRAF and CRAF (see 
below).  In a panel of more than 270 kinases tested outside RAF isoforms, only 
10 kinases were inhibited at a 50% inhibitory concentration (IC50) <100 nM:  LIM 
domain kinase 1 (LIMK1), activin receptor-like kinase 5 (ALK5)/ transforming 
growth factor (TGF)-beta receptor type-1 (TGFβ1R), Never In Mitosis Gene A 
(NIMA)-related kinase 11 (NEK11), salt-inducible kinase 1 (SIK1), salt-inducible 
kinase 2 (SIK2), polycystin-2 (PKD2), protein tyrosine kinase 6/breast tumor 
kinase (BRK), pancreatic eukaryotic initiation factor-2 alpha (eIF2α) kinase 
(PEK)/eIF2α kinase (PERK), endothelium-specific receptor tyrosine kinase 2 
(TIE2) (R849W), and yeast casein kinase 1 (CK1) (IB, 2013a). 
Inhibitory activity of dabrafenib on RAF 
 
BRAFV600E 
BRAFV600K 
BRAFV600D 
wt BRAF 
CRAF 
IC50 
0.65 nM 
0.50 nM 
1.84 nM 
3.2 nM 
5.0 nM 
In a panel of > 110 human tumor cell lines with confirmed BRAF mutational 
status, dabrafenib potently inhibited proliferation of a majority (73%) of BRAFV600E 

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10 
mutant cell lines with growth IC50 (gIC50) < 100 nM (IB, 2013a).  In contrast, there 
was poor or no activity in other BRAF mutants or wt BRAF cell lines. 
Dabrafenib given orally (PO) for 14 days at doses ranging from 0.1-300 mg/kg 
administered once daily (QD), twice daily (BID), or three times daily (TID) 
inhibited tumor growth in mice bearing BRAFV600E A375P F11s or Colo205 tumor 
xenografts.  The effect was generally dose dependent up to 10 mg/kg/day 
(A375P F11s) or 30 mg/kg/day (Colo205), yielding 90-120% tumor reduction 
relative to untreated animals.  However, cessation of treatment was associated 
with regrowth of the tumors.  In A375P F11s melanoma xenografts, inhibition of 
pERK by > 50% in the tumor was seen at doses of ≥ 3 mg/kg.  Based on the 
single-dose studies, ~100 nM (52 ng/mL) dabrafenib in blood at 6 h post-dosing 
was needed for effective pharmacodynamic biomarker inhibition in the tumor.  At 
repeated dosing of 30 mg/kg/day, the tumor pERK levels were reduced by > 50% 
at 8 h after dosing (69% on Day 1 and 53% on Day 14).  Levels of pERK 
returned to baseline 24 h post-dosing.  Similar ↓pERK effects were seen in the 
ES-2 ovarian xenograft model, but pERK inhibition was weaker in the Colo205 
xenograft model.  Of note, concentrations of dabrafenib showing 
pharmacodynamic activity in xenografts did not cause a reduction in pERK/tERK 
levels in the normal intact brain.  
1.5 
Clinical Pharmacokinetics (PK) and Pharmacokinetics of Dabrafenib 
Following single-dose oral administration of dabrafenib HPMC capsules, plasma 
concentrations peaked approximately 2.0 hours post-dose.  Oral bioavailability is 
near complete (94.5%) relative to an intravenous (IV) microdose.   
Dabrafenib is highly bound to plasma proteins (99.6%).  Its volume of distribution 
after IV dosing is 45.5 L.  Intravenous plasma clearance (12.0 L/hr) is low relative 
to liver blood flow, suggesting a low hepatic extraction ratio drug.  Median 
terminal half-life is approximately 8 hours after a single oral dose.  
Three metabolites of dabrafenib were characterized and may contribute to 
activity.  GSK2285403 (hydroxy-metabolite [M7]) PK paralleled that of 
dabrafenib, while the carboxy- (GSK2298683 [M4]) and desmethyl- 
(GSK2167542 [M8]) metabolites exhibited a longer t1/2 (21-22 hours) and 
accumulated following repeat dosing.  M7 is the most abundant, accounting for 
54% of the three metabolites.  Similar to dabrafenib concentrations, exposure for 
all metabolites showed a less than dose proportional increase with repeat dosing. 
Fecal excretion was a major route of dabrafenib elimination in humans, 
accounting for 71.1% of the dose administered, and renal excretion accounted 
for about 23% of drug elimination, recovered as metabolites only. 
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.  
Therefore, the current recommendation is to administer dabrafenib under fasting 
conditions, either 1 h before or 2 h after a meal. 
Drug-drug interactions for dabrafenib: 
Dabrafenib induces CYP3A4 and CYP2C9.  Dabrafenib decreased the systemic 
exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 
substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate).  Co-administration of 

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dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg 
(a CYP3A4 substrate) decreased midazolam AUC by 74%. Co-administration of 
dabrafenib 150 mg twice daily for 15 days and a single dose of warfarin 15 mg 
decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of 
R-warfarin (a CYP3A4/CYP1A2 substrate) by 33%.  
In vitro studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 
while hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Co-
administration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once 
daily (a strong CYP3A4 inhibitor) for 4 days increased dabrafenib AUC by 71%, 
hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. Co-
administration of dabrafenib 75 mg twice daily and gemfibrozil 600 mg twice daily 
(a strong CYP2C8 inhibitor) for 4 days increased dabrafenib AUC by 47%, with 
no change in the AUC of dabrafenib metabolites. Dabrafenib is a substrate of 
human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in 
vitro.   
Pharmacodynamic effect of dabrafenib: 
Median tumor pERK inhibition was 83.9% (range:  38.0 to 93.3%) in BRAF 
mutant melanoma subjects receiving doses of 70 to 200 mg BID.  The 
relationship between exposure and % pERK inhibition was characterized using a 
maximum response (Emax) model with 100% maximum inhibition and IC50 of 134 
ng/mL (95% CI:  92.7, 155) based on the sum of the potency-adjusted parent and 
active metabolite concentrations.  A dose-related decrease in pERK was 
predicted with total daily doses < 200 mg (100 mg BID) dabrafenib, with a 
plateau occurring beyond total daily doses of 200 mg thereafter. 
Selection of the RP2D for dabrafenib monotherapy: 
The single-agent MTD for dabrafenib was not reached.  A dose of 150 mg BID 
was selected for further single-agent development, based on the following 
PK/pharmacodynamics, safety, and activity:  a) dose increases beyond 150 mg 
BID yielded no increase in Cmax and < 50% increase in AUC; b) incidence and 
severity of AEs was similar at 100-300 mg BID; c) pERK target suppression was 
> 80%; and d) the tumor response rate (RR) was 50% at 150 mg BID. 
Antitumor Activity of Dabrafenib Monotherapy  
Activity in patients with BRAF V600E or V600K melanoma in The FTIH 
monotherapy study (BRF112680).  The study enrolled 114 patients with BRAF 
V600 mutant melanoma in the dose escalation phase (Part 1), and 70 patients at 
the RP2D (150 mg BID) in Part 2.  Within this study, a cohort of 10 patients with 
previously untreated asymptomatic brain metastasis was evaluated for 
intracranial response to dabrafenib (Long et al., 2011).  All patients had 
decreases in the size of the brain metastasis; three patients achieved complete 
radiographic resolution of brain lesions  as well as reduction in extracranial 
disease.  The response rates in patients treated at 150 mg BID are shown below. 

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FTIH monotherapy study (BRF112680) response rates in melanoma 
patients 
 
Subgroup 
Patient # 
ORR 
Part 1 
V600E 
77 
50% 
 
V600K 
14 
20% 
Part 2, Cohort A 
V600E/K with brain mets 
10 
40% 
 
V600E/K without brain mets 
20 
55% 
When dabrafenib was used at 50 mg BID (Part 2, Cohort C) in patients with 
BRAF V600E mutant melanoma, the response rate was only 17%. 
Correlative studies in the phase 1 monotherapy trial: 
Preliminary genomic analysis was performed on 37 patients with melanoma, 
using a Sequenom mutation analysis for 11 genes (AKT, BRAF, CDK4, 
CDKN2A, GNAQ, GNA11, Kit, MEK1, MEK2, and NRAS), and PTEN analysis by 
sequencing, comparative genomic hybridization (CGH), and multiplex ligation-
dependent probe amplification (MPLA) (Nathanson et al., 2011).  Nine patients 
(24%) had PTEN genetic alterations including mutation, hemi-/homozygous 
deletion.  PTEN deficiency was associated with lower responses (ORR of 11% 
and 54% in patients with and without PTEN alteration, respectively). 
Phase III trial of dabrafenib versus chemotherapy in patients with advanced 
BRAFV600 mutant melanoma (BREAK3 Trial): 
Patients with previously untreated, unresectable stage III or IV BRAFV600E-
mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib 
(150 mg PO BID) or dacarbazine (DTIC) (1000 mg/m2, IV, every 3 weeks [Q3W]).  
Of 250 patients 187 received dabrafenib and 63 received DTIC.  The hazard ratio 
for PFS was 0.30 (95% CI:  0.18-0.53; P < 0.0001), with median PFS of 5.1 
months for dabrafenib and 2.7 for DTIC.  OS data were immature, with 30 deaths 
reported.  Confirmed RR was 53% for dabrafenib and 19% for DTIC.  Benefits in 
PFS and RR were observed in all subgroups evaluated. 
Activity in BRAF V600E mutant tumors other than melanoma: 
In phase 1 trial, 18 patients had cancers other than melanoma: CRC (7), papillary 
thyroid cancer (PTC) (13), NSCLC (1) and ovarian cancer (1).  Confirmed PRs 
were seen in one patient with CRC, and in 5 patients with PTC; the patient with 
NSCLC had an unconfirmed PR at 6 weeks.  Eleven patients (6 with PTC and 5 
with CRC) had stable disease (SD) as their best response; the ovarian cancer 
patient had SD for approximately 36 weeks. 
1.6 
Clinical Experience with the Combination of Dabrafenib + Trametinib 
Data on 247 patients with metastatic melanoma and BRAFV600 mutations 
participating in the phase 1/2 study of dabrafenib and trametinib, BRF113220, 
have been published (Flaherty et al., 2012). 
PK 
Coadministration of dabrafenib 150 mg twice daily and trametinib 2 mg once 
daily resulted in no clinically relevant pharmacokinetic drug interactions.   

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RP2D for the combination of trametinib and dabrafenib 
In the dose escalation portion (Part B) of study BRF113220, the MTD of the 
combination was not reached, and the RP2D was therefore 150/2 (Flaherty et al., 
2012).  Pyrexia, chills, and nausea were the most common reasons cited for 
dose reductions; pyrexia, chills, and decreased ejection fraction were the most 
common reasons cited for dose interruptions.  Comprehensive safety data for the 
combination of dabrafenib and trametinib are presented in Section 1.7. 
Activity of dabrafenib + trametinib 
In the phase 2 portion of study BRF113220, among 162 patients with BRAFV600E 
or BRAFV600K mutation-positive melanoma, were randomized to 3 arms: 
dabrafenib 150 mg BID + trametinib 2 mg QD, dabrafenib 150 mg BID + 
trametinib 1 mg QD, and single-agent dabrafenib 150 mg BID, efficacy analyses 
were performed in the intention-to-treat population, with a median follow-up of 
14.1 months (Flaherty et al., 2012).  All major efficacy endpoints were improved, 
including PFS, 12-month PFS, ORR, and duration of response (see table below). 
End Point 
(as assessed by the 
investigators) 
Dabrafenib 
Monotherapy 
(n=54) 
Combination 
150/1 
(n=54) 
Combination 
150/2 
(n=54) 
Progression-free Survival – 
months 
Median (95% CI) 
5.8 (4.6-7.4) 
9.2 (6.4-11.0) 
9.4 (8.6-16.7) 
Progression-free Survival at 12 
mo. % (95% CI) 
9 (3-20) 
26 (15-39) 
41 (27-54) 
CR or PR 
Patients (% [95% CI]) 
29 (54 [40-67]) 27 (50 [36-64]) 41 (76 [62-86]) 
Duration of response 
Median months (95% CI) 
5.6 (4.5-7.4) 
9.5 (7.4-NA) 
10.5 (7.4-14.9) 
1.7 
Safety profile of Dabrafenib or Dabrafenib-Trametinib Combination 
Comprehensive Adverse Events and Potential Risks (CAEPR) lists using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) terms for dabrafenib 
and for trametinib are included in Section 3.3 and Section 3.4. 
Based on available AE data from clinical studies involving dabrafenib to date, 
the most common drug-related AE was hyperkeratosis (29%). Other commonly 
reported (>15%) drug-related AEs included alopecia, arthralgia, fatigue, skin 
papilloma,pyrexia, and rash (IB, 2013). 
Based on available AE data from clinical studies involving trametinib to date, the 
most common toxicities are rash and diarrhea.  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. 
Rev. Add13 

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Common Adverse Events of Dabrafenib Monotherapy Based on Phase III 
Trial of Dabrafenib vs. Dacarbazine in Patients with Advanced Melanoma 
(adapted from Dabrafenib Package Insert) 
Adverse Reaction or Laboratory Abnormality 
Dabrafenib 
(n=187) 
Dacarbazine 
(n=59) 
All 
Gradesa 
Grades 
3 and 4b 
All Gradesa 
Grades 
3 and 4 
Skin and subcutaneous tissue disorders 
Hyperkeratosis 
37 
1 
0 
0 
Alopecia 
22 
NAf 
2 
NA 
Palmar-plantar erythrodysesthesia syndrome 
20 
2 
2 
0 
Rash 
17 
0 
0 
0 
Nervous system disorders 
Headache 
32 
0 
8 
0 
General disorders and administration site conditions 
Pyrexia 
28 
3 
10 
0 
Musculoskeletal and connective tissue disorders 
Arthralgia 
27 
1 
2 
0 
Back pain 
12 
3 
7 
0 
Myalgia 
11 
0 
0 
0 
Neoplasm benign, malignant, and unspecified (including cysts and polyps) 
Papillomac 
27 
0 
2 
0 
cuSCCd, e 
7 
4 
0 
0 
Respiratory, thoracic, and mediastinal  
Cough 
12 
0 
5 
0 
Gastrointestinal disorders 
Constipation 
11 
2 
14 
0 
Infections and infestations 
Nasopharyngitis 
10 
0 
3 
0 
a NCI CTCAE v4. 
b Grade 4 adverse reactions limited to hyperkeratosis (n=1) and constipation (n=1). 
c Includes skin pappiloma and papilloma. 
d Includes squamous cell carcinoma of the skin and keratoacanthoma. 
e Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. 
f NA = not applicable. 

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Common Adverse Events of Dabrafenib-Trametinib Combination vs. 
Dabrafenib Monotherapy.  The phase 2 portion of study BRF113220 (referred 
to as Part C) included 3 arms:  dabrafenib 150 mg BID + trametinib 2 mg QD, 
dabrafenib 150 mg BID + trametinib 1 mg QD, and single-agent dabrafenib 150 
mg BID.  The most common AE resulting in permanent discontinuation was 
pyrexia (4%).  AEs led to dose reductions in 49% and dose interruptions in 67% 
of patients treated with dabrafenib in combination with trametinib.  The table 
below presents selected adverse reactions and treatment-emergent laboratory 
abnormalities in this study. 
Selected AEs and Laboratory Abnormalities Occurring in ≥ 10% at (All 
Grades) or ≥ 5% (Grades 3 or 4) of Patients Treated With Dabrafenib in 
Combination With Trametinib 
Adverse Reaction or 
Laboratory Abnormality 
Dabrafenib + 
Trametinib 2mg 
(n=55) 
Dabrafenib + 
Trametinib 1mg 
(n=54) 
Dabrafenib 
(n=53) 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
General disorders and administrative site conditions 
Pyrexia 
71 
5 
69 
9 
26 
0 
Chills 
58 
2 
50 
2 
17 
0 
Fatigue 
53 
4 
57 
2 
40 
6 
Edema peripheralb 
31 
0 
28 
0 
17 
0 
Skin and subcutaneous tissue disorders 
Rashc 
45 
0 
43 
2 
53 
0 
Night sweats 
24 
0 
15 
0 
6 
0 
Dry skin 
18 
0 
9 
0 
6 
0 
Dermatitis acneiform 
16 
0 
11 
0 
4 
0 
Actinic keratosis 
15 
0 
7 
0 
9 
0 
Erythema 
15 
0 
6 
0 
2 
0 
Pruritis 
11 
0 
11 
0 
13 
0 
Gastrointestinal disorders 
Nausea 
44 
2 
46 
6 
21 
0 
Vomiting 
40 
2 
43 
4 
15 
0 
Diarrhea 
36 
2 
26 
0 
28 
0 
Metabolism and nutritional disorders 
Decreased appetite 
22 
0 
30 
0 
19 
0 
Dehydration 
11 
0 
6 
2 
2 
0 
Vascular disorders 
Hemorrhaged 
16 
5 
11 
0 
8 
2 

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Renal and urinary disorders 
Renal failuree 
7 
7 
2 
0 
0 
0 
Hematology 
Leukopenia 
62 
5 
46 
4 
21 
0 
Neutropenia 
55 
13 
37 
2 
9 
2 
Liver function tests 
Increased AST 
60 
5 
54 
0 
15 
0 
Increased alkaline phosphatase 
60 
2 
67 
6 
26 
2 
Increased ALT 
42 
4 
35 
4 
11 
0 
Hyperbilirubinemia 
15 
0 
7 
4 
0 
0 
Chemistry 
Hyperglycemia 
58 
5 
67 
6 
49 
2 
Hyponatremia 
55 
11 
48 
15 
36 
2 
Hypophosphatemia 
47 
5 
41 
11 
40 
0 
Increased creatinine 
24 
5 
20 
2 
9 
0 
a NCI CTCAE v4. 
b Includes the following terms:  peripheral edema, edema, and lymphedema. 
c Includes the following terms:  rash, rash generalized, rash pruritic, rash erythematous, rash popular, rash vesicular, 
rash macular, rash maculo-papular. 
d Includes the following terms:  brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival 
hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. 
e Includes the following terms:  renal failure and renal failure acute. 
AEs of special interest: 
The following events observed with dabrafenib monotherapy and for dabrafenib 
plus trametinib are discussed in further detail because they may represent a 
class effect of BRAF and/or MEK inhibitor compounds, and/or are potentially life-
threatening. AEs of special interest associated with dabrafenib or trametinib 
individually are listed in the table below: 
AEs of special interest that are 
associated with dabrafenib (BRAF 
category AEs) are: 
• 
Skin-related toxicities 
• 
Pyrexia 
• 
Malignancies 
• 
Renal failure (renal failure, renal 
failure acute) 
• 
Uveitis 
• 
Hyperglycemia 
• 
Pancreatitis 
AEs of special interest that are associated with trametinib 
(MEK category AEs) 
• 
Skin-related toxicities (e.g., rash – generalized, macular, 
maculopapular, 
pruritic, erythematous, etc; dermatitis acneiform; 
erythema; skin exfoliation 
• 
Diarrhea 
• 
Ocular events (e.g., RVO, RPED (previously termed 
CSR) 
• 
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 (pneumonitis, interstitial lung disease) 
• 
Hemorrhages 

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In general, the overall profile of “AEs of special interest” observed with the 
combination of trametinib-dabrafenib 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.    
For “MEK-related AEs of special interest,” the overall incidence in the dabrafenib-
trametinib combination arm in trial BRF113220 was 91%, which was similar to 
the incidence reported with trametinib ISS monotherapy  (94%), but higher than 
the incidence in the dabrafenib alone arm.  However, MEK-related skin toxicities, 
diarrhea and hypertension appeared to be lower in the combination arm, as 
compared with the trametinib-only treated population.  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 
combination arm 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 and a decrease in cuSCC and PPES 
when comparing the combination to dabrafenib ISS population. 
The following sections provide more detailed description of the AEs of Special 
Interest.   
Dermatologic toxicities (dabrafenib or dabrafenib-trametinib):   
Dabrafenib monotherapy has been associated with skin-related toxicities 
including hyperkeratosis, skin papilloma, rash, seborrheic keratosis, acrochordon 
as well as rash and pruritis and cutaneous squamous cell carcinoma.    
With the combination of dabrafenib-trametinib at 150/2 (Part C of the phase II 
trial), skin-related toxicity occurred in 65% of subjects (IB, 2013). This incidence 
was lower than observed in the trametinib ISS population (88%, 288 out of 329 
subjects).  The most frequent skin-related toxicities (affecting >10% treated with 
combination) were rash, dermatitis acneiform, erythema, and rash generalized.  
The incidence and severity of the majority of skin-related toxicities and especially 
those most often seen with either trametinib- or dabrafenib therapy alone appear 
to be reduced when both compounds are combined. 
Malignancies (dabrafenib or dabrafenib-trametinib): 
Cutaneous SCC and keratoacanthomas:  SCC and proliferative skin toxicities 
are considered a class effect of BRAF inhibitors such as vemurafenib and 
sorafenib (Long et al., 2011).  SCC was treated with local excision, and treatment 
with dabrafenib was continued.  Most SCCs of the skin have been localized and 
generally treated with curettage, and have been without significant clinical 
sequelae. 
Across clinical trials of dabrafenib monotherapy (n=586), the incidence of 
cutaneous SCC was 11%.  Of those patients who developed new SCC, 
approximately 33% developed one or more SCC with continued administration of 
dabrafenib.   
In randomized trial with dabrafenib vs. dabrafenib-trametinib combination 
(BRF113220), the incidence of cutaneous SCC/keratocanthoma was statistically 
lower with150/2 combination therapy relative to dabrafenib alone (7 vs. 19%).  

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The median time to the first occurrence of keratoacanthoma/cuSCC was 152 
days in the combination treatment group as compared to 30.5 days in the 
dabrafenib alone arm. 
New primary malignant melanoma:  In the randomized trial for dabrafenib-
trametinib combination (BRF113220), new primary melanoma occurred in 2% 
(1/53) on dabrafenib monotherapy [similar to the dabrafenib ISS population (1%)] 
and in none of 55 patients receiving dabrafenib + trametinib (IB, 2013).  The 
overall frequency of new primary melanomas observed with dabrafenib treatment 
approximates that expected for untreated subjects with antecedent melanoma. 
Other treatment-emergent malignancies:  Non-cutaneous secondary 
malignancies have also been reported in patients receiving dabrafenib or 
dabrafenib-trametinib combination.  In patients receiving dabrafenib-trametinib 
combination, five cases out of 365 subjects (1%) were identified as having non-
cutaneous malignancies:  KRAS mutation-positive pancreatic adenocarcinoma 
(n=1), recurrent NRAS mutation-positive CRC (n=1), head and neck carcinoma 
(n=1), glioblastoma (n=1), and pre-existing renal cell carcinoma (n=1) (FDA 
label).  No increase was detected in the overall frequency of treatment emergent 
malignancies in melanoma subjects receiving dabrafenib and trametinib 
treatment in Study BRF113220 as compared to the dabrafenib safety population.  
Dabrafenib should be permanently discontinued for RAS mutation-positive non-
cutaneous malignancies. 
Pyrexia (dabrafenib or dabrafenib-trametinib):  Pyrexia and pyrexia-related 
events, including influenza-like illness, cytokine release syndrome, and systemic 
inflammatory response syndrome are common side effects associated with 
dabrafenib.  In dabrafenib- trametinib combination study BRAF113220 Part C, 
pyrexia and related events in the combination arm (150/2) were increased in 
frequency and severity (76%; 5% grade 3, no grade 4), as compared with 
dabrafenib monotherapy ISS population (33%; 2% grade 3, no grade 4).  Eleven 
percent of subjects in the combination group required hospitalization for episodes 
of serious pyrexia (IB, 2013).  Approximately 50% of the pyrexia-related events in 
the Part C 150/2 arm resulted in dose interruption and/or dose reduction, a 
higher proportion than in the dabrafenib ISS population (15% to 30%).  The 
majority of subjects (>80%) who dose-reduced dabrafenib due to AEs were able 
to be dose re-escalated.  
All SAEs of pyrexia-related events (pyrexia, influenza-like illness, cytokine 
release syndrome, and systemic inflammatory response syndrome) were 
manually reviewed to identify cases described as having experienced serious 
non-infectious febrile events with complications of hypotension, dehydration, 
severe rigors/chills, or renal failure in the absence of another identifiable etiology 
(e.g., infection).  Ten such subjects were identified among 404 subjects (2.5%) in 
the entire combination therapy population as compared to 1% in the dabrafenib 
ISS population; 9 of these subjects were hospitalized.  All of these subjects 
required dose interruption(s) and/or dose modification(s); one subject 
permanently discontinued study drug after experiencing fever, muscle weakness, 
dehydration, and hyponatremia.  All subjects responded to symptomatic therapy 
with either NSAIDs, paracetamol, or corticosteroids and best supportive care 
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Renal failure (dabrafenib or dabrafenib-trametinib):  Renal failure was observed 
in the dabrafenib ISS population (<1%; <1% grade 3/4) and trametinib ISS 
population (2%; no grade 3, <1% grade 4), and was increased in incidence and 
severity in the combination arm in study BRF113220 (7%, all grade 3) (IB, 2013).  
Most cases of acute renal failure presented as a secondary event in the setting of 
pyrexia where dehydration appeared to be a contributing factor and/or in concert 
with other risk factors such as hemolytic uremic syndrome (HUS), antibiotic 
toxicity, or hypercalcemia.  There was one case of advanced renal failure which 
may have been drug-induced but whose precise etiology was not clear.  The 
renal events led to permanent discontinuation of study drugs in one subject, and 
to dose interruptions in three subjects. 
Hypertension (dabrafenib-trametinib): Hypertension has been associated with 
trametinib therapy.  In the combination study of dabrafenib-trametinib, the 
combination arm had a higher rate of hypertension compared to the dabrafenib 
ISS population (9% vs. 2%); however, this rate was lower than that in the 
trametinib ISS population (15%) (IB, 2013).   
In either the combination or the dabrafenib monotherapy population, there were 
no SAEs related to hypertension, and hypertension did not lead to treatment 
discontinuation, dose reduction or dose interruption in any of the patients.   
Cardiac valvular abnormalities (dabrafenib or dabrafenib-trametinib):  Data 
from preclinical studies suggested that dabrafenib has the potential to cause 
cardiac valve abnormalities.  In a 28-day dog toxicology study, high doses (50 
mg/kg/day; approximately 40-fold over the therapeutic dose) of dabrafenib in 1 
dog (n=10) resulted in hypertrophy of the right atrio-ventricular valve (tricuspid 
valve).  Therefore, this was monitored in clinical trials with echocardiograms. 
Cardiomyopathy (dabrafenib-trametinib):  Cardiomyopathy has been associated 
with trametinib use and therefore the incidence was increased in the dabrafenib-
trametinib combination compared to dabrafenib alone.  Cardiac-related AEs 
occurred in 9% of subjects in the Part C 150/2 group, which is the same 
incidence as in the Trametinib ISS population (9%), but a higher incidence 
compared with the Dabrafenib ISS population (2%) (IB, 2013).  Decreased 
ejection fraction was the only AE reported in the Part C 150/2 group, and all 
reports were either grade 1 or 2. 
Ocular adverse events:  Ocular events occurred at a higher frequency in study 
BRF113220 Part C 150/2 combination group (25%) compared to trametinib 
(13%) and dabrafenib (8%) monotherapy ISS populations (IB, 2013).  Blurred 
vision, dry eye, and visual impairment were the most commonly reported ocular 
events in the Part C 150/2 group.  All ocular events in Part C 150/2 were grade 1 
to 2 with the exception of one case of grade 3 retinal pigment epithelial 
detachment (RPED).  
RPED and RVO (dabrafenib-trametinib):  These two events are associated with 
trametinib therapy and therefore were observed in the combination of dabrafenib 
and trametinib.  Of 365 subjects in Study BRF113220, the incidence of RPED 
remained at 1% and is thus similar to the frequency observed in the overall 
trametinib development program so far. Thus, the addition of dabrafenib appears 
to have no impact on the frequency or severity of RPED previously reported for 
trametinib.  

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RVO has not been reported as an AE in the dabrafenib ISS population of 586 
subjects. Addition of dabrafenib to trametinib in the combination treatment 
regimen in Study BRF113220 did not increase the frequency of RVO observed 
thus far with trametinib monotherapy.  
Uveitis, iritis, and iridocyclitis (dabrafenib or dabrafenib-trametinib):  Uveitis 
and iritis can occur when dabrafenib is administered as a single agent or in 
combination with trametinib.  In the 365 subjects with melanoma treated on the 
dabrafenib-trametinib combination arm in Study BRF113220, the incidence of 
ocular events including uveitis, iritis, or iridocyclitis was 2%, and responded to 
symptomatic therapy, which included primarily the use of topical corticosteroids.  
This rate is slightly higher than in the dabrafenib ISS population (1%).  In 
addition, the severity of the inflammatory ocular events also appeared to be 
slightly increased, with 2 cases of uveitis Grade 3 and 1 case of Grade 4. 
Hyperglycemia (dabrafenib or dabrafenib-trametinib):  Hyperglycemia can occur 
when dabrafenib is used as a monotherapy or in combination with trametinib.  In 
study BRF112680 (dabrafenib monotherapy), 5/12 patients with a history of 
diabetes required more intensive hypoglycemic therapy while taking dabrafenib; 
the incidence of grade 3 hyperglycemia was 6% (12/187) in patients treated with 
dabrafenib compared with none of the dacarbazine-treated patients.  In study 
BRF113220 (combination with trametinib), the incidence of hyperglycemia was 
5% (3/55) in patients treated with dabrafenib-trametinib compared with 2% (1/53) 
in patients treated with dabrafenib (FDA label).  
Pancreatitis (dabrafenib or dabrafenib-trametinib):  Pancreatitis (<1%) and/or 
increased lipase/amylase (2%) have been reported at low frequency with 
dabrafenib.  In the phase 2 combination study BRAF113229, AEs of acute 
pancreatitis or pancreatitis occurred in six (1%) subjects on the dabrafenib-
trametinib arm (IB, 2013), and none with dabrafenib monotherapy.  The time to 
onset of pancreatitis ranged from Study Day 21 to 292 (median:  138 days).  At 
the data cut-off, 4 subjects had recovered from the event of pancreatitis.  
Discontinuation of study drugs due to pancreatitis was not deemed necessary by 
the investigators in any of the 6 cases.  The incidence of pancreatitis was <1% in 
the dabrafenib ISS population (2 subjects) and in the trametinib ISS population (1 
subject). 
Hepatic events (dabrafenib-trametinib combination):  In the Part C 150/2 group, 
15% of subjects experienced hepatic AEs as compared to 13% of subjects in the 
trametinib ISS population and 6% of subjects in the dabrafenib ISS population 
(IB, 2013).  Of the hepatic AEs, increased ALT and AST were the most common 
events in all groups, and most were either grade 1 or 2.  No cases of Hy’s law 
(propensity for fatal drug induced liver injury given severe transaminase 
elevations with or without hyperbilirubinemia) were observed among any of the 
subjects in the BRF113220 study. 
Diarrhea (dabrafenib-trametinib combination):  The proportion of subjects in the 
Part C 150/2 group who experienced diarrhea was 36% compared with 49% in 
the trametinib ISS population and 16% in the dabrafenib ISS population (IB, 
2013).  Most subjects across the monotherapy and combination therapy 
dabrafenib and trametinib clinical programs reported grade 1 or grade 2 diarrhea. 
Pneumonitis (dabrafenib-trametinib combination):  Pneumonitis was not 
reported as an AE in the 365 subjects enrolled in Study BRF113220 

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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
21 
(Investigators Brochure, 2013).  However, pneumonitis was the most common 
drug-related SAE (1% of subjects) Trametinib ISS population.  Overall, the 
addition of dabrafenib to trametinib does not appear to increase the frequency or 
severity of pneumonitis previously observed with trametinib monotherapy. 
Hypersensitivity:  There has been a single report of hypersensitivity (blisters) to 
dabrafenib, occurring on the same day as the 1st dose of study drug as well as 
upon rechallenge (IB, 2013).  The subject recovered after interruption and then 
discontinuation of dabrafenib.  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. 
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.”  The subject recovered after discontinuation of trametinib. 
Hemorrhages (dabrafenib-trametinib combination):  Hemorrahge is an AE 
identified with the dabrafenib-trametinib combination therapy.  Hemorrhages, 
including major hemorrhages defined as symptomatic bleeding in a critical area 
or organ, can occur with dabrafenib plus trametinib combination therapy (FDA 
label).  In study BRF113220, treatment with dabrafenib in combination with 
trametinib resulted in an increased incidence and severity of any hemorrhagic 
event:  16% (9/55) of patients treated with trametinib in combination with 
dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a 
single agent.  The major hemorrhagic events of intracranial or gastric 
hemorrhage occurred in 5% (3/55) of patients treated with trametinib in 
combination with dabrafenib compared with none of the 53 patients treated with 
dabrafenib as a single agent.  Intracranial hemorrhage was fatal in two (4%) 
patients receiving the combination of trametinib and dabrafenib.  
Glucose-6-phosphate dehydrogenase (G6PD) deficiency (dabrafenib or 
dabrafenib-trametinib combination):  Dabrafenib, which contains a sulfonamide 
moiety, confers a potential risk of hemolytic anemia in patients with G6PD 
deficiency; these patients should be closely observed for signs of hemolytic 
anemia.   
Embryofetal toxicity:  Based on the mechanisms of action, dabrafenib and/or 
trametinib can cause fetal harm when administered to a pregnant woman.  
Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater 
than the human exposure at the recommended clinical dose.  Trametinib was 
embryotoxic and abortifacient in rabbits at doses greater than or equal to those 
resulting in exposures approximately 0.3 times the human exposure at the 
recommended clinical dose.  
1.8 
Clinical pharmacology of trametinib: 
Trametinib is absorbed rapidly with median Tmax generally occurring 1.50 hours 
after single oral administration of trametinib under fasting conditions.  The 
absolute oral bioavailability of a single trametinib 2 mg tablet is moderate to high 
(72%) relative to a co-administered IV microdose.  

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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
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Following repeat-dosing the mean area under the curve (AUC0-) and maximum 
concentrations (Cmax) increased in an approximately dose proportional manner.  
Trametinib accumulates with repeat dosing with a mean accumulation ratio at the 
recommended dose of 2 mg once daily of 5.97 and a terminal half-life of 5.3 
days. Steady state is achieved by Day 15.   
Trametinib has a high volume of distribution (Vd) of 1060 L.  Fecal excretion is 
the major route of elimination after [14C] trametinib oral dose, accounting for  
> 80% of excreted radioactivity recovered (or 39.2 and 35.0% of the radioactive 
dose in 2 subjects) while urinary excretion accounted for < 19% of excreted 
radioactivity recovered (< 10% of the radioactive dose).   
In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of 
other drugs and that the PK of trametinib is unlikely to be affected by other drugs.  
Trametinib is metabolized predominantly via deacetylation which is likely 
mediated by hydrolytic esterases which are not generally associated with drug 
interaction risk, nor is it a substrate of P-gp or BCRP. 
Rev. Add13 

ECOG-ACRIN 
EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
23 
2. 
Selection of Patients 
In order for a patient to be considered eligible for this study, each of the criteria in the 
following checklist must be met in addition to the eligibility in the MATCH Master 
Protocol. Use the checklist to confirm a patient’s eligibility. For each patient, this 
checklist must be photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
All patients must have the relevant treatment consent form 
2.1 
Eligibility Criteria 
2.1.1 
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patients must have a BRAF V600E or, V600K, V600R or V600D 
mutation, or another aberration, as identified via the MATCH Master 
Protocol and described in Appendix IV. See Appendix IV for 
information on the targeted mutations and the corresponding Levels of 
Evidence (LOE). 
2.1.3 
Patients with a diagnosis of metastatic melanoma from a cutaneous, 
acral, mucosal, or unknown primary site are excluded. 
2.1.4 
Patients with a diagnosis of papillary thyroid cancer are excluded.  
2.1.5 
Patients with a diagnosis of colorectal adenocarcinoma are excluded. 
2.1.6 
Patients with a diagnosis of non-small cell lung cancer are excluded. 
Rev. 8/15 
Rev. 8/15 
Rev.2/16 
Rev.5/16 
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Rev. 8/15 
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EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
24 
2.1.7 
Patients must have normal organ and marrow function as defined 
below: 
• 
Prothrombin time (PT)/International normalized ratio (INR) and 
partial thromboplastin time (PTT) ≤ 1.3x institutional ULN; subjects 
receiving anticoagulation treatment may be allowed to participate 
with INR established within the therapeutic range prior to 
registration to treatment. 
2.1.8 
Patients must have an ECHO or a nuclear study (MUGA or First 
Pass) within 4 weeks prior to registration to treatment and must not 
have a left ventricular ejection fraction (LVEF) < the institutional lower 
limit of normal (LLN). If the LLN is not defined at a site, the LVEF must 
be > 50% for the patient to be eligible. 
Date of ECHO/nuclear study:  _______________ 
2.1.9 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have NONE of the following 
cardiac criteria: 
• 
Clinically important abnormalities in rhythm, conduction or 
morphology of resting ECG (e.g. complete left bundle branch 
block, third degree heart block). 
• 
Treatment-refractory hypertension defined as a blood pressure of 
systolic >140 mmHg and/or diastolic > 90 mmHg which cannot be 
controlled by anti-hypertensive therapy. 
Date of ECG:  _______________ 
2.1.10 
Patients with a history of interstitial lung disease or pneumonitis are 
excluded. 
2.1.11 
Patients must not have known hypersensitivity to dabrafenib and 
trametinib or compounds of similar chemical or biologic composition 
or to dimethyl sulfoxide (DMSO). 
2.1.12 
Patients must not have a history or current evidence/risk of retinal 
vein occlusion (RVO). An eye exam is required at baseline. See 
Appendix III for the Trametinib Ophthalmic Exam Form. 
2.1.13 
Patients who previously received MEK inhibitors (including, but not 
limited to, trametinib, binimetinib, cobimetinib, selumetinib, 
RO4987655 (CH4987655), GDC-0623 and pimasertib) will be 
excluded. 
2.1.14 
Patients who previously received BRAF inhibitors (including, but not 
limited to, dabrafenib (Tafinlar), vemurafenib (PLX-4720) (Zelboraf), 
RAF265, LGX818 (encorafenib), RO5212054 (PLX3603), ARQ 736, 
XL281 (BMS-908662), CEP-32496, and the BRAF/MEK dual inhibitor 
RO5126766) will be excluded. 
2.1.15 
Patients with prior exposure to dabrafenib or trametinib on another 
treatment subprotocol of the MATCH trial are excluded. 
2.1.16 
Current use of a prohibited medication.  Patients receiving any 
medications or substances that are strong inhibitors or inducers of 
Rev. 8/15, 2/16 
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Rev. 8/15 
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ECOG-ACRIN 
EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
25 
CYP3A or CYP2C8 are ineligible.  Current use of, or intended ongoing 
treatment with:  herbal remedies (e.g., St. John's wort), or strong 
inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer 
resistance protein 1 (Bcrp1) should also be excluded.  See Appendix 
II for a list of these prohibited medications.  
2.1.17 
Patients who previously received monoclonal antibody therapy (eg. 
Ipilimumab and others) must have stopped the prior therapy for 8 or 
more weeks before starting on trametinib and dabrafenib. 
2.1.18 
Patients with a history of Hepatitis B Virus (HBV) or Hepatitis C Virus 
(HCV) infection are excluded.  An exception will be patients with 
cleared HBV and HCV infection which will be allowed on study. 
2.1.19 
Patients with history of RAS mutation-positive tumors are not eligible 
regardless of interval from the current study.   
NOTE: 
Prospective RAS testing is not required.  However, if the 
results of previous RAS testing are known, they must be 
used in assessing eligibility. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
26 
3. 
Trametinib/Dabrafenib Treatment Plan 
3.1 
Administration Schedule 
Dabrafenib will be administered in combination with trametinib. The dose of 
dabrafenib is 150 mg orally twice daily, taken approximately 12 hours apart in 
combination with trametinib 2 mg given orally once daily for a 28 days cycle. 
When dabrafenib and trametinib are administered in combination, take the once-
daily dose of trametinib at approximately the same time each day with either the 
morning dose or the evening dose of dabrafenib. The second dose of dabrafenib 
should be administered approximately 12 hours after the morning dose. Study 
medication should be taken orally with approximately 200 mL of water under 
fasting conditions, either 1 hour before or 2 hours after a meal. 
If a subject vomits after taking study medication, the subject should be instructed 
not to retake the dose and should take the next dose as originally scheduled.   
If administration of trametinib is interrupted or permanently discontinued, 
administration of dabrafenib may be continued. If administration of dabrafenib is 
interrupted or permanently discontinued, administration of trametinib may 
continue. 
If a subject misses a dose of dabrafenib, the subject may take the dose 
immediately if the next dose is scheduled for at least 6 hours later.  If the next 
scheduled dose of dabrafenib is due in less than 6 hours, the subject should skip 
the dose and resume dabrafenib dosing at the next scheduled dose.  If a subject 
misses a dose of trametinib, the subject may take the dose immediately if the 
next dose is scheduled for at least 12 hours later. 
3.2 
Adverse Event Reporting Requirements  
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS).  
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1 
Additional adverse event reporting instructions, requirements and 
exceptions for EAY131 – Subprotocol H 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com  or 301-897-7497.  This will 
need to be discussed on a case-by-case basis. 
 
Rev.2/16 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
27 
EAY131 – Subprotocol H specific expedited reporting 
requirements: 
• 
LVEF Changes: If any of the following circumstances occur, 
the event(s) must be reported via CTEP-AERS according to 
the timeframes outlined in the AE table in section 5.3.6 of the 
MATCH Master protocol 
• 
Asymptomatic:  Absolute decrease of >10% in LVEF 
compared to baseline and ejection fraction below the 
institution’s LLN and LVEF does not recover within 4 
weeks 
• 
Symptomatic: Grade 3-4 LVEF 
Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for LVEF Decrease 
• 
Visual Changes:  If RPED (retinal pigment epithelial 
detachments) or RVO (retinal vein occlusion) are diagnosed, 
the event(s) must be reported via CTEP-AERS according to 
the timeframes outlined in the AE table in section 5.3.6 of the 
MATCH Master protocol.  Please refer to the dose modification 
instructions for further information regarding Treatment 
Modification and Management Guidelines for Visual Changes. 
• 
Liver Chemistry Changes:  If any of the following 
circumstances occur, the event(s) must be reported via CTEP-
AERS according to the timeframes outlined in the AE table in 
section 5.3.6 of the MATCH Master protocol 
• 
ALT ≥ 3xULN and bilirubin ≥ 2x ULN or > 35% direct 
bilirubin 
• 
ALT  3xULN and INR ≥ 1.5, if INR measured  (INR 
threshold does not apply if subject is on anticoagulant) 
Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for Liver Chemistry Changes 
• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the subject is on 
Dabrafenib or Trametinib, or within 28 days of the subject’s last 
dose of Dabrafenib or Trametinib, are considered immediately 
reportable events. The pregnancy, suspected pregnancy, or 
positive/ inconclusive pregnancy test must be reported via 
CTEP-AERS within 24 hours of the Investigator’s knowledge.  
Please refer to Appendix VIII in MATCH Master Protocol for 
detailed instructions on how to report the occurrence of a 
pregnancy as well as the outcome of all pregnancies. 
 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
28 
EAY131 – Subprotocol H specific expedited reporting 
exceptions: 
For Subprotocol H, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event. Since this protocol 
uses multiple investigational agents, if an AE is listed on both 
SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
3.2.2 
Second Primary Cancer Reporting Requirements 
NOTE: 
The MATCH Master Protocol outlines the standard 
requirements for the reporting of second primaries. 
Please be aware that there are additional requirements 
for this subprotocol. Please adhere to the guidelines 
outlined below for the reporting of second primaries 
on this subprotocol. 
All cases of second (second malignancy is a cancer that is unrelated 
to any prior anti-cancer treatment, including the treatment on this 
protocol) and secondary malignancies (secondary malignancy is a 
cancer caused by any prior anti-cancer treatment, including the 
treatment on this protocol),   including acute myeloid leukemia (AML) 
and myelodysplastic syndrome (MDS)], regardless of attribution, that 
occur following treatment on NCI-sponsored trials must be reported as 
follows:   
1. Complete a Second Primary Form in Medidata Rave within 14 days. 
2. Report the diagnosis via CTEP-AERS, regardless of attribution, at 
http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology chemotherapy, 
b.) myelodysplastic syndrome, or c.) treatment related secondary 
malignancy,  
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a copy 
of the cytogenetics report (if available) to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP.  
NOTE: 
All new malignant tumors must be reported through 
CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment.  All new 
malignancies should be reported including solid tumors 
(including non-melanoma skin malignancies), hematologic 
malignancies, Myelodysplastic Syndrome (MDS)/Acute 
Myelogenous Leukemia (AML), and in situ tumors.   

ECOG-ACRIN 
EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
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Whenever possible, the CTEP-AERS report should include the 
following:   
• 
tumor pathology 
• 
history of prior tumors 
• 
prior treatment/current treatment including duration 
• 
any associated risk factors or evidence regarding how long the 
tumor may have been present 
• 
when and how the tumor was detected 
• 
molecular characterization or cytogenetics or the original tumor (if 
available) and of any new tumor 
• 
tumor treatment and outcome (if available).   
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
 

ECOG-ACRIN 
EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
30 
3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Trametinib 
dimethyl sulfoxide (GSK1120212B, NSC 763093) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 1111 patients. 
Below is the CAEPR for Trametinib dimethyl sulfoxide (GSK1120212B). 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER. Since this protocol uses multiple 
investigational agents, if an AE is listed on both SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
Version 2.5, February 1, 20191 
Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
Anemia (Gr 3) 
CARDIAC DISORDERS 
 
Heart failure 
 
Left ventricular systolic 
dysfunction 
 
Sinus bradycardia 
 
 
EYE DISORDERS 
 
Blurred vision 
 
 
Dry eye 
 
 
Eye disorders - Other 
(chorioretinopathy also 
known as retinal pigment 
epithelial detachment) 
 
Eye disorders - Other 
(retinal vein occlusion) 
 
Eye disorders - Other 
(visual disorders)2 
 
 
Papilledema 
 
Periorbital edema 
 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Abdominal pain (Gr 2) 
Colitis 
 
Colonic perforation 
 
Constipation 
 
Constipation (Gr 2) 
Rev. 2/16 
Rev. 1/17 
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ECOG-ACRIN 
EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
31 
Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
Diarrhea 
 
Diarrhea (Gr 3) 
Dry mouth 
 
Dry mouth (Gr 2) 
Dyspepsia 
 
Dyspepsia (Gr 2) 
Mucositis oral 
 
Mucositis oral (Gr 3) 
Nausea 
 
Nausea (Gr 3) 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
Chills (Gr 2) 
Edema face 
 
 
Fatigue 
 
Fatigue (Gr 3) 
Fever 
 
Fever (Gr 2) 
Generalized edema3 
 
Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction4 
 
 
INFECTIONS AND INFESTATIONS 
 
Folliculitis 
 
Folliculitis (Gr 2) 
Lung infection 
 
 
Paronychia 
 
Paronychia (Gr 2) 
Skin infection 
 
Skin infection (Gr 2) 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase 
increased 
 
Alkaline phosphatase increased 
(Gr 2) 
Aspartate 
aminotransferase 
increased 
 
Aspartate aminotransferase 
increased (Gr 3) 
CPK increased 
 
 
Ejection fraction 
decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
Anorexia (Gr 3) 
Dehydration 
 
Dehydration (Gr 3) 
Hypoalbuminemia 
 
 
Hypomagnesemia 
 
Hypomagnesemia (Gr 2) 
Hyponatremia 
 
Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
Back pain (Gr 2) 
Pain in extremity 
 
Pain in extremity (Gr 2) 
Rhabdomyolysis 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Dizziness (Gr 2) 
Headache 
 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
Cough (Gr 2) 
Dyspnea 
 
Dyspnea (Gr 3) 
Pneumonitis 
 

ECOG-ACRIN 
EAY131-H 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
32 
Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
Alopecia (Gr 2) 
Dry skin 
 
Dry skin (Gr 2) 
Nail changes 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
Pruritus 
 
Pruritus (Gr 2)  
Skin and subcutaneous 
tissue disorders - Other 
(rash)5 
 
 
Skin and subcutaneous tissue 
disorders - Other (rash)5 (Gr 3) 
VASCULAR DISORDERS 
 
Hypertension 
 
Hypertension (Gr 3) 
Thromboembolic event 
(venous) 
 
Vascular disorders - Other 
(hemorrhage)6 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.. 
2 Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, corneal 
graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, visual acuity 
reduced, visual impairment, and vitreous detachment. 
3 Generalized edema includes edema, lymphedema, and edema limbs.. 
4 Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver 
function tests, and visual disturbances. 
5 Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, erythematous rash, 
genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash papular, seborrhoeic 
dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped. 
6 The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal 
intracranial hemorrhages have been reported. 
Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable possibility 
that trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; 
Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive 
cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; Glaucoma; 
Photophobia  
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; 
Esophageal ulcer; Esophagitis; Gastric hemorrhage; Gastric ulcer; Gastritis; Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (pneumatosis 

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intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage; Ileus; Obstruction 
gastric; Pancreatitis; Small intestinal obstruction  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; 
General disorders and administration site conditions - Other (axillary pain); Localized edema; 
Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary 
disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; Device 
related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; Infections and 
infestations - Other (abscess limb); Infections and infestations - Other (necrotizing fasciitis); 
Infections and infestations - Other (oral infection); Pharyngitis; Sepsis; Upper respiratory 
infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising  
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum amylase 
increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other (compression 
fracture); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage; 
Lethargy; Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; Pneumothorax; 
Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
NOTE: 
Trametinib (GSK1120212B) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 

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3.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Dabrafenib 
mesylate (GSK2118436B, NSC 763760) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 1374 patients. 
Below is the CAEPR for Dabrafenib mesylate (GSK2118436B). 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER. Since this protocol uses multiple 
investigational agents, if an AE is listed on both SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
Version 2.4, May 7, 20191 
 
Adverse Events with Possible 
Relationship to Dabrafenib (GSK2118436B) 
(CTCAE 5.0 Term) 
[n= 1374] 
 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia2,3 
 
Anemia2,3(Gr 2) 
EYE DISORDERS 
 
Eye disorders - Other (iritis)4  
Uveitis4 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Abdominal pain (Gr 3) 
Constipation 
 
Constipation (Gr 3) 
Diarrhea 
 
Diarrhea (Gr 3) 
Nausea 
 
Nausea (Gr 3) 
Pancreatitis 
 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
Chills (Gr 2) 
Edema limbs5 
 
Edema limbs5 (Gr 2)  
Fatigue 
 
Fatigue (Gr 3) 
Fever6 
 
Fever6 (Gr 2) 
Flu like symptoms 
 
Flu like symptoms (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction7 
 
INFECTIONS AND INFESTATIONS 
 
Upper respiratory infection 
 
 
Rev.2/16 
Rev.12/16 
Rev. Add21 

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Adverse Events with Possible 
Relationship to Dabrafenib (GSK2118436B) 
(CTCAE 5.0 Term) 
[n= 1374] 
 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
INVESTIGATIONS 
 
Creatinine increased3 
 
Creatinine increased3 (Gr 2) 
Neutrophil count decreased3 
 
Neutrophil count decreased3 
(Gr 3) 
Platelet count decreased3 
 
Platelet count decreased3 (Gr 
2) 
White blood cell decreased3 
 
White blood cell decreased3 
(Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
Anorexia (Gr 2) 
Hyperglycemia3 
 
Hyperglycemia3 (Gr 2) 
Hypokalemia3 
 
Hypokalemia3 (Gr 2) 
Hyponatremia3 
 
Hyponatremia3 (Gr 3) 
 
Hypophosphatemia3 
 
Hypophosphatemia3 (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
Arthralgia (Gr 3) 
Back pain 
 
Back pain (Gr 3) 
Myalgia 
 
Myalgia (Gr 3) 
Pain in extremity 
 
Pain in extremity (Gr 3) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (squamous cell 
carcinoma or 
keratoacanthoma)8 
 
Neoplasms benign, 
malignant and unspecified 
(incl cysts and polyps) - 
Other (squamous cell 
carcinoma or 
keratoacanthoma)8 (Gr 2) 
Skin papilloma 
 
Skin papilloma (Gr 2) 
 
Treatment related secondary 
malignancy (non-SCC)9 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Dizziness (Gr 2) 
Headache 
 
Headache (Gr 2) 
Syncope 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
Cough (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
Alopecia (Gr 2) 
Dry skin 
 
Dry skin (Gr 2) 
Hair texture abnormal 
 
Hair texture abnormal (Gr 2) 
Hyperhidrosis 
 
Hyperhidrosis (Gr 2) 
Hyperkeratosis 
 
Hyperkeratosis (Gr 2) 
Palmar-plantar 
erythrodysesthesia syndrome 
 
Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 2) 

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Adverse Events with Possible 
Relationship to Dabrafenib (GSK2118436B) 
(CTCAE 5.0 Term) 
[n= 1374] 
 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Pruritus 
 
Pruritus (Gr 3) 
Rash10  
 
Rash10 (Gr 2) 
Skin and subcutaneous 
tissue disorders - Other 
(neutrophilic panniculitis)11 
 
VASCULAR DISORDERS 
 
Hypertension 
 
 
Thromboembolic event12 
 
 
Vascular disorders - Other 
(hemorrhage)13 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting  
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent 
should be included in the e-mail. 
2 The incidence of anemia is increased when dabrafenib mesylate (GSK2118436B) is used in 
combination with trametinib dimethyl sulfoxide (GSK1120212B). 
3 The frequencies of these events are based upon laboratory findings rather than being due to patient-
reported outcomes. 
4 Dabrafenib mesylate (GSK2118436B) has been associated with ocular toxicities including 
chorioretinitis, retinitis, iridocyclitis, iritis, and uveitis. 
5 Edema limbs (peripheral edema) is a risk associated when dabrafenib mesylate (GSK2118436B) is 
used in combination with trametinib dimethyl sulfoxide (GSK1120212B) compared to dabrafenib 
mesylate (GSK2118436B) alone. 
6 Fever (pyrexia) can be associated with hypotension and/or (in rare cases) syncope. The frequency of 
fever and serious febrile events is increased when dabrafenib mesylate (GSK2118436B) is used in 
combination with trametinib dimethyl sulfoxide (GSK1120212B). 
7 Manifestations of allergic reactions (hypersensitivity) to dabrafenib mesylate (GSK2118436B) may 
include bullous rash (bullous dermatitis). 
8 Squamous cell carcinoma (SCC), including SCC of the skin, SCC in situ (Bowen’s disease), and 
keratoacanthoma have been observed. 
9 New non-SCC malignancies have been reported including primary melanoma, basal cell carcinoma, 
and non-cutaneous malignancies. 
10 Rash includes the terms: rash, rash acneiform, rash papular, rash maculo-papular, and erythema. 
11 Recurrent neutrophilic panniculitis has been observed in at least one patient treated with dabrafenib 
mesylate (GSK2118436B) in combination with the MEK inhibitor trametinib dimethyl sulfoxide 
(GSK1120212B). 
12 Venous thromboembolic events (including deep vein thrombosis and pulmonary embolism) is a risk 
associated when dabrafenib mesylate (GSK2118436B) is used in combination with trametinib dimethyl 
sulfoxide (GSK1120212B). 
13 Treatment with dabrafenib mesylate (GSK2118436B) in combination with trametinib dimethyl sulfoxide 
(GSK1120212B) resulted in an increased incidence and severity of hemorrhagic events compared to 
patients treated with dabrafenib mesylate (GSK2118436B) as a single agent.  Sites of hemorrhage may 
include, but are not limited to, intracranial, reproductive tract, respiratory tract, and gastrointestinal 
hemorrhage. 

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Adverse events reported on Dabrafenib mesylate (GSK2118436B) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that 
Dabrafenib mesylate (GSK2118436B) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (agranulocytosis); Blood and lymphatic system disorders - Other (pancytopenia); 
Disseminated intravascular coagulation; Febrile neutropenia; Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Heart failure; Left 
ventricular systolic dysfunction; Mitral valve disease; Myocardial infarction; Pericardial effusion; 
Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Eye disorders - Other (amaurosis fugax); Eye disorders - 
Other (vitreous detachment); Floaters; Photophobia; Retinal detachment; Retinopathy; Vision 
decreased. 
GASTROINTESTINAL DISORDERS - Colitis; Colonic perforation; Dry mouth; Dyspepsia; 
Gastritis; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Disease 
progression; Gait disturbance; Localized edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic pain 
INFECTIONS AND INFESTATIONS - Bacteremia; Bronchial infection; Catheter related 
infection; Device related infection; Gallbladder infection; Infections and infestations - Other 
(bacterial peritonitis); Infections and infestations - Other (blood culture positive); Infections and 
infestations - Other (croup infectious); Infections and infestations - Other (Epstein-Barr virus 
infection); Infections and infestations - Other (respiratory tract infection); Lung infection; Otitis 
media; Pharyngitis; Rash pustular; Rhinitis infective; Sepsis; Skin infection; Urinary tract 
infection; Viremia 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Injury, poisoning 
and procedural complications - Other (complication associated with device); Injury, poisoning 
and procedural complications - Other (device occlusion); Injury, poisoning and procedural 
complications - Other (radiation injury, stroke-like migraine attacks after radiation therapy); 
Seroma 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; CD4 lymphocytes decreased; 
Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Lipase increased; Lymphocyte count decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypernatremia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized 
muscle weakness; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (acrochordon); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (bile duct adenocarcinoma); 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (mycosis 
fungoides)  

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NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Hydrocephalus; Lethargy; Nervous system disorders - 
Other (expressive aphasia); Nervous system disorders - Other (intracranial pressure increased); 
Paresthesia; Seizure; Somnolence; Stroke 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Hallucinations; 
Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria; Renal calculi; Urinary frequency; Urinary 
retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Menorrhagia; Prostatic obstruction; 
Reproductive system and breast disorders - Other (hematospermia) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Dyspnea; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleuritic 
pain; Productive cough; Pulmonary edema; Respiratory failure; Rhinorrhea; Sore throat; Stridor; 
Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Eczema; 
Erythroderma; Photosensitivity; Purpura; Skin and subcutaneous tissue disorders - Other 
(palmoplantar keratoderma); Skin and subcutaneous tissue disorders - Other (sunburn); Skin 
hyperpigmentation 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension 
NOTE: 
Dabrafenib (GSK2118436B) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
 

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3.5 
Dose Modifications  
NOTE: 
Patients who interrupt trametinib and dabrafenib for > 2 weeks will be 
removed from this subprotocol, unless the interruption was for 
reduction in LVEF, visual changes or RPED with subsequent recovery 
as described in corresponding tables below. 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
The table below outlines the dose levels to be used for any necessary dabrafenib 
and trametinib dose modifications in studies which include the combination: 
Dose Level 
Dabrafenib Dose/Schedule 
0 
150 mg BID 
-1 
100 mg BID 
-2 
75 mg BID 
-3 
50 mg BID 
 
Dose Level 
Trametinib Dose/Schedule 
0 
2 mg QD 
-1 
1.5 mg QD 
-2 
1.0 mg QD 
Dabrafenib and Trametinib Dose Modification Guidelines 
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.  A dose reduction 
below 50 mg BID for dabrafenib is not allowed.  For dabrafenib-trametinib 
combination, dose below 1 mg once daily for trametinib is not allowed; however, 
if dabrafenib will be permanently discontinued for dabrafenib-related toxicities, 
the patients will be allowed to continue trametinib.  Conversely, if trametinib is 
permanently discontinued for trametinib-related toxicities, patients will be allowed 
to continue dabrafenib. 
The dose modifications may involve one or both agents, and should be based on 
the nature, severity and attributions of the AEs.  General guidelines are provided 
in Tables below, with details stipulated in subsequent sections.  The CTEP drug 
monitors should be consulted if there are questions about the attribution of AEs 
and how the doses should be modified. 
Rev. 12/16 
Rev. Add13 

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3.5.1 
Dabrafenib-Trametinib Dose Modification for Toxicities Not Specified 
in Subsequent Sections 
Dabrafenib-Trametinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
CTCAE Grade 
Action and Dose Modification 
Grade 1 
Grade 2 (tolerable) 
• Continue study treatment at same dose level (no dose modification). 
• Monitor closely. 
• Provide supportive care according to institutional standards. 
Grade 2 (intolerable) 
Grade 3 
• Interrupt study treatment. 
• Monitor closely. 
• Provide supportive care according to institutional standards. 
• When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by one dose level. 
• If the grade 2 (intolerable) or grade 3 toxicity recurs, interrupt study 
treatment. 
• When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by another dose level. 
Grade 4 
• Permanently discontinue, or interrupt, study treatment. 
• Monitor closely. 
• Provide supportive care according to institutional standards. 
• If study treatment was interrupted, restart  study treatment reduced by one 
dose level once toxicity resolves to grade 1 or baseline. 
* If the AEs are thought to be due to one of the two agents, resumption of the other agents may be considered if the 
first agent is discontinued due to toxicities and treatment interruption is < 14 days. The subprotocol Study Chair 
should be consulted for resumption of single agent. 
3.5.2 
Dabrafenib-Trametinib Dose Modification for Pyrexia 
• 
Pyrexia is defined as a body temperature equal to or above 38.5○ 
Celsius or 101.3° Fahrenheit  
• 
Pyrexia is an adverse event associated with dabrafenib and is 
increased in frequency and severity in subjects receiving 
dabrafenib in combination with trametinib.  In a minority of cases, 
pyrexia was accompanied by symptoms such as severe 
chills/rigors, dehydration, hypotension, dizziness or weakness and 
required hospitalization.  
• 
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 anti-pyretics (e.g. ibuprofen or 
acetaminophen/paracetamol) as appropriate to control fever.  The 
use of oral corticosteroids should be considered in those 
instances in which anti-pyretics are insufficient. Monitor serum 
creatinine and other evidence of renal function during and 
following severe events of pyrexia  
Rev. 8/15 

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Dabrafenib-Trametinib dose Modification and Management Guidelines for Pyrexia 
Event 
Management Guideline 
Dose Modification 
Work up: 
• Clinical evaluation for infection and hypersensitivity, especially if pyrexia is complicated by rigors, 
severe chills, dehydration, etc.  
• Laboratory work-up (should include full-blood-count, electrolytes, creatinine, BUN, CRP, liver-function 
tests, blood and urine culture). 
Management:  
• Anti-pyretic treatment should be started immediately at the first occurrence.  Anti-pyretic treatment 
may include acetaminophen (paracetamol), ibuprofen, or suitable anti-pyretic medication per 
institutional standards. 
• Oral hydration is encouraged in subjects without evidence of dehydration.  Intravenous hydration is 
recommended if pyrexia is complicated by dehydration/hypotension. 
• In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled 
with anti-pyretic medication, oral corticosteroids should be started. 
• Prophylactic anti-pyretic treatment is recommended after the 2nd event, or after the 1st event if 
complicated by rigors or severe chills. Prophylactic anti-pyretics may be discontinued after three days 
in absence of pyrexia   
1st Event: 
• Clinical evaluation for infection and 
hypersensitivity 
• Laboratory work-up 
• Hydration as required 
• Administer anti-pyretic treatment if clinically 
indicated and continue prophylactic treatment 
• Interrupt dabrafenib. 
• Continue trametinib.  
• Upon recovery to baseline, restart dabrafenib 
at the same dose level.  If fever was 
associated with dehydration or hypotension, 
reduce dabrafenib by one dose level. 
2nd Event 
• Clinical evaluation for infection and 
hypersensitivity 
• Laboratory work-up 
• 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. 
• Interrupt dabrafenib. 
• Continue trametinib  
• Upon recovery to baseline, restart dabrafenib 
at the same dose level.  If fever was 
associated with dehydration or hypotension, 
reduce dabrafenib by one dose level. 
Subsequent 
Events:  
• Clinical evaluation for infection and 
hypersensitivity 
• Laboratory work-up 
• Hydration as required 
• Blood sample for cytokine analysis 
• Within 3 days of onset of pyrexia: 
 Optimize oral corticosteroid dose as 
clinically indicated for recalcitrant pyrexia. 
 If corticosteroids have been tapered and 
pyrexia recurs, restart steroids. 
 If corticosteroids cannot be tapered, consult 
the subprotocol Study Chair. 
• Interrupt dabrafenib. 
• Continue trametinib. 
• Once pyrexia resolves to baseline, restart 
dabrafenib reduced by one dose level. 
• If dabrafenib must be reduced to < 50 mg 
BID, permanently discontinue dabrafenib. 
Dabrafenib should be reduced by one dose level after three episodes of pyrexia 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. 
Rev. 8/15 
Rev. 12/16 

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3.5.3 
Dabrafenib-Trametinib Dose Modification for Rash  
Rash is a frequent AE observed in patients receiving trametinib, 
dabrafenib, or the combination of both agents.  Recommendations for 
supportive care and guidelines for dose modifications for rash are 
based on experience with other MEK inhibitors and EGFR 
inhibitors32,33 
The institutional standards for the management of skin-related AEs 
can differ from these guidelines.  In this case, best clinical judgment 
should be applied and a consultation with the subprotocol Study Chair 
may be required. 
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Dabrafenib-Trametinib Supportive care and Dose Modification for Rash 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Supportive care: 
Prevention:   
• 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) 
Symptom management: 
• 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  
* Rash prophylaxis is recommended for the first 6 weeks of study treatment  
* Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management  
Grade 1 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue study treatment. 
• If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce study 
treatment with both drugs by one dose level.3 
Grade 2  
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Reduce study treatment with both drugs by 
one dose level. 
• If rash recovers 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 recovery to ≤ grade 
1. 
• Restart study treatment with both drugs at 
reduced dose level.3 
Grade ≥ 3  • Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt study treatment until rash recovers to ≤ 
grade 1. 
• Restart study treatment with both drugs 
reduced by one dose level.3,4 
• If no recovery to ≤ grade 2 within 14 days, 
permanently discontinue study treatment. 
1. Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
2. Moderate-strength topical steroids: Hydrocortisone 2.5% cream or fluticasone propionate concentration 0.05% 
cream. 
3. Study treatment may be escalated to previous dose level if no rash is evident 4 weeks after restarting study 
treatment. 
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3.5.4 
Dabrafenib-Trametinib Dose Modification for palmar-plantar 
erythrodysesthesia syndrome (PPES) 
• 
Lifestyle modification:  avoidance of hot water, traumatic activity, 
constrictive footwear, or excessive friction on the skin and the use 
of thick cotton socks and gloves, and shoes with padded insoles 
• 
Symptomatic treatments:  apply moisturizing creams frequently, 
topical keratolytics (e.g. urea 20-40 % cream, salicylic acid 6%, 
tazarotene 0.1% cream, fluorouracil 5% cream), clobetasol 
propionate 0.05% ointment for erythematous areas, topical 
lidocaine 2%, and / or systemic pain medication such as 
nonsteroidal anti-inflammatory drugs, codeine, and pregabalin for 
pain. 
• 
Dose modification may also be required. – Refer to table for dose 
modification for non-specific AEs 
3.5.5 
Dabrafenib-Trametinib Treatment Modification for New Primary/ 
Recurrent Malignancies 
3.5.5.1 
Cutaneous SCC and New Primary Melanoma 
Dermatologic skin assessments for subjects on treatment 
should be performed by the treating physician before 
initiation of dabrafenib, then every 2 months through 
treatment.  For protocols that start after June 2014, it is 
also recommended that skin exams, per institutional 
standards, should continue every 2-3 months for 6 months 
after discontinuation of dabrafenib or initiation of another 
anti-neoplastic therapy.  Report any new primary/recurrent 
malignancies as SAE through CTEP-AERS if it meets the 
reporting requirements outlined in Section 3.2.2. 
Cutaneous Squamous Cell Carcinoma (cuSCC) 
Cases of cuSCC (which include those classified as 
keratoacanthoma [KA] or mixed keratoacanthoma subtype) 
have been observed in subjects treated with dabrafenib. 
Approximately 70 % of events occurred within the first 12 
weeks of treatment with a median time to onset of 8 
weeks.  
These should be surgically removed according to 
institutional practices.  Dose modification or interruption of 
study treatment is not required for cuSCC or KA, however 
cuSCC should be reported as an SAE (if it meets the 
reporting requirements outlined in Section 3.2.2). In 
addition, a biopsy of the lesion should be taken, where 
possible, and a summary of the results submitted to CTEP 
through the SAE reporting.   
Patients should be instructed to immediately inform their 
physician if new lesions develop.  

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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.  New primary 
melanoma should be reported as SAE through CTEP-
AERS if it meets the reporting requirements outlined in 
Section 3.2.23.2.2. 
3.5.5.2 
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. 
Permanently discontinue dabrafenib in patients who 
develop RAS mutation-positive non-cutaneous 
malignancies.  If used in combination with trametinib, 
trametinib may continue.   
Following discontinuation of dabrafenib, monitoring for 
non-cutaneous secondary/recurrent malignancies should 
continue for up to 6 months or until initiation of another 
anti-neoplastic therapy. 
New non-cutaneous malignancies should be reported as a 
SAE if it meets the reporting requirements outlined in 
Section 3.2.2. In addition, a biopsy should be taken, where 
possible, and a summary of the results submitted to CTEP 
through the SAE reporting. Testing of these biopsies 
should include RAS mutation analysis and may include 
analysis of genomic alterations, which include but not 
limited to DNA, RNA and protein analysis of these biopsy 
specimens, and would analyze the biological pathways 
known to be associated with, and relevant to, BRAF-
mutant tumor activation. 
3.5.6 
Dabrafenib-Trametinib Dose Modification for Hemorrhages 
Dabrafenib-Trametinib Treatment Modifications for Hemorrhage 
Grade 3 
Hold dabrafenib-trametinib for up to 2 weeks 
If improved, resume the drugs at one dose reduction 
If no improvement, permanently discontinue dabrafenib-
trametinib 
Grade 4 
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3.5.7 
Dabrafenib-Trametinib Dose Modification for 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. For changes in treatment, 
please refer to Dose Modification for Toxicities Not Specified in 
Subsequent Sections Section 3.5.1 
3.5.8 
Dabrafenib-Trametinib Dose Modification for 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. For changes in treatment, please refer to Dose Modification 
for Toxicities Not Specified in Subsequent Sections Section 3.5.1 
3.5.9 
Dabrafenib-Trametinib Dose Modification for Renal Insufficiency 
Cases of renal insufficiency have occurred in patients receiving 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 modified if clinically 
possible. 

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Dabrafenib-Trametinib Dose Modification for Renal Insufficiency 
Serum Creatinine Level 
Management Guideline 
Action and Dose 
Modification 
Serum creatinine increase 
> 0.2 mg/dL (18 mcmol/L) 
BUT 
≤ 0.5 mg/dL (44 mcmol/L) 
above baseline 
• Recheck serum creatinine within 1 week. 
• •Serum creatinine increase >1 week: 
contact the subprotocol Study Chair. If 
elevation persists beyond 4 weeks, 
recommend evaluation (consider renal 
biopsy) for etiology; consider nephrology 
consultation. 
• If pyrexia is present, treat pyrexia as per 
guidelines.a 
Continue study treatment 
at the same dose level. 
Serum creatinine increase 
> 0.5 mg/dL (44 mcmol/L) 
ABOVE NORMAL 
OR 
> 2 mg/dL (> 177 mcmol/L) 
• Monitor serum creatinine ≥ 2-times per 
week. 
• Hospitalization may be necessary if serum 
creatinine cannot be monitored frequently. 
• If pyrexia is present, treat pyrexia per 
guidelines. 
• Consult nephrologist if clinically indicated. 
• Perform renal biopsy if clinically indicated, 
for example: 
 Renal insufficiency persists despite 
volume repletion. 
 Patient has new rash or signs of 
hypersensitivity (such as elevated 
eosinophil count). 
• Interrupt study treatment 
for up to 2 weeks until 
serum creatinine 
recovers to baseline. 
• Restart study treatment.b 
a NSAIDs can induce renal insufficiency, especially in patients with dehydration; ;encourage oral fluids or consider IV 
fluids as clinically indicated. See guidelines for pyrexia Section 3.5.2. 
b Investigator 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 the subprotocol Study Chair is required before restarting study treatment if there is evidence of 
thrombotic microangiopathy. 
3.5.10 
Dabrafenib-Trametinib Dose Modification for Reduced Left Ventricular 
Ejection Fraction 
Decreases of the left ventricular ejection fraction (LVEF) have been 
observed in patients receiving dabrafenib plus trametinib.  Therefore, 
ECHO/MUGA must be performed in regular intervals outlined in the 
Study Calendar.  The same procedure (either ECHO or MUGA, 
although ECHO is preferred) should be performed at baseline and at 
follow-up visit(s).   
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Dabrafenib - Trametinib Treatment Modification and Management Guidelines for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Dose Modification 
Asymptomatic 
Absolute decrease of  
> 10% in LVEF 
compared to baseline 
and ejection fraction 
below the institution’s 
LLN. 
• Interrupt trametinib.  Dabrafenib may continue  
• Repeat ECHO within 2 weeks.a 
• If the LVEF recovers within 4 weeks (defined as LVEF ≥ 
LLN and absolute decrease ≤ 10% compared to baseline): 
 Consult with the subprotocol Study Chair and request 
approval for restart. 
 Restart trametinib and dabrafenib at reduced doses by 
one 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 
 Resumption of dabrafenib may be considered after 
consultation with the subprotocol Study Chair. 
 Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until 
resolution. 
Symptomaticb 
• Grade 3:  resting LVEF 
39-20% or > 20% 
absolute reduction 
from baseline 
• Grade 4:  Resting LVEF 
< 20%. 
• Permanently discontinue trametinib.  Report as SAE 
• Hold dabrafenib until LVEF improves.  Consult the 
subprotocol Study Chair for resumption of  dabrafenib 
• Consult with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until 
resolution. 
a If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
b Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and 
edema. 
3.5.11 
Dabrafenib-Trametinib Dose Modification for Hypertension 
Increases in blood pressure (BP) have been observed in patients 
receiving dabrafenib plus trametinib.  Recommendations for BP 
monitoring and management are provided below. 
Monitoring:  All BP assessments should be performed under the 
following optimal conditions: 
• 
The subject has been seated with back support, ensuring that legs 
are uncrossed and flat on the floor. 
• 
The subject is relaxed comfortably for at least 5 minutes. 
• 
Restrictive clothing has been removed from the cuff area, and the 
right cuff has been selected. 
• 
The subject’s arm is supported so that the middle of the cuff is at 
heart level. 
• 
The subject remains quiet during the measurement. 
• 
In subjects with an initial BP reading within the hypertensive 
range, a second reading should be taken at least 1 minute later, 
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with the two readings averaged to obtain a final BP measurement.  
The averaged value should be recorded in the eCRF. 
• 
Visits to monitor increased blood pressure can be scheduled 
independently from the per-protocol visits outlined in the study 
calendar.  Ideally, subsequent blood pressure assessments 
should be performed within 1 week. 
• 
Persistent hypertension is defined as an increase of systolic BP 
(SBP) > 140 mmHg and/or diastolic BP (DBP) > 90 mmHg in three 
consecutive visits with blood pressure assessments from two 
readings. 
• 
Asympomatic hypertension is defined as an increase of SBP  
> 140 mmHg and/or diastolic BP (DBP) > 90 mmHg in the 
absence of headache, light-headedness, vertigo, tinnitus, 
episodes of fainting, or other symptoms indicative of hypertension. 

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Dabrafenib-Trametinib Treatment Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
(Scenario A) 
Asymptomatic and persistenta SBP 
of ≥ 140 and < 160 mmHg, or DBP 
≥ 90 and < 100 mmHg 
OR 
• Clinically significant increase in 
DBP of 20 mmHg (but DBP still 
below 100 mmHg) 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive medication(s) 
during the next 2 weeks to achieve 
well-controlledb BP.   
• If BP is not well-controlled within 2 
weeks, consider referral to a 
specialist and go to scenario (B). 
• Continue study 
treatment. 
(Scenario B) 
Asymptomatic SBP ≥ 160 mmHg, or 
DBP ≥ 100 mmHg,  
OR 
• Failure to achieve well-controlled 
BP within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive medication(s) 
during the next 2 weeks to achieve 
well-controlled BP. 
• Interrupt study treatment 
if clinically indicated. 
• Once BP is well-
controlledb, restart study 
treatment reduced  by 
one dose levelc  
(Scenario C) 
Symptomaticd hypertension  
OR 
• Persistent SBP ≥ 160 mmHg, or 
DBP ≥ 100 mmHg, despite 
antihypertensive medication and 
dose reduction of study treatment 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive medication(s) 
during the next 2 weeks to achieve 
well-controlled BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt study treatment 
• Once BP is well 
controlled, restart study 
treatment  reduced by 
one dose levelc. 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
• Permanently discontinue 
study treatment. 
a. 
Hypertension detected in two separate readings during up to three consecutive visits 
b. 
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings 
during up to three consecutive visits. 
c. 
Escalation of trametinib to previous dose level can be considered if BPs remain well-controlled for 4 weeks after 
restarting of trametinib.  Approval from the subprotocol Study Chair is required. 
d. 
Symptomatic 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 
 
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3.5.12 
Dabrafenib-Trametinib Dose Modification for QTc Prolongation 
Dabrafenib - Trametinib modification for QTc Prolongation 
QTc 
Prolongationa 
Action and Dose Modification 
• QTcB ≥ 501 
msec 
• Interrupt study treatment until QTcB 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 agents that prolong QTc. 
• If the event resolves, restart study treatment at current dose levelb. 
• If the event does not resolve, permanently discontinue study treatment. 
Consider evaluation with cardiologist. 
• If the event recurs, permanently discontinue study treatment. Consider 
evaluation with cardiologist. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s formula 
a) 
Based 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. 
b) 
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the 
subprotocol Study Chair agrees that the subject will benefit from further treatment. 
 
3.5.13 
Dabrafenib-Trametinib Dose Modification for Diarrhea 
Episodes of diarrhea have been observed in patients receiving 
dabrafenib, trametinib, or both therapies in combination.  Other, 
frequent causes for diarrhea including concomitant medications (e.g., 
stool softeners, laxatives, antacids, etc.), infections caused by C. 
difficile or other pathogens, partial bowel obstruction, etc., should be 
clinically excluded. 
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Dabrafenib-Trametinib Treatment Modification and Management Guidelines for Diarrhea 
CTCAE Grade 
Management Guideline 
Action and Dose 
Modification 
Uncomplicated 
Diarrhea,1 
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). 
• Loperamide3:  Initially 4 mg, followed by 2 mg every 
4 hours or after every unformed stool; maximum 16 
mg/day.  Continue until diarrhea-free for 12 hours. 
• Diarrhea > 24 hours:  Loperamide 2 mg every 2 
hours; maximum 16 mg/day.  Consider adding oral 
antibiotics. 
• Diarrhea > 48 hous:  Loperamide 2 mg every 2 
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  
> 48 hours, interrupt study 
treatment until diarrhea 
resolves to grade ≤ 1. 
• Restart study treatment at 
the same dose level. 
Uncomplicated 
Diarrhea,1 
Grade 3 or 4 
 
Any Complicated 
Diarrhea2 
• Clinical evaluation mandatory. 
• Loperamide3:  Initially 4 mg, followed by 2 mg every 
4 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 study treatment  
reduced by one dose 
level.4 
• If 3 dose reductions of 
study treatment are 
clinically indicated, 
permanently discontinue 
study treatment. 
1. 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. 
2. Complicated diarrhea defined by the presence 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. 
3. Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhea. 
4. Escalation of study treatment to previous dose level is allowed after consultation with the subprotocol Study Chair 
and in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose 
reduction. 
3.5.14 
Dabrafenib-Trametinib Dose Modification for Visual Changes 
Episodes of visual changes have been observed in patients receiving 
dabrafenib, trametinib, or the combination of both therapies.  An 
ophthalmologist should be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study 
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treatment (e.g., allergic conjunctivitis), then monitor closely as it may 
be reasonable to defer ophthalmic examination. 
Uveitis and iritis have been associated with dabrafenib, while RPED 
and RVO have been associated with trametinib therapy.  Monitor 
patients for visual signs and symptoms (such as change in vision, 
photophobia, and eye pain) during therapy. Special attention should 
be given to retinal findings (e.g., retinal pigment epithelial detachment 
(RPED) or retinovascular abnormalities (i.e., branch or central retinal 
vein occlusions [RVO]).   
The ophthalmology exam will include best corrected visual acuity, 
visual field examination, tonometry, slit lamp biomicroscopic 
examination of the anterior segment (with special attention to 
inflammation) and the posterior segment, 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 may also be indicated as determined by clinical exam. 
Guidelines regarding event management and dose reduction for 
visual changes considered to be related to study treatment are 
provided in the table below. 
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Dabrafenib-Trametinib Treatment Modification for Visual Changes 
CTCAE Grade 
Management Guideline 
Action and Dose Modification 
Grade 1* 
• Consult ophthalmologist 
within 7 days of onset. 
• If dilated fundus examination cannot be 
performed within 7 days of onset, hold trametinib 
until RPED and RVO can be excluded by retina 
specialist/ ophthalmologist. Dabrafenib may be 
continued. 
• If RPED and RVO excluded, continue (or restart) 
trametinib at same dose level 
• If Uveitis/Iritis, refer to table below for 
Iritis/Uveitis 
• If RPED suspected or diagnosed, refer to RPED 
dose modification table below; report as SAE if 
diagnosed. 
• If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE. 
Grade 2 and Grade 3 • Consult ophthalmologist 
immediately. 
• Hold trametinib.  Dabrafenib may be continued. 
• If RPED and RVO excluded, restart trametinib at 
same dose level after visual AE is ≤ grade 1. If 
no recovery within 4 weeks, discontinue 
trametinib. 
• If Uveitis/Iritis, refer to table below for 
Uveitis/Iritis 
• If RPED diagnosed, see RPED dose 
modification table below; report as SAE. 
• If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE. 
Grade 4 
• Consult ophthalmologist 
immediately. 
• Interrupt trametinib.  Dabrafenib may be 
continued. 
• If RPED and RVO excluded, may consider 
restarting trametinib at same or reduced dose 
after discussion with the subprotocol Study 
Chair. 
• If Uveitis/Iritis, refer to table below 
• If RVO or RPED diagnosed, permanently 
discontinue trametinib and report as SAE. 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious adverse 
event 
*If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but ophthalmic 
examination is not required. 
 
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Dabrafenib-Trametinib Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic 
observations only) 
• Continue trametinib with retinal evaluation monthly until resolution.  
If RPED worsens, follow instructions below. 
• Dabrafenib treatment is not affected 
Grade 2-3 RPED (Symptomatic 
with mild to moderate decrease 
in visual acuity; limiting 
instrumental ADL) 
• Interrupt trametinib.  Continue dabrafenib 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with one dose level 
reduction or discontinue in patients taking trametinib 1 mg daily. 
• If no recovery within 4 weeks permanently discontinue trametinib 
 
Dabrafenib-Trametinib Dose Modification for Uveitis and Iritis 
CTCAE Grade 
Action and Dose Modification 
Uveitis and Iritis 
• Continue study treatment 
• Control ocular inflammation with local therapies  
• If not improved to grade ≤ 1 within 1 week, interrupt dabrafenib until 
resolution of ocular inflammation and then restart dabrafenib 
reduced by one dose level 
• If no recovery within 4 weeks, permanently discontinue dabrafenib.  
Trametinib may be continued. 
3.5.15 
Dabrafenib-Trametinib Dose Modification for Pneumonitis 
Pneumonitis has been observed in patients receiving trametinib in 
combination with dabrafenib.  To reduce the risk of pneumonitis, 
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patients will be monitored closely for symptoms, evaluated with 
imaging and functional tests when appropriate. 
Dabrafenib-Trametinib Treatment Modification for Pneumonitis 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 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 with pulmonologist 
recommended 
• Continue study therapy  at current dose 
Grade 2 
• CT scan (high-resolution with lung 
windows) recommended. 
• 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 
recommended 
• Symptomatic therapy including 
corticosteroids if clinically indicated 
• Interrupt trametinib until recovery to grade ≤ 1 
• Restart trametinib reduced by one dose level  
• Escalation to previous dose level after 4 weeks 
may be considered after consultation with the 
subprotocol Study Chair.  
• If no recovery to grade ≤ 1 within 2 weeks, 
permanently discontinue trametinib.   
Grade 3 
• Same as grade 2 
• Interrupt trametinib until recovery to grade ≤ 1 
• Resumption of trametinib at one dose level 
reduction may be considered after consultation 
with the subprotocol Study Chair. 
• If no recovery to grade ≤1 within 2 weeks, 
permanently discontinue trametinib.   
Grade 4 
• Same as grade 2 
• Permanently discontinue trametinib.   
 

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3.5.16 
Dabrafenib-Trametinib Dose Modification for Liver Chemistry 
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Dabrafenib-Trametinib Dose Modification for Liver Chemistry Changes 
Event 
Treatment modifications and assessment/monitoring 
• ALT ≥ 3x ULN but < 5x ULN 
and TB < 2x ULN, without 
symptoms considered 
related to liver injury or 
hypersensitivity and who can 
be monitored weekly for 4 
weeks 
• May continue study treatment. 
• Report as SAE if CTEP-AERS reporting criteria is met. 
• If liver chemistry stopping criteria are met any time, proceed as described 
below. 
MONITORING: 
Repeat LFT (ALT, AST, ALK, bilirubin) until they return to normal/baseline or 
stabilise (LFT may be every 2 weeks after 4 weeks if ALT < 3x ULN and TB < 2 
ULN). If baseline ALT and Tbili already meet these criteria, then monitoring is 
required only if ALT or TB rises after initiation of study therapy. 
Criteria for discontinuing 
study drug: When any of the 
liver stopping criteria below is 
met, discontinue trametinib 
and dabrafenib 
1. ALT ≥ 3xULN and bilirubin ≥ 
2x ULN or > 35% direct 
bilirubin1, 2 
2. ALT  3xULN and INR >1.5, 
if INR measured2  (INR 
threshold does not apply if 
subject is on anticoagulant) 
3. ALT ≥ 5x ULN 
4. ALT ≥ 3x ULN persists for 
4 weeks. However, if ALT 
was elevated 3-5x at 
baseline due to liver mets, 
then this criteria should not 
be used for treatment 
discontinuation UNLESS the 
ALT improves to < 3x ULN 
and then subsequently rises 
5. ALT ≥ 3x ULN and cannot 
be monitored weekly for 4 
weeks. However, if ALT was 
elevated 3-5x at baseline 
due to liver mets, then this 
criteria should not be used 
for treatment discontinuation 
UNLESS the ALT improves 
to <3x ULN and then 
subsequently rises. 
6. ALT ≥ 3x ULN associated 
with symptoms3  (new or 
worsening) believed to be 
related to  liver injury or 
hypersensitivity 
• Immediately discontinue study treatment. 
• Do not restart/rechallenge unless approved by the subprotocol Study Chair.   
• Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) patients meet 
criteria 1-2. 
• Perform liver event ASSESSMENT AND WORKUP (see below). 
• Monitor the subject until liver chemistries resolve, stabilize, or return to baseline 
(see MONITORING below). 
If applicable, provide details on required follow up assessments (e.g., follow up 
for overall survival or disease recurrence or progression).  
MONITORING: 
In patients stopping for criteria 1-2 (with abnormal TB and INR, indicating potentially 
more significant liver toxicities): 
• Repeat liver chemistries (ALT, AST, ALK, bilirubin) and perform liver event 
follow-up assessments within 24 hours. 
• Monitor subjects twice weekly until LFT return to normal/baseline or stabilize. 
• A specialist or hepatology consultation is recommended. 
In patients stopping for criteria 2-6: 
• Repeat LFT and perform liver event follow up assessments within  24-72 
hours  
• Monitor subjects weekly until LFTs return to normal/baseline or stabilize. 
ASSESSMENT and WORKUP: 
• Viral hepatitis serology.4 
• Serum CPK and LDH. 
• Fractionate bilirubin, if total bilirubin ≥2x ULN. 
• CBC with differential to assess eosinophilia. 
• Record clinical symptoms of liver injury, or hypersensitivity on AE CRF. 
• Record concomitant medications (including acetaminophen, herbal remedies, 
other over the counter medications). 
• Record alcohol use. 
Additional work up for patient stopping for criteria 1-2 (with abnormal TB and INR, 
indicating potentially more significant liver toxicities): 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC assay (in subjects with likely 
acetaminophen use in the preceding). 
• If there is underlying chronic hepatitis B (e.g. positive hepatitis B surface 
antigen):  quantitative hepatitis B DNA and hepatitis delta antibody.5 
• Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
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Footnotes: 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, which indicates direct bilirubin elevations 
and suggesting liver injury. 
2. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (> 35% direct bilirubin) or ALT  3x ULN and INR > 1.5 (if INR 
measured) may indicate severe liver injury (possible “Hy’s Law”).  INR measurement is not required, and the 
threshold value stated will not apply to subjects receiving anticoagulants. 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5. If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) (Le Gal et al., 2005). 
3.5.17 
Dabrafenib-Trametinib Dose Modification for Venous 
Thromembolism (VTE) 
 
Event 
Dabrafenib 
Trametinib 
(When Used in Combination) 
Uncomplicated 
DVT or PE 
Do not modify the 
dose. 
Withhold trametinib for up to 2 weeks. 
• If improved to Grade 0-1, resume at a lower dose level. 
• If not improved, permanently discontinue. 
Life 
Threatening 
PE 
Permanently 
discontinue dabrafenib 
Permanently discontinue trametinib. 
3.6 
General Concomitant Medication and Supportive Care Guidelines 
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
Subjects should receive full supportive care during the study, including 
transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, 
and in accordance with their institutional guidelines.  Use of anticoagulants such 
as warfarin is permitted however, caution should be exercised and additional 
International Normalized Ratio (INR) monitoring is recommended when 
dabrafenib is used concomitantly with warfarin. 
Radiation skin injury has been reported with concurrent use of dabrafenib and 
radiation.  If radiation therapy is permitted on protocol, it is recommended that 
dabrafenib be held for 7 days before and 2 days after XRT in subjects. 
Because there is a potential for interaction of trametinib and dabrafenib with other 
concomitantly administered drugs through the cytochrome P450 system, the case 
report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted 
if the patient is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes.  

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3.7 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies:  
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Disease progression 
3.8 
Duration of Follow-Up  
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 

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61 
4. 
Study Parameters  
4.1 
Therapeutic Parameters for Dabrafenib plus Trametinib Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol at Step 0, the below parameters 
must also be performed for patients receiving Dabrafenib plus Trametinib treatment.  
NOTE: 
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG). 
Test/Assessment 
Prior to 
Registration to 
Treatment 
Treatment 
End of 
Treatment 
Follow UpF 
Every Cycle, prior to 
treatment 
Every 2 
Cycles 
H&P, Weight, Vital signsA 
X 
 XJ 
 
 
X 
Performance status 
X 
 XJ 
 
 
X 
CBC w/diff, pltsB 
X 
 XJ 
 
 
X 
Serum chemistryB 
X 
 XJ 
 
 
X 
PT/INR and PTT 
X 
 
 
 
 
Radiologic evaluationD 
X 
 
 XD 
 
 XF 
-HCGC 
X 
 
 
 
 
Toxicity AssessmentG 
 
X 
 
X 
 XF 
Pill Count/DiaryH 
 
X 
 
X 
 
ECGK,L 
X 
 XL 
 
 
 
Echocardiogram or Nuclear StudyL 
X 
 XL 
 
 
 
Dermatologic ExamM 
X 
 
 XM 
X 
 XM 
Eye Exam 
X 
XI 
 
 
 
Tumor biopsy and  blood sample for MATCH Master ProtocolE 
 
 
X 
X 
 
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle). 
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium, SGOT[AST], SGPT[ALT], 
sodium, magnesium, and serum tumor markers (including LDH, PSA if appropriate). For eligibility purposes, participants with creatinine levels 
above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance. CBC w/diff, platelets and serum chemistries should be 
performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of new cycle). CBC with 
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NCI Update Date: August 12, 2015 
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differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to ≤ grade 3. CBC and 
serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease. 
C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment. 
D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. 
Submit at the following time points, as applicable: 
• Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead. On-treatment kits for blood sample collections will be automatically shipped 
to sites upon registration to the treatment step. 
• Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up 
(with a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH 
Master Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of 
the MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle. 
H. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle. 
I. As clinically indicated. 
J. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications. 
K. Within 8 weeks of treatment assignment. 
L. Cardiac monitoring with ECG and ECHO/nuclear study (MUGA or First Pass) is needed week 5, week 13, and every 12 weeks thereafter unless 
clinically indicated sooner. The same modality should be used at baseline and thereafter. 
M. Test can be done by the treating physician and should be done every 2 months during study treatment, and every 2-3 months for 6 months 
following discontinuation of study treatment or until initiation of other anti-neoplastic agent. Refer to Section 3.5.5 for further instructions. 
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63 
5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information) The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents. The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov).  Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
64 
5.1 
Trametinib (NSC 763093) 
5.1.1 
Other Names  
MEKINIST™, GSK1120212, JTP-74057, JTP-78296, JTP-75303 
5.1.2 
Classification  
MEK inhibitor 
5.1.3 
Mode of Action 
Trametinib dimethyl sulfoxide is a reversible, highly selective, 
allosteric inhibitor of mitogen-activated extracellular signal regulated 
kinase 1 (MEK1) and MEK2. Tumor cells commonly have 
hyperactivated extracellular signal-related kinase (ERK) pathways in 
which MEK is a critical component. Trametinib dimethyl sulfoxide 
inhibits activation of MEK by RAF kinases and MEK kinases. 
5.1.4 
Storage and Stability  
Storage: Store tablets at 2°C -8°C in the original bottle. Do not 
repackage tablets or remove desiccant. Bottles should be protected 
from light and moisture. 
If a storage temperature excursion is identified, promptly return 
trametinib to 2°C -8°C and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Refer to the package label for expiration. 
5.1.5 
Dose Specifics  
2 mg orally once daily  
5.1.6 
Preparation  
Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg 
(as free base) tablets.  
Each commercially-labeled bottle contains 30 tablets with a desiccant. 
The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (non-
animal), colloidal silicon dioxide and sodium lauryl sulfate. 
• 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated 
with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 
Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow. 
• 
2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ 
debossed on one face and ‘HMJ’ on the opposing face. Aqueous 
film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80, iron oxide red. 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
65 
5.1.7 
Route of Administration  
Oral. Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal. If a dose of trametinib is missed, the dose can be 
taken if it is more than 12 hours until the next scheduled dose. 
5.1.8 
Incompatibilities  
In vitro studies suggest that trametinib dimethyl sulfoxide is not a 
substrate of CYP enzymes or of human BCRP, MRP2, OATP1B1, 
OATP1B3, OATP2B1, OCT1 or MATE1 transporters. Trametinib 
elimination by deacetylation to metabolite M5 is dependent on 
carboxylesterases (CES1b, CES1c and CES2). M5 is eliminated by 
CYP3A4 and other pathways, presenting the clinically relevant, albeit 
low, potential for drug-drug interaction. Trametinib is a substrate for P-
gp and BSEP, but this is not expected to be clinically relevant due to 
trametinib’s high permeability. 
Trametinib dimethyl sulfoxide is an in vitro inhibitor of CYP 2C8, and 
is anticipated to have overall low potential for drug interactions as a 
perpetrator. It is also a weak CYP3A4 inducer and expected to have 
little clinical effect on sensitive substrates. Trametinib is not an 
inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not an 
inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 
MRP2 and MATE1. 
5.1.9 
Side Effects  
See Section 3.3 for side effects. 
5.1.10 
Nursing/Patient Implications 
Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for 4 
months after the last dose of trametinib. 
5.2 
Dabrafenib (NSC 763760) 
5.2.1 
Other Names  
GSK2118436, GSK2118436A (free base); Tafinlar 
5.2.2 
Classification  
BRAF inhibitor 
5.2.3 
Mode of Action  
Dabrafenib mesylate (GSK2118436B) is a potent and selective BRAF 
kinase inhibitor. This inhibition suppresses downstream activity of 
pERK, a biomarker, and has antiproliferative activity against BRAF 
mutant tumors. The mode of action is consistent with ATP-competitive 
inhibition. 
5.2.4 
Storage and Stability  
Storage: Store between 15°C to 30°C (59°F to 86°F). [see USP 
Controlled Room Temperature] 
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66 
If a storage temperature excursion is identified, promptly return 
dabrafenib mesylate (GSK2118436B) to room temperature and 
quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of 
the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
Stability: Refer to the package label for expiration. 
5.2.5 
Dose Specifics  
150 mg orally twice daily  
5.2.6 
Preparation  
Dabrafenib mesylate (GSK2118436B) capsules are supplied by 
Novartis and distributed by the DCTD, NCI as 50 mg and 75 mg 
capsules (equivalent to the free-base) for oral administration. 
Each commercially-labeled bottle contains 120 capsules and a silica 
gel desiccant. 
• 
50 mg capsule is dark red and imprinted with ‘GS TEW’ and ‘50 
mg.’ 
• 
75 mg capsule is dark pink and imprinted with ‘GS LHF’ and ‘75 
mg.’ 
Capsule excipients include microcrystalline cellulose, magnesium 
stearate (vegetable source), and colloidal silicon dioxide. Capsule 
shells contain hypromellose, red iron oxide (E172), and titanium 
dioxide (E171). 
5.2.7 
Route of Administration  
Oral administration. Take dabrafenib mesylate (GSK2118436B) by 
mouth one hour prior or two hours after a meal. If a dose is missed, it 
should not be taken if it is less than 6 hours until the next dose. 
5.2.8 
Incompatibilities  
In vivo data shows that metabolism of dabrafenib mesylate 
(GSK2118436B) and its metabolites is mediated by CYP3A4 and 
CYP2C8. Use caution if strong inducers or inhibitors of CYP2C8 or 
3A4 are co-administered with dabrafenib. Although in vitro studies 
indicate dabrafenib mesylate and its metabolites are substrates for P-
glycoprotein (P-gp) and BCRP transporters, the apparent high oral 
bioavailability and permeability indicate modulation of efflux 
transporters will have minimal impact on dabrafenib 
pharmacokinetics. 
Dabrafenib mesylate (GSK2118436B) and its metabolites showed 
moderate inhibition of CYP 2C8, 2C9, 2C19 and 3A4 in human 
microsomes studies. Use caution in patients who are taking sensitive 
substrates of these enzymes. Additionally, dabrafenib and its 
metabolites showed inhibition of OATP1B1, OATP1B3, OAT1, OAT3 
and OCT2 transporter systems and weak to moderate inhibition of 
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NCI Update Date: August 12, 2015 
67 
BCRP.  Neither dabrafenib nor its metabolites show inhibition of P-gp 
in vitro. 
Dabrafenib mesylate (GSK2118436B) induces CYP3A4, 2C9 and 
possibly 2B6, 2C8, 2C19 enzymes, UDP glucuronosyltransferase and 
P-gp. Use caution in patients who are taking substrates of these 
pathways, such as warfarin or hormonal contraceptives. 
Dabrafenib solubility is pH-dependent and experiences decreased 
solubility at higher pH. Use caution in patients who are taking drugs 
that elevate gastric pH due to the theoretical risk of decreasing oral 
bioavailability of dabrafenib. 
5.2.9 
Side Effects  
See Section 3.4 for side effects. 
5.2.10 
Nursing/Patient Implications  
In the case of overdose, patients should be treated symptomatically 
since there is no specific antidote. Hemodialysis is likely to be 
ineffective since dabrafenib mesylate is highly bound to plasma 
proteins. 
Advise women study participants of reproductive potential to use 
effective non-hormonal contraception methods while receiving study 
treatment and for 16 weeks after the last dose of dabrafenib. 
Hormonal contraceptives can be ineffective when taken concurrently 
with dabrafenib. 
 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
68 
6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies. 
7. 
References 
1. 
Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK–RAS–RAF 
signaling pathway in cancer therapy. Expert Opinion on Therapeutic Targets 
2012;16:103-19. 
2. 
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. 
Nature 2002;417:949-54. 
3. 
Salama AKS, Flaherty KT. BRAF in Melanoma: Current Strategies and Future 
Directions. Clinical Cancer Research 2013;19:4326-34. 
4. 
Gorden A, Osman I, Gai W, et al. Analysis of BRAF and N-RAS Mutations in 
Metastatic Melanoma Tissues. Cancer Research 2003;63:3955-7. 
5. 
Libra M, Malaponte G, Navolanic PM, et al. Analysis of BRAF Mutation in Primary 
and Metastatic Melanoma. Cell Cycle 2005;4:1382-4. 
6. 
Kumar R, Angelini S, Czene K, et al. BRAF Mutations in Metastatic Melanoma: A 
Possible Association with Clinical Outcome. Clinical Cancer Research 
2003;9:3362-8. 
7. 
Ascierto P, Kirkwood J, Grob J-J, et al. The role of BRAF V600 mutation in 
melanoma. Journal of Translational Medicine 2012;10:85. 
8. 
Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat 
Rev Mol Cell Biol 2004;5:875-85. 
9. 
Cardarella S, Ogino A, Nishino M, et al. Clinical, Pathologic, and Biologic Features 
Associated with BRAF Mutations in Non–Small Cell Lung Cancer. Clinical Cancer 
Research 2013;19:4532-40. 
10. 
Klein O, Clements A, Menzies AM, O’Toole S, Kefford RF, Long GV. BRAF 
inhibitor activity in V600R metastatic melanoma. European Journal of Cancer 
2013;49:1073-9. 
11. 
Chapman PB, Hauschild A, Robert C, et al. Improved Survival with Vemurafenib in 
Melanoma with BRAF V600E Mutation. New England Journal of Medicine 
2011;364:2507-16. 
12. 
Hauschild A, Grob J-J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The 
Lancet;380:358-65. 
13. 
Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK Inhibition 
versus BRAF Inhibition Alone in Melanoma. New England Journal of 
Medicine;0:null. 
14. 
Alcalá AM, Flaherty KT. BRAF Inhibitors for the Treatment of Metastatic 
Melanoma: Clinical Trials and Mechanisms of Resistance. Clinical Cancer 
Research 2012;18:33-9. 
15. 
Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) Is an Inhibitor 
of MEK Activity and Activation with Favorable Pharmacokinetic Properties for 
Sustained In Vivo Pathway Inhibition. Clinical Cancer Research 2011;17:989-1000. 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
69 
16. 
Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in 
BRAF-Mutated Melanoma. New England Journal of Medicine 2012;367:107-14. 
17. 
Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in 
Melanoma with BRAF V600 Mutations. New England Journal of Medicine 
2012;367:1694-703. 
18. 
Corcoran RB, Falchook G, Infante JR. Pharmacodynamic and efficacy analysis of 
the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor 
trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC). 
In: American Society of Clinical Oncology Annual Meeting; 2013; Chicago, IL; 
2013. 
19. 
Wang SS, Slager SL, Brennan P, et al. Family history of hematopoietic 
malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 
211 cases and 11 905 controls from the International Lymphoma Epidemiology 
Consortium (InterLymph). Blood 2007;109:3479-88. 
20. 
Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural 
killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 
2008;26:4124-30. 
21. 
Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, Pacak K. Clinical aspects of 
SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer 
2009;16:391-400. 
22. 
von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in 
human epidermal growth factor receptor 2-positive advanced breast cancer: a 
german breast group 26/breast international group 03-05 study. J Clin Oncol 
2009;27:1999-2006. 
23. 
van Casteren NJ, van Santbrink EJ, van Inzen W, Romijn JC, Dohle GR. Use rate 
and assisted reproduction technologies outcome of cryopreserved semen from 629 
cancer patients. Fertil Steril 2008;90:2245-50. 
24. 
Van Bockstaele F, Verhasselt B, Philippe J. Prognostic markers in chronic 
lymphocytic leukemia: a comprehensive review. Blood Rev 2009;23:25-47. 
25. 
van Beek RD, van den Heuvel-Eibrink MM, Laven JS, et al. Anti-Mullerian hormone 
is a sensitive serum marker for gonadal function in women treated for Hodgkin's 
lymphoma during childhood. J Clin Endocrinol Metab 2007;92:3869-74. 
26. 
Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, 
resistance and future perspectives in HER2-overexpressing breast cancer. Ann 
Oncol 2007;18:977-84. 
27. 
Terenziani M, Piva L, Meazza C, Gandola L, Cefalo G, Merola M. Oophoropexy: a 
relevant role in preservation of ovarian function after pelvic irradiation. Fertil Steril 
2009;91:935.e15-6. 
28. 
Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: 
calling into question the concept of reversibility. J Clin Oncol 2007;25:3525-33. 
29. 
Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, 
cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic 
leukemia. Blood 2008;112:975-80. 
30. 
Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and 
ovarian preservation in chemotherapy treated patients with early breast cancer: 
results from a randomized trial. Breast Cancer Res Treat 2009. 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
70 
31. 
Stilgenbauer S, Bullinger L, Lichter P, Dohner H. Genetics of chronic lymphocytic 
leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and 
clinical course. Leukemia 2002;16:993-1007. 
32. 
Balagula Y, Barth Huston K, Busam K, Lacouture M, Chapman P, Myskowski P. 
Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib 
(AZD6244, ARRY-142886). Invest New Drugs 2011;29:1114-21. 
33. 
Lacouture M, Anadkat M, Bensadoun R-J, et al. Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. 
Support Care Cancer 2011;19:1079-95. 
 

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EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
71 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol H: Trametinib/Dabrafenib 
Appendix I 
 
Patient Pill Calendars 
Pill Calendar Directions 
1. Take your scheduled dose of each tablet or capsule. 
2. If a dose of dabrafenib is missed, it should not be taken if it is less than 6 hours until 
the next dose.  
3. If a dose of trametinib is missed, only take the dose if it is more than 12 hours until 
the next scheduled dose. 
4. Please bring the empty bottle or any leftover tablets or capsules and your pill 
calendar to your next clinic visit.  
5. Take dabrafenib mesylate (GSK2118436B) twice daily by mouth either 1 hour before 
or two hours after a meal. 
6. Take trametinib (GSK1120212) once daily by mouth either 1 hour before or 2 hours 
after a meal. 
7. Swallow dabrafenib capsules whole. Do not crush, chew, or open capsules. 
8. Swallow trametinib tablets whole. Do not crush or chew tablets. 
9. Store dabrafenib at room temperature. 
10. Store trametinib in the refrigerator. Do not freeze. 
 
 
Rev. 12/16, 3/17 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
72 
Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take 
each day.  You should take your scheduled dose of each tablet. Note the times and the 
number of tablets that you take each day. If you develop any side effects, please 
record them and anything you would like to tell the doctor in the space provided.  Bring 
any unused tablets and your completed pill calendar to your doctor’s visits. 
Trametinib 
DAY  
Date 
Time 
tablets 
taken 
Use the space below to make notes about things you 
would like to tell the doctor (including unusual symptoms 
you experience, other medicine you have taken and 
anything else you think would be of interest.) 
Month 
Day 
Year 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
Patient Signature: __________________________________ Date: _____________ 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
73 
Patient Pill Calendar 
This is a calendar on which you are to record the time and number of capsules you take 
each day.  You should take your scheduled dose of each capsule. Note the times and 
the number of capsules that you take each day. If you develop any side effects, 
please record them and anything you would like to tell the doctor in the space provided.  
Bring any unused capsules and your completed pill calendar to your doctor’s visits. 
Dabrafenib 
DAY  
Date 
Time capsules 
taken 
Number of 
capsules taken 
Use the space below to make 
notes about things you would like 
to tell the doctor (including unusual 
symptoms you experience, other 
medicine you have taken and 
anything else you think would be of 
interest.) 
Month 
Day 
Year 
AM 
PM 
AM 
PM 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Patient Signature: __________________________________ Date: _____________ 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
74 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol H: Trametinib/Dabrafenib 
Appendix II 
 
CYP3A4/CYP2C8 Inducers and Inhibitors 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as Facts and Comparisons or Lexicomp; medical reference texts 
such as the Physicians’ Desk Reference may also provide this information. The Principal 
Investigator should be alerted if the subject is taking any agent on these lists. 
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of 
dabrafenib may be decreased 
Class/Therapeutic 
Area 
Drugs/Agents 
Antibiotics 
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine),  
Anticonvulsant 
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-
mephenytoin  
Miscellaneous 
bosentan, St. John’s wort 
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib may be increased 
Class/Therapeutic 
Area 
Drugs/Agents 
Antibiotics 
Clarithromycin, telithromycin, troleandomycin 
Antidepressant 
Nefazodone 
Antifungals 
Itraconazole, ketoconazole, posaconazole, voriconazole 
Hyperlipidemia 
Gemfibrozil  
Antiretroviral 
ritonavir, saquinavir, atazanavir 
Miscellaneous 
Conivaptan  

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
75 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol H: Trametinib/Dabrafenib 
Appendix III 
 
Trametinib Ophthalmic Exam Form 
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? 
o 
If yes, patient is not eligible for the study. 
 
 
 
Signature of Examiner: _____________________________   
Printed Name: _________________________      Date: ______________ 
Rev. 8/15 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
76 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol H: Trametinib/Dabrafenib 
Appendix IV 
 
BRAF Mutations Eligible for Inclusion 
 
Gene Name 
Variant ID 
Variant Type 
Variant Description 
Level of Evidence Code 
BRAF 
COSM1127 
SNV 
p.V600R 
2 
BRAF 
COSM1583011 
SNV 
p.V600R 
2 
BRAF 
COSM308550 
SNV 
p.V600D 
2 
BRAF 
COSM473 
SNV 
p.V600K 
1 
BRAF 
COSM474 
SNV 
p.V600R 
2 
BRAF 
COSM476 
SNV 
p.V600E 
1 
BRAF 
COSM477 
SNV 
p.V600D 
2 
Other novel BRAF V600 mutations not listed in the above table but identified by one of the 
designated outside laboratories as described in the MATCH Master Protocol will also be 
considered actionable mutations (aMOIs) at Level of Evidence Code 3.  Please refer to Section 
1.4.2 of the MATCH Master Protocol for more information. 
 
 
 
Rev. 8/15 
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ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
77 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol H: Trametinib/Dabrafenib 
Appendix V 
 
Patient Drug Information Handout and Wallet Card 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agents Dabrafenib mesylate or Dabrafenib plus Trametinib dimethyl 
sulfoxide.  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient. 
Dabrafenib mesylate interacts with many drugs that are processed by your liver.  Because of 
this, it is very important to tell your study doctors about all of your medicine before you start this 
study.  It is also very important to tell them if you stop taking any regular medicine, or if you start 
taking a new medicine while you take part in this study.  When you talk about your medicine 
with your study doctor, include medicine you buy without a prescription at the drug store (over-
the-counter remedy), or herbal supplements such as St. John’s wort. 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These 
are the things that you and they need to know: 
Dabrafenib mesylate interacts with certain specific enzymes in your liver.  
• 
The enzymes in question are CYP450 3A4, 2C8, 2C9, 2C19, 2B6.  Dabrafenib mesylate 
levels are affected by some of these enzymes and can lower the levels of other medicines 
you take. Dabrafenib mesylate must be used very carefully with other medicines that need 
these liver enzymes to be effective or to be cleared from your system. 
• 
Other medicines may also affect the activity of the enzyme. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance of 
harmful side effects.  Dabrafenib mesylate should not be taken with any other drugs that 
are strong inducers or inhibitors of CYP 3A4 or 2C8.  Prohibited medications include 
azole antifungals, some antiepileptic drugs, some antibiotics and some 
immunosuppressants.  Please check with the study investigator before prescribing or 
dispensing strong inhibitors/inducers of CYP 3A4 or 2C8. Mild/moderate 
inhibitors/inducers should be used with caution. 
o Dabrafenib mesylate is considered an inducer of CYP 3A4, CYP2C8/9, 2B6 and possibly 
2C19, meaning that it can decrease the levels of other drugs that are processed by 
these enzymes.  This can lead to harmful side effects and/or reduce the effectiveness of 
those medications.    
• 
You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category. 
• 
Before you start the study, your study doctor will work with your regular prescriber to switch 
any prohibited medicines that are considered “strong inducers/inhibitors or substrates of 
CYP 3A4 and 2C8.” 
Rev. 8/15 
Rev. 12/16 

ECOG-ACRIN 
EAY131-H 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
78 
• 
Your prescribers should look at a frequently-updated drug reference like Lexicomp to see if 
any medicine they want to prescribe is on a list of drugs to avoid. 
• 
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the generic 
name and determine, with the pharmacist’s help, whether there could be an adverse 
interaction. 
• 
Be careful: 
o If you take acetaminophen regularly:  You should not take more than six 500 mg pills or 
nine regular strength (325 mg) pills a day if you are an adult or four 500 mg pills or 
seven regular strength (325 mg) pills a day if you are older than 65 years of age.  Read 
labels carefully!  Acetaminophen is an ingredient in many medicines for pain, flu, and 
cold. 
o If you take herbal medicine regularly:  You should not take St. John’s wort while you are 
taking dabrafenib mesylate. 
o Avoid antacids and tell your doctor if you are taking any medicine for heartburn 
symptoms. 
Other medicines can be a problem with your study drugs.  
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.   
Your study doctor’s name is  
_____________________________________  
and he or she can be contacted at  
_____________________________________. 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
You are enrolled on a clinical trial using the experimental 
agents dabrafenib mesylate and trametinib dimethyl 
sulfoxide.  This clinical trial is sponsored by the NCI.  
Dabrafenib mesylate interacts with drugs that are 
processed by your liver.  Because of this, it is very 
important to: 
➢ Tell your doctors if you stop taking regular medicine or 
if you start taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ 
assistant, nurse practitioner, pharmacist) that you are 
taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement. 
Dabrafenib mesylate interacts with specific liver 
enzymes called CYP 3A4 and CYP 2C8, and must 
be used very carefully with other medicines that 
interact with these enzymes. 
➢ Before you start the study, your study doctor will 
work with your regular prescriber to switch any 
prohibited medicines that are considered “strong 
inducers/inhibitors or substrates of CYP 3A4 and 
2C8.” 
➢ Before prescribing new medicines, your regular 
prescribers should check a frequently-updated drug 
resource for a list of drugs to avoid, or contact your 
study doctor.   
➢ Your study doctor’s name is 
_____________________________ and can be 
contacted at _____________________________.