Conditions: Follicular Thyroid Cancer Insular Thyroid Cancer Papillary Thyroid Cancer Recurrent Thyroid Cancer
Keywords: BRAF BRAFi thyroid cancer thyroid carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well dabrafenib works with or without trametinib in treating patients with recurrent thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether dabrafenib is more effective when given with or without trametinib in treating thyroid cancer

Detailed description:
PRIMARY OBJECTIVES:

I. To screen two different regimens (GSK2118436 \[BRAFi\] \[dabrafenib\] as a single agent versus the combination regimen of GSK2118436 \[BRAFi\] and GSK1120212 \[MEKi\] \[trametinib\]) and identify which regimen is more promising for subsequent testing in a phase III trial in radioiodine refractory BRAF-mutated differentiated thyroid cancer (DTC) patients.

SECONDARY OBJECTIVES:

I. To understand duration of objective response, progression-free survival and overall survival for each treatment group.

II. To assess tolerability and adverse events of GSK2118436 (BRAFi) as a single agent and the tolerability and adverse events of GSK2118436 (BRAFi) and GSK1120212 (MEKi) in combination, in patients with DTC.

III. To evaluate impact of experimental drugs on serum tumor marker thyroglobulin and its correlation with overall response rate.

IV. To understand pharmacokinetic, pharmacogenetics and pharmacodynamics of experimental drugs using serial tumor biopsies, tumor blocks and peripheral blood.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28. Patients with disease progression may cross-over to arm II.

ARM II: Patients receive dabrafenib PO BID and trametinib PO once daily (QD) on days 1-28.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Arms:
arm 1: Patients receive dabrafenib orally 2 twice a day on days 1-28. Patients with disease progression may cross over to arm II. arm 2: Patients receive dabrafenib orally twice a day and trametinib orally once a day on days 1-28.

Interventions: intervention 1: dabrafenib intervention 2: trametinib
Intervention descriptions: intervention 1: 150 mg orally twice daily given orally intervention 2: 150 mg orally twice daily and GSK1120212 (MEKi) 2 mg orally once daily given orally

Protocol document:
Prot_SAP_000.pdf: 
NCCN Protocol #: NCCNGSK20008 
IRB Approved on 05/06/2022 
OSU Protocol #:  OSU 12064 
 
A Randomized Phase 2 Study of single agent Dabrafenib (BRAFi) vs. 
combination regimen Dabrafenib (BRAFi) and Trametinib (MEKi) in 
patients with BRAF mutation or BRAF gene fusion defect in thyroid 
carcinoma 
 
Coordinating Center: 
The Ohio State University, Arthur G. James Cancer Hospital 
and Richard Solove Research Institute, Columbus, OH 
 
Protocol Chair and 
Principal Investigator: 
Bhavana Konda, MD 
Associate Professor of Internal Medicine 
Division of Medical Oncology 
The Ohio State University 
1800 Cannon Drive, Lincoln Tower Suite 1335 
Columbus, OH 43210 
Tel: 614-293-9779/     Fax: 614-293-4372 
Email: bhavana.konda@osumc.edu 
 
Co-Investigators: 
Naifa L. Busaidy, MD 
Assistant Professor 
Department of Endocrine Neoplasia and Hormonal Disorders 
The University of Texas-MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 1461 
Houston, TX 77030 
Tel: 713-792-2841/ 
Fax: 713-794-7065 
Email: nbusaidy@mdanderson.org 
 
Lori Wirth, MD 
Assistant Professor of Medicine, Harvard Medical School 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Tel: 617-726-0250/ 
Fax: 617-726-0453 
Email: LWIRTH@PARTNERS.ORG 


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Greg Daniels, MD 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093 
Tel: 858-534-3804/Fax: 858-246-0075 
Email: gdaniels@ucsd.edu 
 
 
Jennifer Sipos, MD 
Professor of Internal Medicine 
Division of Endocrinology, Diabetes and 
Metabolism 
The Ohio State University 
5th Floor McCampbell Hall 
1581 Dodd Avenue 
Columbus, OH-43210 
Tel: 614-685-3333/ Fax: 614-366-0345 
Email: Jennifer.Sipos@osumc.edu 
 
Cynthia Timmers, Ph.D. 
Director, Solid Tumor Translational Science 
Resource 
The Ohio State University Comprehensive 
Cancer Center 
460 West 12th Avenue Room 
460BColumbus, OH 43210 
Tel: 614-366-9041 
Email: cynthia.timmers@osumc.edu 
 
 
Mitch Phelps, Ph.D. 
Assistant Professor, College of Pharmacy 
The Ohio State University 
230 Parks Hall 
500 W. 12th Ave. 
Columbus, OH 43210 
Tel: 614-688-4370/ Fax: 614-292-7766 
Email: mitch.phelps@osumc.edu 
 
Ming Poi, PharmD, PhD 
The Ohio State University 
Clinical and Translational Research Fellow 
College of Pharmacy 
Email: ming.poi@osumc.edu 
 
Statistician: 


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Lai Wei, PhD 
The Ohio State University, Center for Biostatistics 
2012 Kenny Rd Columbus, OH, 43221 
Tel: 614-293-6449 
Email: Lai.wei@osumc.edu 
 
Subsite Coordination: 
Clinical Trials Office, The Ohio State University 
Comprehensive Cancer Center 
Fax: 614-366-4721 
Email: OSUCCC-CTO-MCTP@osumc.edu 
 
Study Coordinator: 
Mamdouh Beshara 
Clinical Trials Office, The Ohio State University 
Wexner Medical Center 
660 Ackerman Rd., 5th Floor, Room 526 
Columbus, OH 43202 
Tel: 614- 688-8837 / Fax: 614-293-4468 
Email: Mamdouh.beshara@osumc.edu 
 
Study Data Manager: 
Rajani Jacob 
Clinical Trials Office, The Ohio State University 
Wexner Medical Center 
660 Ackerman Rd., 5th Floor, Unit 55 
Columbus, OH 43202 
Email: Rajani.jacob@osumc.edu 
 
 
 
 
 
 
 
 
Novartis Supplied Agents: 
Tafinlar (Dabrafenib) and Mekinist (Trametinib) 
 
Protocol Type /Version Date: 
October 03, 2017 


 
SCHEMA 
A Randomized Phase 2 Study of single agent Dabrafenib (BRAFi) vs. 
combination regimen Dabrafenib (BRAFi) and Trametinib (MEKi) in 
patients with BRAF mutation or BRAF gene fusion defect in thyroid 
carcinoma 
 
10 Endpoint: Objective Response 
Single Stage Design 
Total Sample size=52 
1:1 Randomization 
 
 
If progression on 
ARM A, may 
cross-over to 
ARM B 
 
 
 
 
 
 
 
 
NCCN protocol no. NCCNGSK20008 
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Locally Advanced or Metastatic Iodine Refractory Differentiated Thyroid Cancer 
Harboring BRAF mutation or BRAF gene fusion 
 Measurable ds 
 Progressive ds per RECIST v1.1 in 13-months prior to study entry 
 No more than 3 prior multikinase inhibitors therapy 
Continuous treatment until disease progression, unacceptable adverse event, 
consent withdrawal, or development of illness prohibiting further treatment. 
Adverse Event assessment every 2 weeks for the first 8 weeks, and then every 4-8 
weeks thereafter (4 weeks = 1 cycle) 
Tumor Markers & Response Assessment by CT scan or MRI scan every 8 weeks 
PET scans pre –study and at 8 weeks as clinically indicated 
Correlative Studies: 
1. Signaling inhibition studies in tumor biopsies (7 pts in each arm; 3-5 pts per center) 
2. BRAF mutation studies in circulating plasma DNA (all study patients) 
3. Mechanisms of drug resistance in tumor biopsies or tumor blocks (5 pts in each arm) 
4. Assess predictors of response (Archival tumor block/unstained slides in all study patients) 
5. Pharmacokinetic studies (First 7 pts enrolled on each arm) 
6. Pharmacogenomics studies (All study patients) 
ARM A: Dabrafenib 
(BRAFi) 150 mg orally 
twice daily 
 
N=26 patients 
ARM B: Dabrafenib (BRAFi) 
150 mg orally twice daily and 
Trametinib (MEKi) 2 mg 
orally once daily 
 
N=26 patients 


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TABLE OF CONTENTS 
 
Page 
SCHEMA ........................................................................................................................................v 
1. OBJECTIVES ..........................................................................................................................9 
1.1 
Primary Objectives ......................................................................................................9 
1.2 
Secondary Objectives ..................................................................................................9 
2. BACKGROUND ......................................................................................................................9 
2.1 
Thyroid Cancer ........................................................................................................... 9 
2.2 
The Role of BRAF mutation in Thyroid Cancer .....................................................10 
2.3 
Dabrafenib (BRAFi) ..................................................................................................12 
2.4 
Trametinib (MEKi) ....................................................................................................16 
2.5 
Rationale .....................................................................................................................21 
2.6 
Correlative Studies Background ..............................................................................22 
3. PATIENT SELECTION ........................................................................................................24 
3.1 
Eligibility Criteria ......................................................................................................24 
3.2 
Exclusion Criteria ......................................................................................................27 
3.3 
Inclusion of Women and Minorities .........................................................................28 
4. REGISTRATION PROCEDURES ......................................................................................28 
4.1 
General Guidelines ....................................................................................................28 
4.2 
Registration Process ..................................................................................................29 
4.3 
Cross over from Arm A to Arm B ........................................................................... 29 
5. TREATMENT PLAN ............................................................................................................30 
5.1 
Agent Administration ................................................................................................30 
5.2 
General Concomitant Medication and Supportive Care Guidelines .....................32 
5.3 
Prohibited Medications ............................................................................................ 32 
5.4 
Cautionary Medications ........................................................................................... 32 
5.5 
Duration of Therapy ..................................................................................................33 
5.6 
Duration of Follow Up ...............................................................................................33 
5.7 
Criteria for Removal from Study .............................................................................34 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................34 
6.1 
Dabrafenib Delays/Modifications (applicable to ARM A and ARM B patients) 34 
6.2 
Trametinib Delays/Modifications (applicable to patients on ARM B). ................ 46 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................51 
7.1 
Expected Adverse Events for Dabrafenib (BRAFi) ................................................52 
7.2 
Expected Adverse Events for Trametinib (MEKi) ................................................ 53 
7.3 
Expected Adverse Events for Dabrafenib and Trametinib ....................................55 
7.4 
Adverse Event Characteristics ..................................................................................56 
7.5 
Expedited Adverse Event Reporting ........................................................................57 
7.6 
Specific Reporting of Pregnancy ............................................................................. 58 


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8. PHARMACEUTICAL INFORMATION ........................................................................... 59 
8.1 
Dabrafenib ................................................................................................................. 59 
8.2 
Trametinib ................................................................................................................. 60 
9. CORRELATIVE STUDIES ................................................................................................. 61 
9.1 
Tumor pharmacodynamics (PD) evaluation .......................................................... 62 
9.2 
BRAF mutation quantification in circulating plasma DNA .................................. 63 
9.3 
Tumor mutation screening/Mechanisms of Drug Resistance ............................... 64 
9.4 
Predictive Markers of Response (Archival Tumor Block) .................................... 65 
9.5 
Pharmacokinetics (PK)_ ........................................................................................... 65 
9.6 
Pharmacogenetics (PGx) .......................................................................................... 67 
10. STUDY CALENDAR ...................................................................................................... 67-70 
11. MEASUREMENT OF EFFECT/RESPONSE ................................................................... 71 
11.1 
Antitumor Effect – Solid Tumors ............................................................................ 71 
12. DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 78 
12.1 
Data Reporting .......................................................................................................... 78 
13. STATISTICAL CONSIDERATIONS ................................................................................ 78 
13.1 
Study Design/Endpoints ........................................................................................... 78 
13.2 
Sample Size/Accrual Rate ........................................................................................ 80 
13.3 
Stratification Factors ................................................................................................ 81 
13.4 
Analysis of Secondary Endpoints ............................................................................ 81 
13.5 
Reporting and Exclusions ......................................................................................... 82 
REFERENCES ............................................................................................................................ 84 
APPENDICES 
APPENDIX A 
Performance Status Criteria ............................................................................................. 87 
APPENDIX B 
Prohibited Medications .................................................................................................... 88 
 
APPENDIX C 
Cautionary Mediations ............................................................................................... 89-90 
 
APPENDIX D 
Sample Calendar .............................................................................................................. 91 
 
APPENDIX E 
Patient Pill Diary ............................................................................................................. 92 


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APPENDIX F ...................................................................................................................... 93 
Patient Trametinib Storage & Dosing Instruction Cards 


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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
a.  To screen two different regimens [Dabrafenib (BRAFi) as a single agent versus  
the combination regimen of Dabrafenib (BRAFi) and Trametinib (MEKi)] and 
identify which regimen is more promising for subsequent testing in a Phase III 
trial in radioiodine refractory BRAF-mutation or BRAF gene fusion defect 
positive differentiated thyroid cancer (DTC) patients. 
 
The primary endpoint for each of the treatment arms of this trial is overall response 
rate, defined as the proportion of patients who have a minor response, partial 
response, or complete response within the first 6 cycles of therapy. 
 
1.2. 
Secondary Objectives 
 
a. To understand duration of objective response, progression-free survival and 
overall survival for each treatment group. 
 
b. To assess tolerability and adverse events of Dabrafenib (BRAFi) as a single agent 
and the tolerability and adverse events of Dabrafenib (BRAFi) and Trametinib 
(MEKi) in combination, in patients with DTC. 
 
b. To evaluate impact of experimental drugs on serum tumor marker thyroglobulin 
and its correlation with overall response rate. 
 
d. To understand pharmacokinetic, pharmacogenetics and pharmacodynamics of 
experimental drugs using serial tumor biopsies, tumor blocks and peripheral 
blood. 
 
 
2. BACKGROUND 
 
2.1 
Thyroid Cancer 
 
Thyroid cancer is the most common endocrine malignancy, accounting for 96% of all 
endocrine cancers. There are an estimated 56,000 new thyroid cancer cases in the 
United States in 2012 (1). Distant metastases occur in less than 10% of patients with 
differentiated thyroid cancer (DTC), but represent the most common cause of thyroid 
cancer related death.  DTC comprises 90% of all thyroid cancer cases and includes  
the histological groups of papillary thyroid cancer (PTC) and follicular thyroid cancer 
(FTC). 
Based on the results of placebo-controlled international multicenter phase III trial, 
sorafenib was approved through the FDA in Nov. 2013 for the treatment of locally 
recurrent or metastatic, progressive differentiated thyroid cancer that does not  
respond  to   radioactive   iodine   treatment. Median   progression   free  survival   for 


patients on sorafenib was 10.8 months compared to 5.8 months for participants 
receiving a placebo. Given the modest benefits and significant side effect profile of 
sorafenib, several new targeted therapies are being explored in early phase clinical 
trials. BRAF plays critical role in pathogenesis of thyroid cancer and this trial 
evaluates the role of potent BRAF inhibitor in the treatment of such cancers. 
 
In this population of patients, the expected survival declines rapidly (2-4) with reports 
of 10% survival at 10 years in patients without any initial I131 uptake as compared to 
92% survival rate in patients with I131 uptake who achieve negative studies after 
treatment (4). Currently, patients with progressive and metastatic iodine refractory 
thyroid cancer are offered treatment with clinical trial, small molecule kinase 
inhibitors including sorafenib, sunitinib, or pazopanib, or best supportive care. 
 
2.2 
The role of BRAF gene defects in thyroid cancer 
 
RAS/RAF/MEK/ERK or the "MAPK pathway" is an intracellular signaling pathway 
that plays a critical role in transmission of cell signals to the cell nucleus, where it 
mediates cell differentiation, proliferation, apoptosis, and survival. The MAPK 
pathway is activated in a variety of human malignancies, often through gain-of- 
function mutations in components of the RAS and RAF family. RAF is  a  
cytoplasmic serine-threonine kinase with three isoforms: ARAF, BRAF, and CRAF. 
The BRAF gene, found of chromosome 7, is the strongest activator of the MAPK 
pathway. Furthermore, constitutive activation of the BRAF gene by point mutations  
is a well-described and common genetic event in many human cancers, including 
melanoma, papillary thyroid carcinoma, colon cancers and ovarian cancers (5-7). As 
depicted below in Figure 1, the MAPK-signaling cascade is initiated through 
activation of the receptor tyrosine kinase, which in turn activates RAS. RAS then 
facilitates homo- or heterodimerization of wild-type BRAF. Activated BRAF 
phosphorylates MEK, which in turn phosphorylates ERK, leading to multiple cellular 
effects that are critical to cell proliferation and survival. Mutated BRAF can bypass 
RAS activation and directly dimerize and activate BRAF. BRAF can also form a 
heterodimer with CRAF and result in downstream activation of MEK/ERK pathway. 
KSR, or kinase suppressor of RAS, is able to trigger BRAF activation through side- 
to-side  
heterodimerization,  
further highlighting  the 
complexity 
of 
this 
pathway (8). 
 
 
Figure 1. Mutant BRAF 
and its role in the MAPK 
pathway. 
 
Reproduced from Caronia 
L  M  et  al.  Clin  Cancer 
 
 
 
 
NCCN protocol no. NCCNGSK20008 
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Res 2011 
 
 
 
 
The prevalence of BRAF mutations in papillary thyroid cancer (PTC) ranges from 
29% to 83%, with an average frequency of 44% (7). PTC is the most common 
histologic subtype of thyroid cancer, accounting for greater than 80% of all cases. 
Substitution of glutamic acid for valine in the 600 position of BRAF protein, or 
V600E, is characteristic of the mutation found in PTC, but also is found in poorly 
differentiated and anaplastic thyroid cancer derived from PTC (9). The oncologic 
activity of BRAF V600E mutation as an initiating event in thyroid cancer 
development has been demonstrated in studies of BRAF V600E positive transgenic 
mice. Transgenic mice developed invasive PTC and poorly differentiated thyroid 
cancer with progressive local invasion (10, 11). Further, PTC in human tumors with 
BRAF mutations are present with greater frequency in the advanced setting, and have 
been associated with older age, extra thyroidal extension, and more frequent 
presentation at Stage III and IV (12). 
 
BRAF Gene Fusion as a Molecular Target for RAF and MEK inhibitors 
Analogous to a mutation in the BRAF gene causing constitutive activation of this kinase 
in melanoma and thyroid cancer (BRAF V600E), gene fusions involving BRAF and a 
number of different upstream partners have been shown to activate the kinase activity of 
BRAF. Although genetically the BRAF gene is wild type in these fusions, the end result 
of elevated kinase activity can be considered the same as in an activating mutation. 
 
Background on BRAF Fusions. Work by Ciampi et al. published in 2005 revealed an 
intrachromosomal inversion that generated a AKAP9-BRAF fusion in papillary thyroid 
carcinoma. Further characterization of this fusion gene predicted loss of the N-terminal 
autoinhibitory domains of BRAF, however the kinase domain remained intact. In vitro 
experiments showed the kinase activity of the AKAP9-BRAF fusion to be greater than 
that of the well characterized BRAFV600E mutant. Additionally, the downstream MAPK 
target ERK was shown to be elevated in cells expressing the BRAF fusion gene. 
 
Our group has observed presence of another BRAF fusion gene defect in patient with 
thyroid cancer. KLHL7-BRAF gene fusion involves KLHL7 and BRAF genes on 
chromosome 7, translocating to form a new gene fusion, with intact gene structure or 
open reading frame. This is predicted to have similar structure and function as other gene 
fusions, where loss of an inhibitory domain of the BRAF gene leads to persistence 
activation of the kinase. 
 
Fusions involving BRAF and other N-terminal partners have been observed in multiple 
other malignancies including an AGTRAP-BRAF fusion in gastric cancer and SLC45A3- 
BRAF fusion in prostate cancer. In both cases, the inhibitor domain is lost and the kinase 
domain of BRAF is retained2. Expression of the SLC45A3-BRAF fusion in prostate 


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epithelial cells induced both MEK and ERK phosphorylation and these cells became 
sensitive to treatment with the RAF inhibitor Sorafenib and the MEK inhibitor U0126. 
 
More recently, BRAF fusions were identified in melanocytic neoplasms and were found 
to have several different N-terminal fusion partner3. Analysis of six melanocytic tumors 
and a cutaneous melanoma cell line once again revealed retention of an intact kinase 
domain in these BRAF fusions. Further study using the melanoma cell line confirmed 
previous results by demonstrating constitutive activation of the MAPK pathway. Both p- 
ERK and p-MEK levels were elevated to levels similar to two BRAFV600E mutant 
melanoma cell lines, and were shown to be decreased upon treatment with the RAF 
inhibitor Sorafenib. 
 
RAF Inhibitors. Importantly, only agents that inhibit wildtype BRAF have pre-clinical 
activity or are predicted to have activity, including Sorafenib and Dabrafenib. 
 
Summary. Due to the similar kinase activity found in the context of both BRAF  
mutation and BRAF fusion genes, using a RAF inhibitor such as Dabrafenib or a MEK 
inhibitor such as Trametinib is a rational choice for treatment of tumors containing these 
fusion genes. Combination therapy with Dabrafenib and Trametinib would also be a 
rational consideration. 
 
 
2.3 
Dabrafenib (BRAFi) 
 
Dabrafenib is an orally bioavailable potent and selective inhibitor of BRAF kinase 
with a mode of action consistent with adenosine triphosphate (ATP)-competitive 
inhibition. 
Dabrafenib 
has 
demonstrated 
suppression 
of 
downstream 
pharmacodynamic biomarker, phosphorylated ERK (pERK) in tumor cell lines, anti- 
proliferative activity against multiple BRAF mutant tumor cell lines and achieved 
biomarker suppression and tumor regression in BRAF mutant xenograft models 
(Investigator Brochure). Results from early phase clinical studies suggest that 
Dabrafenib has a favorable pharmacologic and toxicologic profile. 
 
2.3.1 Mechanism of Action 
 
The mechanism of action of Dabrafenib is consistent with competitive inhibition of 
ATP binding. It is most potent at inhibiting mutant BRAFV600E and mutant 
BRAFV600K, and less potent at inhibiting BRAFV600D. 
 
2.3.2 Nonclinical Studies 
 
Dabrafenib is a potent and selective RAF kinase inhibitor against human wild type 
(WT) BRAF and CRAF enzymes with IC50 values of 3.2 and 5.0 nM, respectively, as 
well as against the mutant forms BRAFV600E, BRAFV600K, and BRAFV600D, having 
IC50 value of 0.65, 0.5, and 1.85 nM, respectively. Dabrafenib was highly selective  
for inhibition of BRAFV600E with a selectivity of at least 375-fold for BRAFV600E in 


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panels of >270 protein and lipid kinases, with the exception of 8 kinases, for which 
IC50 values of Dabrafenib were <100 nM. Two of the three active metabolites of 
Dabrafenib [GSK2285403 (M7) and GSK2167542 (M8)] demonstrated similar 
selectively against a small panel of kinases. 
 
Dabrafenib caused a dose-dependent decrease in pERK and phosphorylated MEK 
(pMEK), with IC50 of 3 nM, in ES-2 human ovarian carcinoma cell lines with a 
BRAFV600E mutation. It also decreased pERK in other BRAFV600E cell lines with 
similar potency (IC50 of 3 - 120 nM), while cell lines with WT BRAF or RAS 
mutations were much less sensitive to Dabrafenib (pERK IC50 values >900 nM). In 
BRAFV600E cell lines, Dabrafenib induced a concentration-dependent cell cycle arrest 
in G0/G1 phase at 24 hours followed by apoptosis. In a panel of 110 human tumor 
cell lines, Dabrafenib potently (IC50 <100 nM) inhibited proliferation of 73% of 
BRAFV600E containing cell lines, with generally little or no growth inhibition in tumor 
cell lines with WT BRAF or in cell lines containing activated RAS. 
 
2.3.3 Nonclinical Pharmacokinetics and Metabolism 
 
In mouse, rat, and dog, oral bioavailability of Dabrafenib (from solution formulation) 
was moderate to high (46-82%). Blood clearance was moderate in the mouse, rat and 
monkey (32-50% of liver blood flow), but low in the dog (12% of liver blood blow) 
and volume of distribution was moderate to low (1.4 to 0.6 times total body water). 
 
Preclinical in vitro studies showed that Dabrafenib was primarily metabolized by 
CYP2C8 and CYP3A4. Dabrafenib is also substrate of human P-glycoprotein (Pgp) 
and murine breast cancer resistant protein 1 (Bcrp1) in vitro. However, the relative 
contribution of these various pathways is yet to be elucidated. 
 
2.3.4 Animal Toxicology 
 
The principal dose-limiting toxicity seen in animal toxicology studies conducted with 
Dabrafenib was gastrointestinal side effects. These effects were dose-dependent 
effects in rats and dogs with doses > 10 mg/kg/day and included infrequent emesis, 
changes in fecal consistency, decreased food consumption and body weight loss. 
 
In Dogs, Dabrafenib minimally inhibited hERG repolarization (IC25 of 11.7 μM; 6.1 
μg/mL) and its principal metabolites did not significantly inhibit hERG (IC50 >30 
μM). There was no prolongation of QTc interval or other ECG changes in dogs; 
therefore, Dabrafenib administration has a low potential for QTc prolongation in 
humans. 
 
2.3.5 Clinical Studies 
 
Dabrafenib is an experimental oral drug that is being studied in patients with various 
types of cancers. There are multiple ongoing, concluded or completed phase I, II or  
III studies in patients with solid tumor including following studies: There are four 


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Phase I studies, including the First-time-in-Human (FTIH) study (BRF112680), a  
food effect/particle size evaluation study with two different capsule shells 
(BRF113468), a human mass balance study (BRF113463) and an absolute 
bioavailability study (BRF113479). In addition, there are four Phase II studies 
(BRF113710,  BRF113928,  BRF  113929  and  BRF114144),  one  Phase  III  study 
(BRF113683), and a Phase 1/2 combination study (BRF113220) with Trametinib, a 
MEK inhibitor. 
 
2.3.5.1 Pharmacology in Clinical Studies 
 
Single and Repeat Dose Pharmacokinetics (PK) 
Following single dose oral administration of Dabrafenib in gelatin capsules, plasma 
concentrations peaked approximately 1.0 to 2.5 hours post-dose and decreased 
thereafter following a bi-exponential decline. Median terminal half-lives ranged  from 
4.0 to 6.8 hours following administration of single doses ranging from 12 to 300 mg. 
Increases in maximum observed concentration (Cmax) and area under the 
concentration-time curve (AUC) were generally dose-proportional following single 
doses up to 300 mg, but less than dose proportional to dose following repeat-dosing. 
A 2-fold increase in dose (150 mg BID vs. 300 mg BID) resulted in a 43% increase in 
AUC (0-τ) and no increase in predose concentrations (Cτ). There was no 
accumulation with daily doses ranging from 12 mg to 600 mg administered using 
twice- daily administration; mean accumulation AUC Day 15/Day 1 ratios were <1.0 
for all cohorts. Following administration of Dabrafenib 150 mg BID, AUC was 37% 
lower on Day 18 relative to Day 1. The decrease in exposure noted with repeat dosing 
of Dabrafenib was likely due to induction of its own metabolism. 
 
Metabolism and Excretion 
Based on preclinical and in vitro studies, hepatic metabolism and biliary secretion are 
likely to be the primary route of elimination of GSK2118436. Dabrafenib 
concentrations are likely to be increased in subjects with hepatic impairment and 
dosage adjustment may be required. 
 
In human hepatocytes, Dabrafenib produced dose-dependent increases in CYP2B6 
and CYP3A4 mRNA levels up to 32 times the control levels. The single-dose 
exposure to midazolam, a CYP3A4 substrate was reduced by 74 % with co 
administration of Dabrafenib150 mg BID following repeat-dose administration. Thus, 
Dabrafenib induces CYP3A4-mediated metabolism and may induce other enzymes 
such as CYP2B6 and CYP2C family (2C8, 2C9, and 2C19). Co-administration of 
Dabrafenib and drugs which are primarily metabolized by these enzymes may result  
in decreased concentrations and loss of efficacy. 
 
Dabrafenib inhibited CYPs 2C8, 2C9, 2C19 and 3A4 in human liver microsomes with 
IC50 values in the range of 8 to 32 μM. Drugs that are substrates of  CYP2C8, 
CYP2C9, and CYP2C19 that are highly sensitive to inhibitors or that have a low 
therapeutic index should be used with caution. 


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Three metabolites of Dabrafenib were characterized and may contribute to clinical 
activity. GSK2285403 (hydroxy-metabolite) pharmacokinetics paralleled that of 
parent while the carboxy- (GSK2298683) and desmethyl- (GSK2167542) metabolites 
exhibited a longer half-life and accumulated following repeat dosing. Similar  to 
parent concentrations, exposure for all metabolites showed a less than dose 
proportional increase with repeat dosing. Preliminary results following single dose 
administration showed a total recovery of radioactivity of 93.8 % of the dose with 
faecal excretion being the major route of elimination, accounting for 71.1% of the 
dose. 
 
Relative Bioavailability and Food Effect Evaluation 
The relative bioavailability of single dose of Dabrafenib administered in an 
hydroxypropyl methylcellulose (HPMC) capsule relative to the same formulation in a 
gelatin capsule was evaluated in a non-randomized fashion across 2 separate cohorts 
of subjects enrolled in Study BRF113468. Preliminary results obtained in 14 out of  
28 subjects (7 per cohort) showed higher exposure with HPMC relative to gelatin 
capsule with geometric least squares mean ratios (90% CI) for Cmax and AUC(0-∞) 
of 3.24 (2.08, 5.05) and 2.20 (1.31, 3.67), respectively. HPMC capsules are currently 
being used in the clinical studies BRF113683 (Phase 3) and BRF113929 (Phase 2 
study with brain metastases) while gelatin capsules are being used in Study 
BRF113710 (Phase 2). 
 
The current recommendation is to administer Dabrafenib under fasting conditions, 
either one hour before or 2 hours after a meal. Preliminary results of the food effect 
study showed a decrease in Dabrafenib Cmax and AUC (0-∞) after single dose 
administration. 
 
Drug Drug Interaction 
Preliminary results of the effect of repeat dose administration of Dabrafenib150 mg 
BID on the single dose pharmacokinetics of midazolam, a CYP3A4 probe, showed a 
decrease in midazolam exposure. The geometric least squares mean ratio (90% CI) 
for Cmax and AUC of midazolam with Dabrafenib vs. midazolam alone is 0.388 
(0.241, 0.626) and 0.258 (0.210, 0.318), respectively, indicating that Dabrafenib 
induces CYP3A4-mediated metabolism. Co-administration of Dabrafenib and drugs 
which are affected by the induction of these enzymes may result in decreased 
concentrations and loss of efficacy. If co-administration of these medications is 
necessary, monitor subjects for loss of efficacy or consider substitutions of these 
medications. 
 
2.3.5.2 Safety data in Clinical Studies 
 
Safety data provide below for various studies are updated as of 25 March 2011. 
Dabrafenib (BRAFi) Monotherapy Studies: 
Preliminary  safety  data  are  available  for  the  BRF112680  FTIH  study  and  the 


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BRF113710 phase II monotherapy study in metastatic melanoma. 
 
In the BRF112680 first time in human (FTIH) study, 184 patients have received at 
least one dose of study drug. Doses ranged from 12 mg QD to 300 mg BID and 
patients have received study drug up to a maximum of 626 days. A total of 127 
subjects (69%) have withdrawn from the study as of 25 March 2011, primarily due to 
progression of disease (121 subjects, 66%). Across all 184 subjects,  98%  
experienced at least 1 AE of any grade. The most common AEs experienced by ≥20% 
subjects were fatigue, pyrexia, headache, nausea, hyperkeratosis, skin papilloma, pain 
in extremity, rash, decreased appetite, diarrhea, vomiting and alopecia. Most AEs 
were grade 1 or 2. Seventy seven subjects (42%) experienced a grade 3 adverse event, 
and 15 subjects (8%) experienced grade 4 adverse events; the most common grade 3 
or 4 AEs experienced by ≥4% subjects were squamous cell carcinoma, anemia, 
hyponatremia, hypophosphatemia and lymphopenia. Sixty six  (36%)  subjects 
reported SAEs; the most common SAEs were SCC (11%), pyrexia (5%), and urinary 
tract infection (3%). No subjects have permanently discontinued study drug due to 
AEs/SAEs. Fifty seven subjects (31%) had study drug interrupted due to the 
occurrence of AEs, primarily due to pyrexia (9%). Thirty deaths due to the 
progression of disease under study have been reported. No fatal AEs/SAEs (grade 5) 
have been reported. 
 
In the phase II BRF113710 study, 92 patients have received at least one dose of study 
drug (150 mg BID). The majority of the subjects (94%) have received 6 months or 
less of study treatment. Across all 92 subjects 87% have experienced at least 1 AE of 
any grade. AEs were primarily grade 1 or 2. The most common AEs experienced by 
≥15% subjects were arthralgia, hyperkeratosis, pyrexia, fatigue, nausea and headache. 
Sixteen subjects (17%) experienced a grade 3 adverse event, and 7 subjects (8%) 
experienced a grade 4 adverse event; grade 3 AEs experienced by more than 1 subject 
include anemia, hyperphosphatemia, lymphopenia, squamous cell carcinoma and 
headache. Sixteen (17%) subjects reported SAEs, SAEs reported by more than 1 
subject include SCC, anemia and vomiting. No subjects have permanently 
discontinued study drug or withdrawn from the study due to AEs/SAEs. Twenty-six 
subjects (28%) had study drug interrupted due to the occurrence of AEs, primarily 
due to hyperphosphatemia (5%). Eight deaths due to the progression of disease under 
study have been reported. No fatal AEs/SAEs (grade 5) have been reported. 
 
Dabrafenib (BRAFi) in Combination with Trametinib (MEKi) 
As of 25 March 2011, there is 1 ongoing combination study, the Phase I/II study 
BRF113220 in which Dabrafenib has been administered as monotherapy or in 
combination with Trametinib. One hundred and thirty seven subjects have been 
enrolled. A total of 15 subjects (11%) have withdrawn from the study primarily due  
to lack of effect and progression of disease (9%). Thirty two (23%) patients have 
experienced SAEs, with the most common SAEs being pyrexia (n=7, 5%), 
hypotension (n=5, 4%) and nausea (n=4, 3%). Overall, 106 (77%) of patients 
experienced AEs, with the most common AEs experienced by ≥20% subjects being 
pyrexia (n=36, 26%), fatigue (n=35, n=26%) and nausea (n=28, 20%). Two subjects 


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have permanently discontinued study drug due to AEs (retinal vein occlusion, 
cerebrovascular accident). Four deaths have been reported in the study, 3 due to the 
progression of disease a 1 death from complications following surgery. 
 
 
2.4 
Trametinib (MEKi) 
 
Trametinib is an orally bioavailable reversible, highly selective, allosteric inhibitor of 
mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. 
Trametinib is non-competitive towards ATP and inhibits activation of MEK by 
RAF kinases as well as MEK kinase activity. Trametinib has demonstrated 
suppression of downstream pharmacodynamic biomarkers, phosphorylated MEK 
(pMEK) and phosphorylated ERK (pERK) in tumor cell lines, anti-proliferative 
activity against multiple BRAF or RAS mutant tumor cell lines and achieved 
biomarker suppression and tumor regression in BRAF or RAS mutant xenograft 
models (Investigator Brochure). Results from early phase clinical studies suggest that 
Trametinib has a favorable pharmacologic and adverse event profile. 
 
2.4.1 Mechanism of Action 
 
Trametinib is an allosteric inhibitor of MEK1 and MEK2. Inhibition of MEK1 
and MEK2 is expected to reduce proliferation of cells that are dependent on 
the MAPK pathway for growth. 
 
Phosphorylation of ERK by MEK enzyme in presence of ATP (2.5, 5, 10 and 20 μM) 
and Trametinib (0.125, 0.25 and 0.5 μM) demonstrated that the inhibition constants 
(Ki values) were 0.38 μM and 0.29 μM against phosphor-MEK (pMEK) and the 
pMEK-ATP complex, respectively. These data demonstrate that Trametinib is an 
inhibitor of pMEK activity and is not competitive with ATP binding, as Ki values 
were similar in the absence or presence of ATP. 
 
Trametinib demonstrated equal potency against activated MEK1- and MEK2- 
mediated phosphorylation of ERK (sequence identity of 85% across the whole protein 
and 100% in the active site for humans). Trametinib demonstrated preferential 
inhibition of Raf-mediated MEK1 activation (IC50 = 0.60 nM) over pMEK1 kinase 
activity (IC50 = 13 nM). Trametinib exerted no effect on B-RAF or c-Raf kinase 
activity, as Trametinib (0.1 to 10 μM) did not affect the phosphorylation of myelin 
basic protein mediated by B-RAF or c-Raf. Phospho-mapping identified that 
Trametinib blocks phosphorylation by activated Raf kinase of Ser218 and not Ser222 
on MEK. 
 
2.4.2 Nonclinical Studies 
 
Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated 
extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are critical 
components  of  the  extracellular  signal-related  kinase  (ERK)  pathway  which  is 


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commonly hyperactivated in tumor cells. Oncogenic mutations in both B-RAF and 
RAS signal through MEK1 and MEK2. Trametinib is non-competitive towards ATP 
and inhibits activation of MEK by RAF kinases as well as MEK kinase activity. The 
specificity of Trametinib to MEK1 and MEK2 was confirmed against a panel of 183 
kinases, including MEK5, the closest kinase homolog to MEK1 and MEK2, and no 
significant inhibitory activity was measured. 
 
In vitro, 80% of cell lines carrying activating mutations of B-Raf and 72% of Ras 
mutant cancer cell lines were sensitive to Trametinib in cell proliferation assays, and  
a majority (83%) of hematopoietic cancers from acute or chronic myeloid leukemia 
(AML or CML, respectively) origins were also very sensitive. 
 
Anti-tumor Activity in vitro 
Cancer cells expressing high constitutive levels of activated ERK (pERK) tended to 
be more sensitive to Trametinib than those with lower levels of pERK, suggesting  
that tumors with B-RAF or RAS mutations and/or high levels of pERK may respond 
to Trametinib treatment. In all cell lines, pERK was strongly inhibited following 
treatment with Trametinib and was independent of their proliferative response, 
suggesting that pERK inhibition is necessary but not sufficient to inhibit cell 
proliferation. In cell lines that were sensitive to the anti-proliferative activity of 
Trametinib, the response was associated with arrest in G1 phase of the cell cycle, 
accumulation of p27, reduction of cyclin D1 and phospho-retinoblastoma protein. 
Induction of apoptosis was demonstrated in some cell lines. Inhibition of pERK and 
inhibition of cancer cell proliferation were fully reversible following compound 
removal, suggesting that sustained exposure to Trametinib, or potential combination 
with other drugs, may be required for full activity. 
 
When Trametinib was combined with standard of care drugs against human cancer 
cell lines in vitro, an additive effect was observed for pancreatic cancer with 
gemcitabine or erlotinib and for colon cancer with 5-FU or irinotecan. The 
combination of Trametinib with rapamycin, ara-C, bexarotene or sorafenib produced 
an additive effect against most AML cell lines tested. In addition, combination of 
Trametinib with an investigational phosphoinositide 3-kinase (PI3K) inhibitor, as  
well as with a Centromer Protein-E (CENP-E) inhibitor, was synergistic on inhibition 
of cell growth in various cancer (pancreas, colon, lung) cells. Additionally, the 
combination of Trametinib and a CENP-E inhibitor increased caspase activity, 
indicating enhanced apoptosis in colon cancer cell lines. 
 
While many proliferating human cells are sensitive to Trametinib in vitro, Trametinib 
did not affect non-dividing normal cells and did not completely inhibit bone marrow 
progenitor cells at concentrations demonstrating anti-proliferative activity on very 
sensitive cancer cell lines. 
 
Anti-tumor Activity in vivo 
Trametinib was orally bioavailable in mice, and doses as low as 1 mg/kg reached 
blood concentrations that caused sustained reductions of pERK, an accumulation of 


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p27, and a decrease of Ki67 in tumor xenografts; brain exposure levels were ~10% of 
those in blood, and no significant pERK inhibition was measured in brain tissue. In 
mice, exposure to Trametinib produced dose- and schedule-dependent anti-tumor 
responses correlating with blood levels. Typically, B-RAF--mutant xenografts 
responded with tumor regression while K-RAS-mutant xenografts responded with 
tumor growth inhibition.  In vivo combination studies testing Trametinib together  
with various other anticancer drugs showed good potential for synergistic effects. 
 
2.4.3 Non-clinical Pharmacokinetics and Metabolism 
 
Trametinib exhibited low plasma clearance among nonclinical species (mouse, rat, 
dog and monkey) with varied but generally long half-lives. Oral bioavailability  
ranged between 42% and 100%. Since Trametinib is a low solubility, high 
permeability molecule, its absorption is likely limited by solubility and dissolution. 
Plasma protein binding was high in nonclinical species and human (>95%) and blood 
cell association was low. Consistent with high permeability, Trametinib had moderate 
to high volume of distribution among the nonclinical species studied and drug- 
related material (DRM) was widely distributed into rat tissues. 
 
No apparent human-specific metabolite was observed in the in vitro cross-species 
[14C] Trametinib metabolism study. [14C]Trametinib was also found to metabolize 
predominantly via a non-cytochrome P450 (CYP) mediated deacetylation with 
secondary oxidation or glucuronidation biotransformation pathways. CYP3A4 was 
implicated in the in-vitro formation of M7, a metabolite mediated by both non-CYP 
and CYP pathways. The relative contribution of CYP3A4 to the total metabolic 
clearance of Trametinib in human in vivo is not currently understood and, therefore, 
the possibility of a metabolic drug interaction cannot be eliminated. Elimination of 
DRM in rat and dog after oral administration occurred predominantly via the feces 
(>60% of dose), with urinary excretion (<7% of dose) representing a minor route. 
 
Trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9 and 2C19, 
inducer of CYP3A4 and inhibitor of the transporters (OATP1B1, OATP1B3, Pgp and 
BCRP), the low clinical Trametinib systemic exposure relative to these in vitro 
inhibition values suggests a low potential for Trametinib as a perpetrator in clinical 
drug-drug interactions. However, drugs with a narrow therapeutic index that are 
substrates of CYP2C8, the CYP with the lowest inhibition IC50, should be used with 
caution. There was no evidence of time-dependent inhibition with any of the CYP 
enzymes investigated. In addition, Trametinib was not found to be an in vitro  
substrate of the transporters Pgp and human breast cancer resistance protein (BCRP). 
 
2.4.4 Animal Toxicology 
 
Systemic toxicity of Trametinib has been evaluated following oral dosing in rats and 
dogs for up to 13 weeks. In the most sensitive nonclinical species, rat, the principal 
adverse effects seen in oral toxicity studies of up to 13 weeks with daily dosing were 
skin  and  stomach  erosions,  skin  ulcerations,  which  were  secondary  to  reduced 


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proliferation, altered phosphate homeostasis that resulted in soft tissue mineralization, 
hepatocellular 
necrosis, 
bone 
marrow 
degeneration/necrosis 
and 
ovarian  
perturbations. 
 
Trametinib inhibited hERG channel repolarization in HEK293 with an IC50 of 1.54 
μM (950ng/mL). In a rabbit left ventricular wedge assay, Trametinib had no 
significant effect on QT interval at concentrations up to 30 μM (18450 ng/mL; limit  
of solubility). In addition, single oral doses up to 1.5 mg/m2 in dogs produced no 
changes in arterial blood pressure, heart rate, body temperature or ECG intervals, 
including QTc. While Trametinib affected cardiac electrophysiology in vitro, no 
effects were observed in vivo at doses that were maximally tolerated in dogs. This 
difference in responses is likely related to the very low Cmax (~10 ng/mL total drug) 
at tolerated doses in dogs and the high protein binding (97% in dogs) of Trametinib. 
The concentrations at which effects were seen in these in vitro studies are 
significantly higher than the free fraction observed in nonclinical toxicology studies  
or the clinical dose (2 mg). These results suggest a low risk for cardiovascular effects 
in the clinic. 
 
2.4.5. Clinical Studies: 
 
The effect of Trametinib in subjects with a variety of refractory cancers is currently 
under evaluation in 14 ongoing clinical studies. Following clinical data derived from 
these studies are updated as of April 14 2011. 
 
Trametinib has been administered as monotherapy in 6 of these studies, and as 
combination therapy in the other 8 studies. As of 14 April 2011, 657 subjects with 
cancer have received at least one dose of Trametinib in the 13 ongoing Phase I/II/III 
clinical studies. This number does not include subjects from 2 randomized trials 
(MEK113487 and MEK114267), from the blinded part of the combination trial 
(BRF113220), and from another combination trial (P3K113794). 
 
2.4.5.1 Pharmacology in Clinical Studies 
 
Preliminary Trametinib pharmacokinetics were determined after single- and repeat 
dose oral administration of Trametinib tablets in subjects with solid tumors. 
Trametinib is absorbed rapidly with median Tmax generally occurring within 1-3 
hours after oral administration of Trametinib under fasting conditions. Following 
repeat-dosing the mean area under the curve (AUC0-τ) and maximum concentrations 
(Cmax) increased in an approximately dose proportional manner. Trametinib 
accumulates with repeat dosing with a mean effective half life of approximately 5 
days. 
 
2.4.5.2 Safety data in Clinical Studies 
 
Based on the adverse events (AEs) observed in the dose escalation phase of the first- 
time   in-human   (FTIH)   study   MEK111054,   the   maximum  tolerated   dose was 


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established at 3.0 mg once daily (QD), and the recommended Phase II dose (RP2D)  
of Trametinib was identified as 2.0 mg QD. 
 
Of the 241 subjects in the 2.0 mg dose group in the 3 monotherapy trials 
(MEK111054,   MEK111759,   and   MEK113583),   99%   to   100%   of   subjects 
experienced at least one AE, and 26% to 71% of all subjects experienced SAEs. Of 
the 241 subjects, 4% to 23% permanently discontinued study treatment due to AEs. In 
these trials, the most common AEs experienced were rash, diarrhea, nausea, fatigue, 
vomiting, anemia, peripheral edema, abdominal pain, constipation, dermatitis 
acneiform, decreased appetite, pruritus, dyspnea, pyrexia, pneumonia, febrile 
neutropenia, AST increased, ALT increased, and dry skin. 
 
In the 5 combination therapy trials of Trametinib for which data are available 
(MEK112110, MEK112111, MEK113486, open-label parts of BRF113220, and 
TAC113886), 89% to 100% of all 296 subjects in any dose group experienced at least 
one AE and 21% to 45% of all 388 subjects in any dose group experienced at least 
one SAE. Of these 296 subjects, 4% to 10% permanently discontinued study  
treatment due to AEs. In the 5 combination trials for which data are available, the 
most common AEs experienced were nausea, fatigue, diarrhea, vomiting, decreased 
appetite, pyrexia, rash, constipation, neutropenia, dry skin, dermatitis acneiform, 
anemia, mucosal inflammation, stomatitis, exfoliative rash, thrombocytopenia, 
peripheral edema, abdominal pain, cough, chills, and AST increased. 
 
2.5 
Rationale 
 
Differentiated thyroid cancer (DTC) accounts for 95% of all endocrine cancers and 
papillary thyroid carcinoma (PTC) is the most common (85%) type of DTC. There is 
no standard treatment for patients with metastatic, radioiodine resistant DTC.  
Aberrant signaling through the RAS/RAF/MEK/ERK pathway has been identified in 
many human malignancies (13). BRAF mutations are present in approximately 44% 
of PTC cases, and with greater frequency in the advanced setting (12, 14). The role of 
BRAF in development of PTC is well established (8). 
 
BRAF or MEK inhibitors in PTC: Our group reported significant biologic and  
clinical activity of sorafenib, an orally active multi-kinase inhibitor targeting BRAF 
and angiogenesis, in patients with advanced PTC (15). While we showed drastic 
>95% decrease in pERK in tumor biopsies obtained from the PTC patients treated 
with sorafenib, the mechanism of action remains unclear. Of note, we also observed 
significant anti-angiogenic effect (dramatic decline in pVEGFR in tumor biopsies and 
in tumor perfusion in index lesions in dynamic contrast enhanced-MRIs).(16) 
Clinically, sorafenib has efficacy with objective response rates of 15-25% in phase 2 
trials (16-18) and is now recommended by NCCN for the treatment of advanced 
iodine-refractory DTC. In a phase I trial of PLX4032, a selective ATP competitive 
BRAF inhibitor, one patient with PTC had a partial response (PR) and 2 patients had 
stable disease (SD) with response ranging 8 to 13 months (19). Single agent MEK 
inhibitor, AZD6244 has been tested in a phase 2 clinical trial in patients with iodine- 


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refractory PTC (20). Of a total of 39 individuals enrolled in the trial, best response 
was evaluable in 32 patients of whom 1 had a PR (3%) and 21 had SD (54%). Of  
note, a relatively high frequency of progressive disease (PD) (43%) was seen in this 
study. 
 
Dabrafenib and Trametinib in solid tumors: Dabrafenib is a highly potent and 
selective ATP competitive BRAF inhibitor with selectivity for mutant BRAF over 
wild type BRAF. In the first time in human (FTIH) study (21), the recommended 
phase 2 dose (RP2D) was defined as 150 mg twice daily. Trametinib is a potent, 
highly selective allosteric inhibitor of MEK1 and MEK 2. In the FTIH study (22), the 
maximum tolerated dose (MTD) was defined as 2 mg daily. Both of these agents  
were well tolerated and resulted in >90% pERK inhibition in tumors of patients with 
melanoma. While dramatic objective responses in melanoma are observed with both 
single agents, benefit of BRAF inhibitor was restricted to patients with BRAF 
mutated melanoma. Dramatic antitumor activity has been demonstrated with the 
combination of Trametinib and Dabrafenib a phase I/II trial of patients with BRAF 
mutated solid tumors (23). The RP2D was Trametinib 2 mg daily in combination with 
Dabrafenib 150 mg twice daily. Adverse events included rash, neutropenia, pyrexia, 
vomiting, fatigue and sepsis like syndrome. No cutaneous squamous cell carcinoma 
(SCC) was observed. In 10 patients who received Dabrafenib 150 mg twice daily and 
Trametinib >1mg daily, 9 had PR and 1 SD. 
 
Pre-clinical data in thyroid cancer: In preclinical thyroid models, BRAF V600E 
mutation confers preferential sensitivity to both BRAF and MEK inhibition (24, 25). 
Singly, BRAF and MEK inhibitors effectively reduced MAPK signaling in BRAF 
mutated thyroid cell lines by decreasing pERK, and inhibited growth of BRAF 
mutated xenograft tumors (Figure 2) (26-28). Mechanisms of acquired resistance to 
BRAF inhibition, including RAF isoform switching and overexpression of PDGFR, 
N-RAS, or COT, have been described in preclinical melanoma studies (29-31). MEK 
inhibition with Trametinib was shown to prevent ERK activation and proliferation in 
a melanoma cell line resistant to BRAF inhibition (29). 
 
Given the above preclinical and clinical data, we hypothesize that single agent 
Dabrafenib will have efficacy in the treatment of advanced, BRAF mutated DTC and 
that combination therapy with Dabrafenib and Trametinib will result in greater 
clinical efficacy than Dabrafenib alone, through vertical inhibition of the 
RAS/RAF/MEK/ERK pathway and mitigation of potential mechanisms of resistance. 
 
2.6 
Correlative Studies Background 
Figure 
2. 
Trametinib 
causes 
durable 
responses in DTC xenograft tumors. 5x106 
cells from the indicated line, suspended in 
matrigel were injected into the right flank of 4 
to 6 week old athymic nu/nu mice. After 
tumors reached 0.1 cm3, they were randomized 
in groups of 13 to receive Trametinib 1mg/kg 
or pazopanib 100 mg/kg, both drugs combined, 
or vehicle control by oral lavage. 


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2.6.1 Tumor pharmacodynamics (PD) evaluation: Mutations in BRAF, specifically the 
BRAF V600E mutation, are the most commonly described mutations in DTC (7, 12, 
32, 33). Preclinical models have confirmed that these mutations are oncogenic (10) 
and result in constitutive activation of the MAPK (RAS/RAF/MEK) pathway (34). 
Inhibition of BRAF and other signaling molecules in the MAPK pathway is thus 
conceptually appealing and early clinical trials evaluating BRAF inhibitors have been 
promising in patients with advanced thyroid cancer (35). Our primary hypothesis is 
that combination therapy with Dabrafenib (BRAFi) and Trametinib (MEKi) in 
patients with BRAF-mutant DTC will accentuate the vertical blockade of the MAPK 
pathway when compared to GSK2118438 alone, and that MAPK blockade will be 
associated with response to therapy. We propose using fine needle aspiration (FNA) 
tumor biopsies for PD monitoring. We have previously demonstrated in our study of 
sorafenib (a multikinase inhibitor with relatively weak BRAF inhibition) in papillary 
thyroid cancer that FNAs, obtained serially prior to and during treatment, can be used 
for PD monitoring of treatment with BRAF inhibitors (16). We performed 
immunohistochemistry (IHC) in biopsy specimens and tested for pERK, pAKT and 
pVEGFR. Monitoring of the same pharmacodynamics markers was also used with  
the potent and selective BRAF inhibitor PLX4032 in patients with metastatic 
melanoma (19).  In the phase I PLX4032 trial, tumor biopsies obtained at baseline  
and day 15 was available for seven patients. Tumor levels of pERK, cyclin D1, and 
Ki-67 were markedly reduced at day 15 as compared with baseline in all specimens 
tested. These studies support the hypothesis that decreases in tumor pERK and Ki-67 
will be seen with treatment, reflecting down regulation of MAPK. Increases in the 
levels of the sodium-iodine symporter (NIS) may also be seen, as BRAF activation 
suppresses NIS expression, leading to a loss of RAI sensitivity (36). 
 
2.6.2 BRAF V600E quantification in circulating plasma DNA: Several investigators have 
demonstrated the ability to detect the BRAF V600E mutation in circulating plasma 
DNA samples from patients with BRAFV600E mutant neoplasms, including melanoma 
(37-39) and thyroid cancer (40). With the emergence of new technology, it is now 
possible to develop highly sensitive assays to detect and obtain absolute 
concentrations of rare mutant alleles (41). We hypothesize that plasma levels of 
mutant BRAF alleles can be correlated to radiographic response as defined by 
RECIST, with improved sensitivity and specificity in comparison to traditional 
serologic correlates such as thyroglobulin (Tg), potentially allowing for the early 
detection of disease progression and resistance to therapy. 
 
2.6.3 Tumor mutation screening: Third, we propose to study the potential mechanisms of 
resistance to BRAFi and MEKi in a subset of patients with initial response to therapy 
followed by subsequent progression. Several mechanisms of resistance to BRAF 
inhibitors have been described in melanoma, including BRAF-independent activation 
of the MAPK pathway (e.g., NRAS mutations), as well as upregulation of alternative 
signaling pathways that are independent of MAPK (e.g., PDGFRβ, COT) (30, 31). 
However, it is unclear if these same pathways can be implicated in the development  
of resistance in thyroid carcinoma. Patterns of resistance are anticipated to differ in 


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patients treated with both BRAFi and MEKi as opposed to BRAFi alone: we expect 
that additional activating mutations of the MAPK pathway (e.g., NRAS) will be 
restricted to patients treated with BRAFi alone. IHC and tumor mutational screening 
will be performed at baseline and at progression as part of this analysis. 
 
2.6.4.Predictive markers of response: Pre-clinical studies show that Trametinib responds 
better in tumors that have high levels of pERK expression. If we observe significant 
clinical response, we will evaluate levels of pERK, pAKT, pMEK expression in 
archival tumor samples.  Alternative mechanism of funding will be sought. 
 
2.6.5 Pharmacokinetics (PK): We will evaluate PK of both Dabrafenib (BRAFi) and 
Trametinib (MEKi). A recent study reported no drug-drug interactions between these 
two agents in a population of melanoma patients (23). Therefore, we will not evaluate 
the potential for drug-drug interaction. However, it will be important to characterize 
the PK of both agents, as well as the PK of GSK2285403 and GSK2167542, the 
active metabolites of GSK2118436. 
 
2.6.6 Pharmacogenetics (PGx): Finally, we will assess the impact of PGx on drug 
disposition (absorption, distribution, metabolism, and elimination) in this patient 
population. An alternative source of funding will support PGx studies. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have histologically or cytologically confirmed papillary thyroid 
cancer, follicular thyroid cancer (Tall cell variant, insular thyroid cancer, 
follicular variant of papillary thyroid cancers, poorly differentiated thyroid 
cancer or any of the above mixed histology will be allowed). Patients with 
anaplastic thyroid cancer are excluded. 
 
3.1.2 
Presence of BRAF mutation or genes fusions involving BRAF in tumor tissue. 
 
3.1.3 
Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm 
with conventional techniques or as ≥ 10 mm with spiral CT scan, MRI, or 
calipers by clinical exam. Malignant lymph nodes will be considered 
measurable if they are ≥ 15 mm in short axis. See Section 11 for the 
evaluation of measurable disease. 
 
3.1.4 
Patients must have progressive disease within the thirteen months prior to 
study enrollment.  Progressive disease is as defined in RECIST 1.1, which is  
at least a 20% increase in the sum of diameters of target lesions and the sum 
must also demonstrate an absolute increase of at least 5 mm. The appearance 
of one or more new lesions is also considered progressive disease. 


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3.1.5 
Patients must have disease that is refractory (unresponsive) to radioactive 
iodine (RAI) treatment as defined by one of the following: 
 
a. One or more measurable lesions that do not demonstrate RAI uptake 
b. One or more measurable lesions progressive by RECIST 1.1 within 12- 
months of prior RAI therapy and/or the appearance of one or more new 
lesion within 12 months of prior RAI therapy. 
c. Cumulative RAI dose of >600 mCi. 
d. Measurable disease that is Fludeoxyglucose (18F) PET scan positive. 
 
3.1.6 
Prior therapy allowed: 
 
3.1.6.1 Patients may have been previously treated with up to three regimens of 
oral multikinase inhibitors, including sorafenib, sunitinib and pazopanib. 
3.1.6.2 Patients may have been previously treated with external beam radiation 
or cytotoxic chemotherapy therapy. 
 
3.1.7 Age >18 years. 
 
Because no dosing or adverse event data are currently available on the use of 
Dabrafenib or Trametinib, each respectively as monotherapy or as 
combination therapy in patients <18 years of age, children are excluded from 
this study, but will be eligible for future pediatric trials. 
 
3.1.8 ECOG performance status <2 (Karnofsky >60%, see Appendix A). 
 
3.1.9 Patients must have normal organ and marrow function as defined below: 
 
 Absolute neutrophil count 
>1,500/mcL 
 Platelets 
>100,000/mcL 
 Total bilirubin 
<1.5  X  institutional  upper  limit of normal 
(unless due to Gilbert’s disease) 
 AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
 Serum creatinine 
<1.5 X institutional upper limit of normal 
 Left ventricular EF 
≥ 50% 
3.1.10 Patient must have a calcium phosphate product (CPP) ≤4.0mmol2/L2 or 50 
mg2/dL2). 
3.1.11 Female patients of childbearing potential are required to have a negative 
serum pregnancy test within 14 days prior to the first dose of study 
medication. 
 
a. Females are required to use an effective method of contraception from the 
time of negative serum pregnancy test, throughout the study duration, and for 


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4 months after the last dose of study medication. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in 
this study, she should inform her treating physician immediately. Men treated 
or enrolled on this protocol must also agree to use adequate contraception 
prior to study enrollment, for the duration of study participation, and for 16 
weeks after completion of the last dose of study drug. 
 
b. Specific contraception requirements for females: Female subjects of 
childbearing potential must not become pregnant and are required to be 
sexually inactive by abstinence or use contraceptive methods with a failure 
rate of < 1%. Sexual inactivity by abstinence must be consistent with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post ovulation methods) and withdrawal are not 
acceptable methods of contraception. Contraceptive methods with a failure 
rate of < 1% include the following: 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% 
failure rate as stated in the product label, 
• Male partner sterilization (vasectomy with documentation of Azoospermia) 
prior to the female subject's entry into the study, and this male is patient’s sole 
sexual partner. For this definition, “documented” refers to the outcome of the 
investigator's/qualified physician designee’s medical examination of the 
subject or review of the subject's medical history for study eligibility, as 
obtained via a verbal interview with the subject or from the subject’s medical 
records. 
• Double barrier method: condom and occlusive cap (diaphragm or 
cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) 
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The 
investigator is responsible for ensuring subjects understand how to properly 
use these methods of contraception. 
 
c. Specific contraception requirements for males: To prevent pregnancy in  
a female partner or to prevent exposure of any partner to the 
investigational product from a male subject’s semen, male subjects 
must use one of the 
following contraceptive methods during the study and for a total of 16 
weeks following the last dose of study drug (based upon the lifecycle of 
sperm): 
• Abstinence, defined as sexual inactivity consistent with the preferred 
and usual lifestyle of the subject for 14 days prior to first dose of study 
drug, through the dosing period, and for at least 16 weeks after the last 
dose of study drug. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
• Condom (during non-vaginal intercourse with any partner - male or 
female) OR 


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• Condom and occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent (foam/gel/film/cream/suppository) (during sexual 
intercourse with a female) 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had external beam radiotherapy, cytotoxic chemotherapy,  
or oral multikinase inhibitors within 4 weeks prior to study enrollment. 
 
3.2.2 Patients who have been treated with radioactive iodine within 24 weeks prior 
to study enrollment (radioactive iodine within 24 weeks will be allowed if 
negative post-treatment scan or progressive disease defined by RECIST 1.1). 
 
3.2.3 Patients that have not recovered from adverse events related to prior 
chemotherapy, radiation therapy or multikinase inhibitors to CTCAE 4.0  
grade 1 or less except for alopecia. 
 
3.2.4 Patients previously treated with potent BRAF inhibitor or MEK inhibitor, 
including PLX4032/vemurafenib, ARQ 736 for more than 10 days. Previous 
treatment with sorafenib is permitted. 
 
3.2.5 Patients that are receiving any other investigational agent. 
 
3.2.6 Patients that are currently taking any prohibitive medication. (Appendix B). 
Patients on therapeutic dose of warfarin. This is due to potential for  
significant interactions between warfarin and study agents. 
 
3.2.7 Patients with a known history of infection with Hepatitis B Virus (HBV) or 
Hepatitis C Virus (HCV). 
 
3.2.8 Patients with a history of other malignancy. Patients who have been disease- 
free from other malignancy for 5 years or greater, or patients with a history of 
resected non-melanoma skin cancer, or patients with a history of treated in  
situ carcinoma will be allowed. 
 
3.2.9 Patients with uncontrolled brain metastases. Patients who are on a stable dose 
of corticosteroids for more than 1 month or off corticosteroids for 2 weeks 
prior to study enrollment can be enrolled. Enzyme-inducing anti-epileptic 
drugs are not permitted. 
 
3.2.10 Patients with a known history of retinal vein occlusion (RVO) or central serous 
retinopathy  (CSR)   or  predisposing  factors  to  RVO  or  CSR  (e.g. 


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uncontrolled 
glaucoma or ocular hypertension, uncontrolled systemic disease such 
as 
hypertension, diabetes mellitus, or history of hyper viscosity or 
hypercoagulability syndromes). 
 
3.2.11. Visible retinal pathology as assessed by ophthalmic exam that is 
considered a 
risk factor for RVO or CSR such as: 
a. Evidence of new optic disc cupping 
b. Evidence of new visual field defects 
c. Intraocular pressure > 21 mm Hg as measured by tonography 
 
 
3.2.12 Patients with Class II, III, or IV heart failure as defined by the New York 
Heart Association (NYHA) functional classification system. 
a. Abnormal 
cardiac valve morphology (subjects with minimal 
abnormalities, can be entered on study with approval). 
 
3.2.13 QTc interval greater than or equal to 480 msecs (≥ 500 msec for subjects with 
Bundle Branch Block). 
 
3.2.14 Patients with uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.2.15 Pregnant women and nursing women are excluded from this study because 
Dabrafenib has the potential for teratogenic or abortifacient effects. In 
embroyfetal developmental studies in rats, developmental toxicities including 
reduced fetal body weight, embryo-lethality, cardiac ventricular septal defect 
malformations, delayed skeletal development and variation in thymic shape 
have been observed. 
 
3.2.16 HIV-positive patients or those on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with 
Dabrafenib. In addition, these patients are at increased risk of lethal infections 
when treated with marrow-suppressive therapy. 
 
3.2.17 Subjects with a history of pneumonitis or interstitial lung disease. 
 
3.2.18 History of acute coronary syndromes (including myocardial infarction 
and unstable angina), coronary angioplasty, or stenting within 6 
months prior to study enrollment. 
 
3.2.19 History of uncontrolled arrhythmias. Subjects with controlled atrial 
fibrillation for >1 month prior to study enrollment are not excluded. 


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3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. 
REGISTRATION PROCEDURES 
4.1 
General Guidelines 
 
OSU patients will be registered by the OSU research coordinator. 
 
Subsite patients will have eligibility verified and will be entered on study centrally at 
the Ohio State University by the Study Coordinator. All subsites should call the 
Subsite Coordinator, Jennifer Sexton, at 614-366-5642 to verify slot availabilities.  
The required forms, including Eligibility Criteria Checklist and Registration Form, 
can be found in the Supplemental Forms Document. 
 
Following registration, patients should begin protocol treatment within 5 business 
days. Issues that would cause treatment delays should be discussed with the Principal 
Investigator and Subsite Coordinator. If a patient does not receive protocol therapy 
following registration, the patient’s registration on the study may be canceled. The 
Subsite Coordinator should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order study 
agents directly from Novartis. Agents may be ordered by a participating site only  
after the initial IRB approval for the site has been forwarded to the Coordinating 
Center. 
 
 
4.2 
Registration Process 
 
To register a subsite patient, the following documents should be completed by the 
research nurse or data manager and faxed or e-mailed to the Subsite Coordinator: 
 Copy of all required laboratory and radiologic tests per the protocol calendar. 
Screening tests must be within the specified window. 
 Signed patient consent form 
 HIPAA authorization form 
 Eligibility Criteria Checklist 
 Registration Form 
 Source documents verifying every inclusion & exclusion criteria 
 Emails and other signed forms used as source documentation 
 
The subsite research nurse or data manager at the participating site will then call or 
email the Subsite Coordinator to verify eligibility. To complete the registration 
process, the Coordinator will: 


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 assign a patient study number 
 register the patient on the study 
 randomize the patient to treatment ARM A or ARM B 
 advise if patient will need Pharmacokinetic studies (as it is restricted to first  
10 pts on each arm) 
 fax or e-mail the patient study number and assigned treatment ARM to the 
participating site 
 
4.3 
Cross-over from Arm A to Arm B 
 
 
 At the treating physician’s discretion, patients that experience disease 
progression on ARM A, may cross over from ARM A to ARM B. Each 
participating center needs to re-register the patient by contacting the 
coordinating 
center 
with 
the 
following 
data: 
Progressive 
disease 
documentation form (e.g. local Tumor Measurement Form) 
 Reports of relevant CT/MRI scans including baseline and on study until 
progression 
 
Patients that cross over to ARM B will not be eligible to participate in the 
Pharmacokinetics (PK) or the Pharmacogenetics (PGx) correlative studies. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Patients will receive treatment depending on which treatment ARM patients are 
randomized to (see Figure 3. Treatment Schema). Please review entire Section 5.0 to 
review treatment of study agents as well as caution with concomitant medications. 
 
Treatment will be administered on an outpatient, continuous basis. One cycle is 
defined as 28 days. Reported adverse events and potential risks are described in 
Section 7. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies may be administered with the intent 
to treat the patient's thyroid cancer. 
 
The patient will be requested to maintain a medication diary documenting the dose of 
medication(s) and the date and time of each dose taken. The medication diary will be 
returned to clinic staff at the end of each cycle. 
 
It is preferred that patients take all planned study agent on day 1 of each new cycle. 
Patients should be instructed to take scheduled doses on clinic visit days. Any dose 
delayed > 1 hour from scheduled time on day 1 of a new cycle due to pending safety 
assessments may still be taken so long as there is at least 12 hours between doses (per 
IBs). Alternatively, one dose of Trametinib and/or one or more doses of Dabrafenib 
may be missed on day 1 of a new cycle, if per local standard practice patients are 


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instructed by the treating physician to hold all dosing on clinic days until after the 
safety assessments have been completed. All missed doses and reasons are to be 
clearly documented in the source records and study case report forms. 
 
 
Figure 3. Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1. Administration of Dabrafenib (BRAFi) [For ARM A and ARM B] 
 
Dabrafenib will be taken on an outpatient basis at the dose of 150 mg orally 
twice a day, or approximately every twelve hours, and on a continuous basis. 
Dabrafenib capsules are supplied as 50 mg, and 75 mg capsules for oral 
administration. 
 
Dabrafenib should be taken under fasting conditions, either one hour before a 
meal or 2 hours after a meal.  It should be taken with approximately 240 mL  
(8 fluid ounces) of water at approximately the same time each day. Patients 
should abstain from ingestion of Seville oranges, grapefruit or grapefruit juice, 
pummelos, or exotic citrus fruits or grapefruit hybrids while on the study, and 
avoid ingestion of such fruit(s) for at least 24 hours prior to the start of dosing, 
due to potential increased plasma Dabrafenib concentrations due to inhibition 
of intestinal CYP3A4. 
 
If a patient vomits after taking study medication, the patient should be 
instructed not to retake the dose and should take the next scheduled dose. 
 
Medication should be taken within a two hour window of the scheduled dose. 
If a patient misses the dose (falls outside of the scheduled 2 hour window) of 
study medication for some reason, the patient should just skip that dose and 
should take the next scheduled dose. 
 
5.1.2    Administration of Trametinib (MEKi) [For ARM B ONLY] 
If progression on ARM A, may 
cross-over to ARM B after re- 
registering the patient 
ARM A 
 
Dabrafenib (BRAFi) 
150 mg orally twice daily 
ARM B 
 
Dabrafenib (BRAFi) 
150 mg orally twice daily 
And 
Trametinib (MEKi) 
2 mg orally once daily 


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Trametinib will be taken on an outpatient basis at the dose of 2 mg orally once 
daily in the morning and on a continuous basis. Trametinib tablets are  
supplied as 0.5 mg, and 2 mg (as free base) tablets for oral administration. 
 
Trametinib should be administered under fasting conditions, either one hour 
before or 2 hours after a meal, at approximately the same time each day. It 
should be taken with approximately 240 mL (8 fluid ounces) of  water. If a 
patient vomits after taking study medication, the patient should be instructed 
not to retake the dose and should take the next scheduled dose. 
 
Trametinib should be taken within a two hour window of the scheduled dose. 
If a patient misses the dose (falls outside of the scheduled 2 hour window) of 
study medication for some reason, the patient should just skip that dose and 
should take the next scheduled dose. 
 
Trametinib and the morning dose of Dabrafenib may be taken at the same 
time. 
 
Patients who are selected for pharmacokinetics (PK) blood draws will take 
Dabrafenib (BRAFi) only once in the morning (instead of twice) on C1D1 and 
C2D1. On these days, patients on ARM B will take their daily dose of 
Trametinib (MEKi) in the morning. These patients will be instructed to bring 
and take their study drug(s) in the clinic on C1D15 for a pre-dose PK sample. 
Patients will take study med(s) in the clinic on C1D1 and C2D1, as timed for 
PK sampling. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 General Concomitant Medication Use 
Because there is a potential for interaction of Dabrafenib or Trametinib 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. 
 
Appendix C presents guidelines for identifying medications/substances that could 
potentially interact with the study agent(s). 
 
5.2.2 Supportive Care Guidelines 
 
Anti-emetics and anti-diarrheal treatment are not recommended for prophylactic use. 
Specific guidelines for management of adverse events are described in Section 6. 
 
Proton Pump Inhibitors (PPIs) or H2 Blockers (acid reducers) may be used as 
supportive care for early symptoms of nausea and/or heartburn as nausea/heartburn 
might indicate early symptoms of gastritis/peptic ulcer that might be associated with 
study drugs. 


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5.3 
Prohibited Medications 
 
Dabrafenib induces CYP3YA-mediated metabolism, and administration  of 
Dabrafenib with drugs that are affected by the induction of these enzymes, may result 
in decreased concentrations and loss of efficacy of the study drug. Drugs that are 
strong inhibitors or inducers of CYP3A or CYP2C8, Pgp or Bcrp transporters are 
contraindicated.  These prohibited medications can be found in Appendix B. 
 
5.4 
Cautionary Medications 
 
The following medications should be used with caution: (see Appendix C for a listing 
of these medications) 
 
 
Drugs that are substrates of CYP2C8, CYP2C9, and CYP2C19 that are 
highly sensitive to inhibitors or that have a low therapeutic index because 
concentrations of these substrates may be altered by Dabrafenib. 
 
Drugs that are mild/moderate inhibitors or inducers of CYP3A, CYP2C8, or 
Pgp or Bcrp transporter because they may alter Dabrafenib concentrations. 
 
Additionally, Dabrafenib may induce CYP3A4 and CYP2B6. Other enzymes 
such as CYP2C8, CYP2C9, and CYP2C19 may be affected as well. Co- 
administration of Dabrafenib and medications that are affected by the 
induction of these enzymes may result in loss of efficacy. If  co- 
administration of these medications is necessary, investigators should  
monitor subjects for loss of efficacy or consider substitutions of these 
medications.  The list may be modified based on emerging data. 
 
Patients that are taking Anti-Platelets or Anti-Coagulants such as: Aspirin, 
Clopidogrel, Dabigatran, Warfarin, Enoxaparin, or any other blood thinning 
agent, will need to have a CBC every 2 weeks during the first 4 months for 
close monitoring as GI haemorrhage has been seen with study drugs and 
above agents might increase such risk. 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
 
Disease progression for patients on ARM B (Patients who develop 
progression on ARM A may be crossed-over to ARM B after re- 
registering patient with coordinating center). Disease progression in this 
case is defined as 20% increase in sum of index lesions compared with 
baseline (not the best response); or unequivocal diagnosis of new non- 
bony tumor lesion.  Patients who are noted to have ‘new’ or ‘worsening’ 


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bony lesions can stay on treatment if the patient has clinical benefit (it has 
been challenging to diagnose bony metastasis response/progression while 
patients are treated with such new class of drugs). 
 
 
Off of study drug continuously for more than 28 days for any reason. 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s) or meets any dose stopping criteria  
(Section 6) 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.6 
Duration of Follow Up 
 
Patients will either be seen in the clinic, or contacted by phone every 3 months for 1 
year post study treatment. 
 
Follow up data to be collected: 
 
Survival status 
 
Disease status (progressed/stable) 
 
If any additional cancer therapy was initiated (name & start date) 
 
Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.7 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.5 
applies. The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dabrafenib Delays/Modifications (applicable to ARM A and ARM B patients): 
 
For Arm B patients, please see section 6.2 also. 
 
6.1.1 Guidelines for Dabrafenib Dose Modification and Treatment of Adverse Events 
The severity of adverse events will be graded utilizing the Common Terminology Criteria 
for Adverse Events Version 4.0 (CTCAE v4.0). Dose modifications of Dabrafenib will  
be made according to the dose levels outlined in Table 1. 


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Table 1.  Dabrafenib Dose Levels 
Dose Level
Dabrafenib Dose/Schedule
0
150 mg BID
- 1
100 mg BID
- 2
75 mg BID
- 3
50 mg BID
 
Guidelines for dose modifications and interruptions for management of toxicities 
associated with the study treatment other than those pertaining to neutropenia, fever, rash, 
hand foot skin reactions (HFSR), renal insufficiency, liver chemistry abnormalities, left 
ventricular ejection fraction (LVEF) are provided in Table 2. 
Dose modifications specifically for neutropenia are outlined in Table 3. Prophylactic 
antibiotics are recommended for treatment of neutropenic fever (defined as a single  fever 
>38.3ºC (101ºF), or a sustained temperature >38ºC (100.4ºF) for more than one hour in a 
patient with absolute neutrophil count (ANC) <500 cells/microL, or <1000 cells/microL 
with a predicted nadir of <500 cells/microL). The choice of antibiotic for neutropenic 
fever is per the treating physician and the institution’s hospital policy. 
Dose modifications for fever are provided in Table 4. Antipyretic use is permitted for 
symptomatic relief of fever. In the absence of severe neutropenia, the use of antibiotics is 
at the clinical discretion of the examining physician/investigator. For complicated fever, 
defined as Grade ≥3 fever or any grade with signs and symptoms including; rigors, 
dehydration, hypotension, dizziness or weakness, the administration of both Dabrafenib 
and Trametinib should be interrupted/held. 
Dose modifications for rash and general recommendations for rash management are 
provided in Table 5. 
 
Dose modifications for hand foot skin reaction (HFSR) are provided in Table 6. 
Treatment of squamous cell carcinoma (SCC), keratoacanthoma (KA), and actinic 
keratosis (AK) lesions should be based upon institutional practice. Dose interruptions or 
modifications are usually not required for SCC/KA. Biopsies of any new skin lesions 
suspicious for malignancy and pre-malignancy (SCC, AK, KA) are recommended. 
 
Dose modifications for renal insufficiency are outlined in Table 7. 


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Table 2. Dose Modification Table for Toxicities Other Than **Neutropenia, Fever, Rash, HFSR, LVEF, renal 
insufficiency or liver chemistry abnormalities 
Non-hematologic 
and 
hematologic 
Toxicity (except**) 
 
Dose Modification Algorithmsa, b, d, e 
Grade 1 
Continue Dabrafenib at full dose, monitor as clinically indicated. 
Grade 2 
For Grade 2 Diarrhea with accompanying risk factorsc Hold Dabrafenib until 
return to  Grade 1, provide supportive care. 
 
All other toxicities: Consider holding Dabrafenib until resolution to Grade 1 or 
baseline; provide supportive care as clinically indicated. Monitoring of 
laboratory values should occur as clinically indicated. 
 
For Grade 2 or higher respiratory symptoms (i.e. cough, dyspnea, hypoxia 
etc.), evaluation by a CT scan is recommended. 
Grade 3 
For Grade 3 toxicity, hold Dabrafenib until toxicity is Grade 1 or baseline then 
reduce dose of Dabrafenib by 1 dose level. The subject may be continued at the 
same dose if, in the judgment of the investigator, the toxicity is considered to 
be unrelated to Dabrafenib.  Continue to monitor as clinically indicated. 
 
If any Grade 3 toxicity recurs, hold dosing until Grade 1 or baseline, then 
reduce current dose of Dabrafenib by one dose level. 
Grade 4 
Discontinue Dabrafenib. Continue to monitor as clinically indicated,  and  
provide supportive care as needed 
 
If in the investigator’s judgment the toxicity is unlikely to recur then, hold until 
toxicity is Grade 1 or baseline, then reduce dose of Dabrafenib by 1 dose level.  
If Grade 4 toxicity recurs after dose reduction, discuss continuation of study drug 
with the PI.
**  Neutropenia, Fever, Rash, HFSR, LVEF, renal insufficiency or liver chemistry abnormalities 
a. The minimum dose is 50 mg BID. If a subject requires dose reduction below 50 mg BID then the 
subject must be discontinued from study medication. 
b. For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase laboratory  
samples should be collected. 
c. Risk factors for cancer treatment-induced diarrhea include: fever, orthostatic symptoms (i.e. 
dizziness), abdominal pain/cramping, or weakness. 
d. If the patient has a Grade 3 or 4 laboratory abnormality, that in the judgment of the investigator, is not 
considered clinically significant, dose modification is not required. 
e. For subjects who develop symptoms associated with uveitis including blurry vision, eye pain or 
erythema ophthalmologic consult is required. 


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Table 3.  Dose Modification Table for Neutropenia 
 
 
 
Grade
ANC   value
/mm3 
Management of Neutropenia 
Dabrafenib Dose Adjustment 
1 
1500-LLN 
 
Monitor per protocol time 
and events table 
Continue at current dose 
2 
1000-<1500 
 
Re-check ANC in 1 week. 
If improvement to grade 1, 
continue to monitor per 
protocol time and events 
table. 
 
If stable at grade 2, 
monitor ANC every 2 
weeks until resolution to 
grade 1 or until stable for  
4 weeks 
 
If worsens to grade 3 or 4 
follow below. 
Any occurrence: continue at current dose 
3 
500-<1000 
 
Re-check ANC at least 
weekly 
during 
dose 
interruption. 
 
If resolved to grade 1, re- 
check ANC 3 days after 
rechallenge 
with 
Dabrafenib and then 1 
week later. 
 
Any occurrence: hold until return to 
grade 1, then reduce one dose level 
 
1st 
recurrence: 
 
Discontinue 
Dabrafenib or hold until return to 
grade 1, then reduce one dose level 
 
2nd 
recurrence: 
Discontinue 
Dabrafenib. 
4 
<500 
 
Re-check ANC at least 
weekly 
 
If resolved to grade 1, re- 
check ANC 3 days after 
rechallenge 
with 
Dabrafenib and then 1 
week later. 
 
Discontinue or hold until return to 
grade 1, then reduce Dabrafenib by 
one dose level. 
 
1st 
recurrence: 
discontinue 
Dabrafenib. 


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Table 4. Dose Adjustments for Fever (Pyrexia) a, b 
 
Occurrence
Management
Study drug adjustment
1st event 
 
Clinical evaluation for infection 
and hypersensitivityc 
 
Laboratory work-upc 
 
Hydration as requiredd 
 
Administer anti-pyretic treatment if 
clinically indicatede 
 
Continue or Interrupt dabrafenib 
depending on severity of pyrexia 
and associated conditions-for 
example, if fever was associated with 
dehydration, hypotension, or renal 
insufficiency, hold dabrafenib and 
reduce dabrafenib by one dose level 
when restarted. 
 
Once pyrexia resolves to baseline, 
restart dabrafenib at the same dose if 
dabrafenib was held.
2nd event
 
Work-up at physicians’ discretion 
 
Same as for 1st event and: 
 
Administer anti-pyretic treatment if 
clinically indicatedf 
 
Consider oral corticosteroids (i.e., 
prednisone 10 mg/d) for at least 5 
days or as clinically indicatedf 
Subsequent 
events 
 
Work-up at physicians’ discretion 
 
Same as for 1st event and: 
 
Administer anti-pyretic treatment 
if clinically indicatede 
 
Optimize oral corticosteroid dose 
as clinically indicated for 
recalcitrant pyrexiaf 
 
If corticosteroids have been 
tapered and pyrexia recurs, restart 
steroids 
 
If corticosteroids cannot be 
tapered or escalating doses are 
required, consult protocol chair. 
 
If associated with dehydration, 
hypotension or renal insufficiency 
(on 2 or more occasions), reduce 
dabrafenib by one dose level 
 
 
 
BUN = blood urea nitrogen; 
a. Fever (pyrexia) is defined as a body temperature equal to or above 38.5○ Celsius 
or 101.3○ Fahrenheit. 


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b. For subjects experiencing fever (pyrexia) complicated by rigors, severe chills,  
etc., a clinical evaluation is mandatory for each event; anti-pyretic treatment should  
be started immediately at the first occurrence and prophylactic anti-pyretic treatment 
is recommended 
c. Thorough clinical history for symptoms of infection or hypersensitivity is 
required; laboratory work-up may include complete-blood-count, electrolytes, 
creatinine, BUN, liver-function tests, blood culture, and urine culture. 
d. Oral hydration should be encouraged in subjects without evidence of dehydration. 
Intravenous hydration is recommended in subjects experiencing pyrexia complicated 
by dehydration/hypotension. 
e. Anti-pyretic treatment may include acetaminophen (paracetamol), ibuprofen, or 
suitable anti-pyretic medication according to institutional standards. Prophylactic 
anti-pyretic treatment may be discontinued after three days in the absence of pyrexia 
f. In subject experiencing pyrexia complicated by rigors, severe chills, etc., which 
cannot be controlled with anti-pyretic medication, oral corticosteroids should be 
started at the 2nd event and prednisone doses should be gradually increased for 
subsequent events. 


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Table 5.   Dose Modification for Skin Rash 
 
Skin Toxicity Grade 
(CTCAE v 4.0) 
Guideline for Management 
Dose Reductiona 
1 
Topical corticosteroids 
(mometasone, betamethasone, or 
fluocinonide creams) 
None 
2 
Topical steroids with the addition 
of diphenhydramine 50 mg bid, 
consider oral prednisoneb (short 
course) 
None: if unacceptable to subject or 
medically concerning then hold until 
recovery to Grade 1. Restart at same 
dose. 
3 
Hold until recovery to Grade 1. Then 
reduce the dose by one dose level. 
 
For subjects with Grade 3 or 4 extensive 
or symptomatic dermatologic event, or 
chronic, persistent or recurring lower 
grade skin events, dermatology consult is 
encouraged. 
a. If no recovery after 2 weeks of holding drug, subjects must be withdrawn from study treatment unless 
in the opinion of the investigator there is a reason to believe that the subject will experience clinical 
benefit from future treatment. 
b. The use of topical corticosteroids are preferred except in the event of severe skin toxicity(ies) to avoid 
the potential drug-drug interaction between the investigational agents and corticosteroids; at physician’s 
  discretion 
 


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Table 6.  Dose Modifications for Hand-Foot Skin Reaction (HFSR) 
 
 
HFSR Grade
Occurrence
Dose Modificationa 
1 
Any occurrence. 
Continue treatment with Dabrafenib and 
start topical therapyb for symptomatic 
relief. 
2 
1st occurrence. 
Continue treatment with Dabrafenib and 
start topical therapyb for symptomatic 
relief. 
Instruction 
on 
life-style 
modifications should also be given.c 
If no improvement within 28 days, see 
below
No improvement 
within 
28 
days 
additional occurrence.
 
or
Interrupt Dabrafenib treatment until 
toxicity resolves to Grade 0-1.d 
When resuming treatment, decrease 
Dabrafenib dose by one dose level. 
Continue 
topical 
therapyb 
for 
symptomatic relief. Instruction on life- 
style modifications should also be 
given.c 
 
Grade 
grade 2
3
or
intolerable
1st or 2nd occurrence. 
Interrupt Dabrafenib treatment until 
toxicity resolves to Grade 0-1. d. 
When resuming treatment, decrease 
Dabrafenib dose by one dose level. 
Continue 
topical 
therapyb 
for 
symptomatic relief. Instruction on life- 
style    modifications    should    also  be 
given.c 
3rd occurrence. 
Discontinue Dabrafenib treatment. 
a. No dose adjustment is required on the basis of subject age, gender, or body weight. 
b. Topical therapy includes the following options; keratolytics (e.g. urea 40%), high potency 
corticosteroids (fluocinonide, clobetasol), oral analgesia (NSAIDs or narcotics) 
c. Lifestyle modifications include; avoidance of excessive temperatures, exercise, and ill-fitting 
clothing/shoes. Use of soft slippers (Tempurpedic or Crocs), friction-relieving measures (calfskin, 
gels). 
  d. HSFR usually resolves within 2-4 weeks of drug cessation. 
 


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Table 7.  Dose Modifications and Guidelines for Renal Insufficiency 
 
Serum Creatinine
Guidelines for Management
For subjects with  serum 
creatinine 
 
increase 
>0.2 mg/dL  (18  umol/L) but 
0.5 mg/dL (44 umol/L) 
above baseline: 
1. Continue Dabrafenib and re-check serum creatinine within 1 week 
2. If subject has fever (T >/= 38.5C): treat pyrexia as per guidelines 
(please note NSAIDs can induce renal insufficiency, especially in 
subjects with dehydration); encourage oral fluids 
3. If elevation in serum creatinine persists beyond 1 week, please 
contact study coordinator 
For subjects 
with serum 
creatinine rise >0.5 mg/dL 
(44 umol/L) above baseline 
or          serum        creatinine 
>2 mg/dL (> 177 umol/L) 
1. Interrupt Dabrafenib 
2. If subject has fever (T >/= 38.5C): treat pyrexia as per guidelines 
(please note NSAIDs can induce renal insufficiency, especially in 
subjects with dehydration); consider IV hydration 
3. Follow serum creatinine at least twice weekly (or consider 
hospitalization if serum creatinine cannot be monitored frequently) 
4. Consider renal consultation 
5. If serum creatinine returns to baseline, may restart study treatment at 
the same dose, or reduced by one dose level at the investigator’s 
discretion. 
6. Consider renal biopsy if clinically indicated, for example: 
a. Renal insufficiency persists despite volume repletion 
b. Subject has new rash or signs of hypersensitivity (such as 
elevated eosinophil count) 
7. Approval of PI is required to re-initiate therapy if 
c. Subject’s serum creatinine has not returned to baseline 
d. There is evidence of thrombotic microangiopathy 
 
6.1.2 Dose Stopping Safety Criteria 
 
6.1.2.1 Liver Chemistry Stopping Criteria 
Dabrafenib will be stopped if any one of the following criteria is met: 
 ALT  3 times (x) upper limit of normal (ULN) and bilirubin  2 x ULN 
(Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick indicating direct bilirubin elevations and suggesting liver injury) 
 ALT  5 x ULN 
 ALT  3 x ULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash or eosinophilia) 
 ALT  3 x ULN and persists for  4 weeks 


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 ALT  3 x ULN and cannot be monitored weekly for  4 weeks 
Patients with ALT  3 x ULN and <5 x ULN and bilirubin < 2 x ULN, and who 
do not have hepatitis symptoms or rash, can continue study drug Dabrafenib as 
long as liver enzymes can be monitored weekly for 4 weeks. 
When any of the liver chemistry stopping criteria 1-5 is met, do the 
following: 
• Immediately withdraw investigational product for that subject 
• Report the event within 24 hours of learning its occurrence 
• Complete the liver event CRF and SAE data collection tool if the event also 
meets the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN 
(>35% direct bilirubin) (or ALT ≥ 3xULN and INR>1.5, if INR measured; INR 
measurement is not required and the threshold value stated will not apply to 
patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis). 
NOTE: If serum bilirubin fractionation is not immediately available,  withdraw 
study drug for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury. 
• Complete the liver imaging and/or liver biopsy CRFs if these tests are 
performed 
• Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 
• Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below. 
• Do not re-challenge with investigational product. 
 
In addition, for criterion 1: 
• Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow up assessments (see below), and 
close monitoring 
• A specialist or hepatology consultation is recommended 
• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values for 
criteria 2, 3, 4 and 5: 
• Make every reasonable attempt to have subjects return to clinic within 24-72 
hrs for repeat liver chemistries and liver event follow up assessments  (see 
below) 
• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible. 
Subjects with ALT ≥3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks 
• Notify within 24 hours of learning of the abnormality to discuss subject safety. 
• Can continue investigational product must return weekly for repeat liver 
chemistries 


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(ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return  
to within baseline) 
• If at any time these subjects meet the liver chemistry stopping criteria, proceed 
as described above 
• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within 
baseline values. 
 
For criteria 1-5, make every attempt to carry out the liver event follow up 
assessments described below: 
• Viral hepatitis serology including: 
• 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 
• Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of the 
last dose is unclear, provide the subject’s best approximation. If the date/time of the last 
dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin≥2xULN 
• Obtain complete blood count with differential to assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form 
• Record use of concomitant medications, acetaminophen, herbal remedies, and 
other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form. 
• Record alcohol use on the liver event alcohol intake case report form 
The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN 
(>35% direct) but are optional for other abnormal liver chemistries: 
• 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 (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week (James LP. Drug Metab Disp 2009; 37:1779–1784). 
• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) 
to evaluate liver disease. 
 
6.1.2.2 Left Ventricular Ejection Fraction (LVEF) Stopping Criteria 


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ECHO or MUGA must be performed at baseline and at follow-up visit(s) per the 
schedule in the Study Calendar. Subjects who have an asymptomatic, absolute 
decrease of > 10% in LVEF compared to baseline and the ejection fraction is 
below the institution’s lower limit of normal (LLN) should  temporarily 
discontinue Dabrafenib and have a repeat evaluation of LVEF within 1 week. 
ECHO or MUGA should be repeated every 1-2 weeks for 4 weeks or until LVEF 
recovery to above institutional lower limit of normal and within 10% of baseline 
If the LVEF recovers (defined as ≥ LLN and absolute decrease ≤ 10% compared 
to baseline) at any time during the next 4 weeks, the subject may be restarted on 
Dabrafenib at reduced dose level, after consultation and approval of the Protocol 
Chair. For such subjects, monitoring of LVEF will then be performed 2 and 4 
weeks after rechallenge, and every 4 weeks thereafter for 12 weeks and then per 
protocol. 
If repeat LVEF does not recover within 4 weeks, then the subject should 
permanently discontinue Dabrafenib. Ejection fraction should continue to be 
monitored every 4 weeks for 16 weeks or until resolution. 
Subjects with a Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction 
must discontinue Dabrafenib. Ejection fraction should continue to be monitored 
every 4 weeks for 16 weeks or until resolution. If recovery occurs (LVEF to  
above institutional LLN and symptom resolution) within 4 weeks, the subject may 
restart Dabrafenib at a reduced dose after consultation and approval of the 
Protocol Chair. 
 
6.1.2.3 Valvular Toxicity Stopping Criteria 
 
Subjects who have an asymptomatic, moderate regurgitation or stenosis by ECHO 
(Grade 2 mitral/tricuspid/aortic valvular toxicity per CTC AE v4.0) should 
temporarily discontinue Dabrafenib and have a repeat evaluation by ECHO within 
1 week. ECHO should be repeated every 1-2 weeks for 4 weeks or until valve 
recovery to baseline. 
If the valve recovers to baseline any time during the next 4 weeks, the subject may 
be restarted on Dabrafenib at a reduced dose(s). For such subjects, monitoring of 
the valve via ECHO will then be performed 2 and 4 weeks after rechallenge, and 
every 4 weeks thereafter for 12 weeks and then per protocol 
If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
subject should permanently discontinue Dabrafenib. The valve should continue to 
be monitored via ECHO every 4 weeks for 16 weeks or until resolution. 
Subjects with a Grade 3 or 4 valvular toxicity (symptomatic, severe 
regurgitation/stenosis by imaging, with symptoms controlled by medical 
intervention) must discontinue Dabrafenib.  Valvular toxicity should continue o  
be monitored every 4 weeks for 16 weeks or until resolution. If recovery occurs 
(return to baseline via imaging AND symptom resolution) within 4 weeks, the 


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subject may restart Dabrafenib at a reduced dose after consultation and approval  
of the Protocol Chair. 
 
 
 
 
 
 
 
 
6.1.2.4 QTc Stopping Criteria 
 
If QTc corrected (QTcB) is greater than or equal to 530 milliseconds1, the study 
drug Dabrafenib will be held. 
1 If ECG demonstrates greater than 500 millisecond QTc (grade 3 or 4), obtain 2 
more ECGs over a brief period, and then use the averaged QTc values of the 3 
ECGs to determine if averaged QTc greater than or equal to 530 millisecond. If 
that is the case, the subjects should have study medication withheld. 
 
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re- 
started on the study medication if after the Protocol Chair agrees that the subject 
will benefit from further treatment. 
 
6.2 
Trametinib Delays/Modifications (applicable to patients on ARM B): 
 
Given that there are several overlapping AEs between Dabrafenib and Trametinib, 
dose modification/stopping guidelines for all patients on ARM B must follow 
guidelines for Dabrafenib. In each of those categories, dose reduction, dose 
holding or dose continuation of Trametinib must follow similar criteria as for 
Dabrafenib. If there is discrepancy between two guidelines for a given AE, please 
follow guidelines for Dabrafenib for patients on ARM B. Diarrheas, 
peripheral/periorbital edema, acneiform rash, please follow guidelines given in 
section 6.2. 
Table 8. Trametinib Dose Levels 
 
Dose Level
Trametinib Dose
0
2 mg once a day
- 1
1.5 mg once a day
- 2
1 mg once a day
A maximum of two Trametinib dose level reductions are allowed. If a third dose 
level reduction is required, treatment will be permanently discontinued. If a dose 
reduction of Trametinib is required, but the toxicity resolves and no additional 
toxicities are seen after two cycles of treatment, the dose of Trametinib may be re- 
escalated but should not exceed 2 mg once a day. 


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Trametinib dose modification guidelines are outlined in Table 9 for clinically 
significant toxicities that are deemed related to Trametinib (i.e. peripheral and 
periorbital edema). 
 
Dose modification guidelines for rash are outlined in Table 10. 
Table 9.  Dose Delay and Modification for Trametinib related AEs (for peripheral edema, 
periorbital edema) 
 
Toxicity Gradea 
Dose Modification of Trametinib
Grade 1 
Continue at current dose level. 
 
Grade 2 
Interrupt treatment until toxicity resolves to Grade 1 or baseline. Upon 
resolution, restart treatment at current dose level with supportive care as 
clinically indicated.  Consider dose reduction by at least one dose level. 
Grade 3 
Interrupt  treatment  until  toxicity  resolves  to  Grade  1 or baseline. Upon 
resolution, consider dose reduction by at least one dose level. 
Grade 4 
Permanently discontinue Trametinib 
 
Treatment with Trametinib may be interrupted for up to 21 days to allow resolution of 
toxicity, or based on investigator discretion. If the investigator concludes that  
continued treatment will benefit a subject who has experienced a treatment delay >21 
days, then the subject may continue Trametinib therapy. 


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Table 10.  Dose Modification Rash Management Guidelines for Trametinib 
 
Step 
Rash 
grading 
Rash severity 
Management of Rash 
Trametinib 
Dose Adjustment 
1 
Mild 
Localized 
Minimally 
symptomatic 
No impact on ADL 
No sign of 
superinfection 
Initiate prophylactic regimen 
if not already started. 
Consider using moderate 
strength topical steroid.* 
 
Reassess after 2 weeks; if 
rash worsens or does not 
improve, proceed to step 2
Continue current dose. 
 
 
Reassess after 2 weeks; if 
rash worsens or does not 
improve, proceed to step 2 
2 
Moderate 
Generalized 
Mild symptoms (eg, 
pruritis, tenderness) 
Minimal impact on 
ADL 
No sign of 
superinfection 
Initiate prophylactic regimen 
if not already started, using 
moderate strength topical 
steroid.* 
 
Reassess after 2 weeks; if 
rash worsens or does not 
improve, proceed to step 3 
Reduce dose by at least 
one dose level or consider 
interrupting treatment until 
resolution to Grade 1. If 
toxicity resolves, can 
consider re-escalation to 
initial dose level. 
 
Reassess after 2 weeks; if 
rash worsens or does not 
improve, proceed to step 3
3
Severe
Generalized
Initiate prophylactic regimen
Interrupt treatment until
 
 
Severe symptoms
if not already started, using
rash improves (moderate,
 
 
(e.g., pruritis,
moderate strength topical
mild) or resolves, then
 
 
tenderness)
steroids PLUS
follow steps outlined for
 
 
Significant impact on
methylprednisolone dose
the appropriate grading.
 
 
ADL
pack.
 
 
 
Sign of or potential for 
superinfection 
 
Consider obtaining 
Reassess after 2 weeks; if 
rash worsens or does not
 
 
 
dermatology consultation.
improve, permanently
 
 
 
Manage rash per
discontinue treatment with
 
 
 
dermatologist’s
Trametinib.
 
 
 
recommendation.
 
*e.g., hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream 


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6.2.1 Diarrhea Management/Dose Modifications 
 
Consider other concomitant causes. These include medications (e.g., stool softeners, 
laxatives, antacids, etc), infection by C. difficile or other pathogens, partial bowel 
obstruction etc. 
 
6.2.1.1 Supportive care guidelines for uncomplicated Grade 1 to 2 
diarrhea (i.e., mild to moderate and defined as CTCAE Grade 1-2 
with no complicating signs or symptoms): 
 Dietary modifications: stop all lactose containing products and eat small 
meals.  A BRAT (banana, rice, apples, toast) diet can be helpful 
 Hydration: drink 8-10 large glasses of clear liquids per day (e.g., Gatorade 
or broth) 
 Consider administration of standard dose of loperamide (subjects should 
have loperamide available in order to start at the first signs of diarrhea): 
 Initial dose of 4 mg followed by 2 mg every four hours or after every 
unformed stool; maximum 16mg/day. 
 Continuation of loperamide is suggested until diarrhea free for 12 hours. 
 Consider interruption of treatment with Trametinib until symptoms have 
resolved to baseline or Grade 1. Re-treatment with Trametinib may then 
be resumed at the same dose level or at the reduced dose. If dose was 
reduced, re-escalation may be considered if toxicity resolves. 
 If mild to moderate diarrhea persists for more than 24 hours, administer 
loperamide 2 mg every two hours; maximum 16mg/day. Consider  
adding oral antibiotics. 
 If mild to moderate diarrhea persists after 48 hours total treatment with 
loperamide, start budesonide or other second-line agents (octreotide, or 
tincture of opium).  Consider adding oral antibiotics. 
6.2.1.2 
Supportive care guideline for Grade 3 to 4 diarrhea or 
complicated  Grade  1  to  2  diarrhea  (i.e.,  cramping,  nausea/vomiting 
≥Grade 2, decreased performance status, fever, sepsis, Grade 3 or 4 
neutropenia, frank bleeding, dehydration): 
 The subject must call the investigator immediately for any complicated 
severe diarrhea event. 
 Interrupt treatment with Trametinib until symptoms resolve to Grade 1 or 
baseline. Re-start therapy at a reduced dose level. Re-escalation may be 
considered if toxicity resolves. 
 If loperamide has not been initiated, initiate loperamide immediately. 
Initial dose 4 mg followed by 2 mg every two hours or after every 
unformed stool; maximum 16mg/day. 


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 For dehydration, use intravenous fluids as appropriate; if severe 
dehydration, administer octreotide. 
 Administer antibiotics as needed (e.g., fluoroquinolones), especially if 
diarrhea is persistent beyond 24 hours or there is fever or Grade 3 to 4 
neutropenia. 
 Intervention should be continued until the subject is diarrhea free for at 
least 24 hours. 
 Intervention may require hospitalization for subjects most at risk for life- 
threatening complications. 
 
6.2.2 Dose modification for Visual Changes 
 
6.2.2.1 CTCAE v 4.0 Eye Disorders 
 
Grade
Description
1 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated
2 
Moderate; minimal, local or noninvasive 
intervention indicated; limiting age-appropriate 
instrumental ADL
3 
Severe or medically significant but not 
immediately sight-threatening; hospitalization or 
prolongation of existing hospitalization indicated; 
disabling; limiting self care ADL
4 
Sight-threatening consequences; urgent 
intervention indicated;  blindness (20/200 or worse) 
in the affected eye 
 
 
For all visual changes, regardless of grade, a blood sample for pharmacokinetics 
analysis must be drawn as close as possible to the time of the event. 
 
6.2.2.2 Grade 1 visual change: 
 
 If the changes are clearly not due to retinal or retinal vein abnormalities or are 
clearly unrelated to study drug (e.g. conjunctivitis), Trametinib treatment may 
continue with close observation. 
 If drug attribution or etiology is unclear, immediately refer the subject for 
ophthalmic exam; if an ophthalmic exam cannot be performed within 7 days, 
interrupt treatment with Trametinib until exam can be performed. 
 If a retinal abnormality is noted, interrupt treatment with Trametinib immediately 
and consider referral to a retinal specialist, if available, for further evaluation 
o If RVO is diagnosed, report as SAE and permanently discontinue  
treatment with Trametinib. 


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o If CSR is diagnosed, interrupt treatment with Trametinib until signs and 
symptoms have resolved. Resume treatment with Trametinib at reduced 
dose by one dose level. 
o If there is no evidence of RVO or CSR, resume treatment with Trametinib 
at the same dose level. 
 
6.2.2.3 Grade 2 or Grade 3 visual changes: 
 
 Immediately interrupt treatment with Trametinib and refer subject to an 
ophthalmologist for evaluation with an ophthalmic exam. 
 For all subjects with findings consistent with RVO or CSR based on the 
ophthalmic exam, referral to a retinal specialist, if available, should be considered 
for further evaluation. 
o If RVO is diagnosed, report as SAE and permanently discontinue 
Trametinib. 
o If CSR is diagnosed, interrupt treatment with Trametinib until signs and 
symptoms have resolved and then resume treatment with Trametinib at 
reduced dose by at least one dose level. 
o If there is no evidence of RVO or CSR, interrupt treatment with 
Trametinib until signs and symptoms have returned to Grade 1 or  
resolved. Resume treatment with Trametinib at reduced dose by one dose 
level. Treatment with Trametinib at the same dose level  may  be 
considered if visual changes are clearly unrelated to study drug. 
 
6.2.2.4 Grade 4 visual changes require permanent discontinuation of treatment 
with Trametinib. 
 
6.2.3 Supportive Care Measures for Respiratory Symptoms 
For Grade 2 or higher respiratory symptoms (i.e., cough, dyspnea, hypoxia, etc.), 
evaluation by a CT scan is recommended. 
 
6.2.4 Supportive Care Measures for Abdominal Pain or Suspected Pancreatitis 
For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase 
laboratory samples should be collected. 
 
6.2.5 Supportive Care Measures for Anemia 
For patients that develop Grade 2 anemia, or patients with preexisting 
Grade 2 anemia that experience a drop in hemoglobin of 1g/dL, A GI bleed 
work up should be considered, e.g.: EGD (Esphagogastroduodenoscopy) 
and a colonoscopy. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 


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7.1. 
Expected Adverse Events for Dabrafenib (BRAFi) 
 
Presented below are AEs considered related to dabrafenib treatment, 
observed in 
subjects with unresectable and metastatic melanoma treated with dabrafenib 
(150 mg 
BID), including subjects in BREAK-2 (data cut-off 7 July 2011), BREAK-MB 
(data cutoff 28 November, 2011), the randomized arm of BREAK-3 (data cut-off 
19 December2011), the monotherapy arm of BRF113220 (data cut-off 1 
September 2011), and specific cohorts in the first-time-in-human study 
BRF112680 (data cut-off 25 March 2011). The total number included in this 
analysis is 578 subjects. Approximately 30 % of patients received treatment  
with dabrafenib for more than 6 months. Adverse reactions are listed below by 
MedDRA body system organ class and by frequency. The frequency categories 
used are: 
 
 
Very common: ≥ 1/10 (≥ 10%) 
Common: ≥1/100 and <1/10 (≥ 1% and <10%) 
Uncommon: ≥1/1,000 and <1/100 (≥0.1% and <1%) 
Rare: ≥1/10,000 and <1/1,000 (≥0.01% and <0.1%) 


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Table 11.  Adverse Events for Dabrafenib (BRAFi) as monotherapy 
MedDRA SOC
Preferred Term
Neoplasms 
benign 
and 
malignant 
(including cysts and polyps) 
Very Common: Skin papilloma, papilloma 
Common: Squamous cell carcinoma (SCC), including SCC of 
the skin and 
SCC in situ (Bowen’s disease) and keratoacanthoma 
Acrochordon (skin tags) 
Seborrhoeic keratosis 
Uncommon: New primary malignant melanoma or other non-skin 
type malignancies.
Blood 
and 
the 
lymphatic 
system 
disorders 
Very Common: Anemia 
Common: Leukopenia, Neutropenia 
Vascular disorders
Uncommon: Venous thromboembolism, Pulmonary Embolism
Immune System Disorders
Uncommon: Hypersensitivity
Metabolism and nutrition disorder 
Very Common: Decreased appetite 
Common: Hypophosphatemia 
Nervous system disorders 
Very Common: Headache 
Rare: Encephalopathy 
Eye Disorders
Uncommon: Uveitis
Respiratory, thoracic and mediastinal 
disorders 
Very Common: Cough 
Gastrointestinal disorders 
Very Common: Nausea, Vomiting, Diarrhea 
Common: Constipation, Gastrointestinal Bleeding, Peptic Ulcer, 
Gastrointestinal Ulcer 
Uncommon: Pancreatitis 
Skin and subcutaneous tissue disorders 
Very Common: Skin effects (rash, hyperkeratosis) Alopecia, 
Palmar-plantar erythrodysaesthesia syndrome 
Common: Skin effects (Actinic keratosis, Skin lesion,Dry skin, 
Erythema)
Musculoskeletal, connective tissue and 
bone disorders 
Very Common: Arthralgia, Myalgia, Pain in extremity 
General disorders and administration 
site conditions 
Very Common: Asthenia, Fatigue, Pyrexia (some cases have 
been associated with hypotension and/or syncope), Chills 
Common: Influenza like illness
Renal and urinary disorders 
Uncommon: Renal failure, Acute renal failure 
Reproductive System 
Impaired spermatogenesis, potentially irreversible 
 
7.2 
Expected Adverse Events for Trametinib (MEKi) 
 
The following undesirable effects have been observed in subjects with metastatic 
melanoma receiving trametinib 2 mg once daily in the integrated safety population 
as of 25 June 2012 cutoff date (n=329). Of these 329 subjects, 211 were from 
MEK114267 (Phase III randomized open label study), 97 were from MEK113583 
(Phase II study), and 21 were from MEK111054 (FTIH study). The most common 
adverse reactions (≥ 20 %) for trametinib include rash, diarrhoea, fatigue, oedema 
peripheral, nausea, and dermatitis acneiform. In clinical trials with trametinib, 


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adverse reactions of diarrhoea and rash were managed with appropriate supportive 
care. Adverse reactions are listed below by MedDRA body system organ class. The 
following convention has been utilized for the classification of frequency: 
Very common: ≥ 1/10 (≥ 10%) 
Common: ≥1/100 and <1/10 (≥ 1% and <10%) 
Uncommon: ≥1/1,000 and <1/100 (≥0.1% and <1%) 
Rare: ≥1/10,000 and <1/1,000 (≥0.01% and <0.1%) 
Categories have been assigned based on frequencies of AEs (considered related to 
trametinib) observed in the integrated safety summary (ISS) data (n=329). 
Table 12: Adverse Events for  Trametinib as monotherapy
MedDRA SOC
Preferred Term
Neoplasms benign and malignant (including 
cysts and polyps) 
Uncommon: New primary malignant melanoma or other non- 
skin type malignancies.
Hepatobiliary disorders
Very Common: Aspartate aminotransferase (AST)increased 
Common: Alanine aminotransferase (ALT) increased, Blood 
alkaline phosphatase(ALP) increased
Immune system disorders 
Common: Hypersensitivity (May present with symptoms such 
as fever, rash, increased LFT’s, and visual disturbances.
Blood and the lymphatic system disorders
Common: Anemia
Cardiac disorders 
Common: Left ventricular dysfunction, Ejection fraction 
decreased 
Uncommon: Cardiac failure
Vascular disorders 
Very Common: Hypertension 
Common: Lymphoedema 
Uncommon: Venous thromboembolism, Pulmonary 
Embolism
Respiratory, thoracic, and mediastinal 
disorders 
Very Common: cough, dyspnea 
Common: Epistaxis, pneumonitis 
Uncommon: Interstitial lung disease
Metabolism and nutrition disorder
Common: Dehydration, Hyperglycemia
Eye Disorders 
Common: Periorbital oedema, Vision blurred, Visual 
impairment 
Uncommon: Retinal Pigment Epithelial Detachment (RPED), 
Papilloedema, retinal vein occlusion, retinal detachment
Gastrointestinal disorders 
Very Common: Dry mouth, Diarrhea, Nausea, Vomiting, 
Constipation, Abdominal pain 
Common: Stomatitis, Gastrointestinal Bleeding, Peptic Ulcer, 
Gastrointestinal Ulcer
Skin and subcutaneous tissue disorders 
Very common: Alopecia, Rash (macular, maculopapular, 
erythematous or pruritic), Dermatitis acneiform rash, Pruritus, 
Dry skin 
Common: Erythema, palmar-plantar erythrodysaesthesia 
syndrome, skin chapped, skin fissures
Musculoskeletal, connective tissue and bone 
disorders 
Common: Blood creatinine phosphokinase increased (CPK) 
increased 
General   disorders   and   administration   site 
conditions 
Very Common: Fatigue, peripheral edema, Pyrexia 
Common: Asthenia, Facial edema, Mucosal inflammation 
Infections and infestations
Common: Cellulitis, Folliculitis, Paronychia, Rash pustular


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7.3 
Expected Adverse Events for Dabrafenib and Trametinib 
 
The safety of Dabrafenib and Trametinib have been studied in the 
combination study BRF113220data cutoff 25 May 2012; n=365). AEs 
associated with combination therapy are outlined in Table 13. In general, 
skin cancers such as keratoacanthoma are less common in patients 
treated 
with 
combination 
therapies 
as 
opposed 
to 
Dabrafenib 
monotherapy. 
AEs associated with individual study drug can occur in patients treated with 
combination therapy (See sections 7.1 and 7.2). Included in the table below and 
marked by an asterisk (*) are events considered related to study drug treatment 
based on analysis of monotherapy data, but which were not observed in Part C 
subjects receiving combination therapy (dabrafenib 150 mg BID +trametinib 2 mg 
QD). 
 
Adverse events for Dabrafenib and Trametinib in combination are listed in Table  
13, by MedDRA body system organ class and preferred term, with associated 
frequency categories: 
Very common:  1/10 ( 10%) 
Common:  1/100 and <1/10 ( 1% and <10%) 
Uncommon:  1/1,000 and <1/100 ( 0.1% and <1%) 
Rare:  1/10,000 and <1/1,000 ( 0.01% and <0.1%) 
 
 
 
Table 13. Adverse Events for Dabrafenib in combination with Trametinib 
MedDRA SOC
Preferred Term
Neoplasms 
benign 
and 
malignant 
(including cysts and polyps) 
Common: Squamous cell carcinoma (SCC), including SCC of 
the skin, SCC in situ (Bowen’s disease) and keratoacanthoma, 
Skin papilloma, papilloma 
Acrochordon (skin tags) 
Seborrhoeic keratosis 
Uncommon: New Primary Malignant Melanoma*
Blood and the lymphatic system disorders 
Very Common: Neutropenia, Anemia 
Common: Thrombocytopenia 
Uncommon: Leukopenia** 
Immune systems disorders
Common: Drug hypersensitivity 
Metabolism and nutrition disorders 
Very Common: Dehydration, Decreased appetite 
Common: Hyponatremia, Hypophosphatemia* 
Nervous system disorders 
Very Common: Headache, Dizziness 
Eye disorders 
Common: Vision blurred, Visual impairment, 
Chorioretinopathy, Papilloedema 
Uncommon: Retinal Vein Occlusion*, Uveitis*
Cardiac disorders 
Uncommon: Cardiac Failure* 


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Vascular disorders 
Common: Hypertension, Hypotension, Lymphoedema 
Musculoskeletal, connective tissue and bone 
disorders 
Very Common: Arthralgia, Myalgia, Pain in extremity, 
Muscle spasms 
Rare: Rhabdomyolysis
Renal and urinary disorders 
Common: Renal failure, acute renal failure 
Respiratory, 
thoracic, 
and 
mediastinal 
disorders 
Very Common: Cough 
Common: Dyspnoea, Epistaxis 
Uncommon: Pneumonitis**
Gastrointestinal disorders 
Very Common: Abdominal pain (including abdominal pain 
upper), Constipation, Diarrhea, Nausea, Vomiting, 
Dry Mouth 
Common: Stomatitis, Pancreatitis, Gastrointestinal Bleeding, 
Peptic Ulcer, Gastrointestinal Ulcer
Skin and subcutaneous tissue disorders 
Very Common: Dry skin, Pruritus, Rash (including rash 
generalized, rash maculopapular), Dermatitis acneiform 
Erythema, Actinic keratosis, Night sweats 
Common: Hyperkeratosis, Alopecia, 
Palmar-plantar erythrodysaesthesia syndrome, Skin chapped 
Skin lesion, Hyperhidrosis 
Uncommon: Rash Pustular* 
General disorders and administration site 
conditions 
Very Common: Fatigue, Oedema peripheral (including face 
oedema and periorbital oedema), Pyrexia, Chills 
Common: Asthenia, Mucosal inflammation, 
Influenza-like illness 
Rare: Panniculitis 
Infections and infestations 
Very Common: Urinary tract infection 
Common: Cellulitis, Folliculitis, Paronychia 
Investigations 
Common: Alanine aminotransferase increased, 
Aspartate aminotransferase increased 
Blood alkaline phosphatase increased 
Gamma-glutamyltransferase increased 
Ejection fraction decreased 
Uncommon: Blood creatine phosphokinase increased*
*Events considered related to study drug treatment based on analysis of monotherapy data, but which 
were   not  observed   in  Part  C   subjects   receiving   combination   therapy  (dabrafenib  150  mg   BID 
+trametinib 2 mg QD). 
**Frequency was based on total subjects enrolled in dabrafenib/trametinib combination studies. 
 
7.4 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
 
 Attribution of the AE:


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- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.5 
Expedited Adverse Event Reporting 
 
Expedited AE reporting for this study must be submitted to the institutional review 
board (IRB), to coordinating sites as well as to study collaborators including NCCN 
and Novartis. 
 
 
7.5.1 Reporting to Institutional Review Board (IRB) and Data Safety 
Monitoring Board (DSMB) 
 
Investigators and research staff are responsible for reporting to their local IRB 
and DSMB per institutional guidelines about unanticipated problems 
involving risks to subjects or others. The convened IRBs are responsible for 
making the final determination that a reported event (e.g., adverse event) is an 
unanticipated 
problem 
involving 
risks 
to 
subjects 
or 
others. 
(http://orrp.osu.edu/irb/osupolicies/documents/EventReporting.pdf) 
 
Serious adverse event (SAE): An adverse event that is fatal or life 
threatening, disabling or incapacitating, requires or prolongs hospitalization,  
or results in significant disability, congenital anomaly, or birth defect or which 
may require intervention to prevent the previously stated outcomes. 
 
All Serious Adverse Events (SAE) should be reported to the IRB using the 
Event Reporting Form version 3.0 (http://orrp.osu.edu/irb/event/index.cfm) 
within 10 days of the Investigator’s or research staff member’s learning of the 
event. Events resulting in temporary or permanent interruption of study 
activities by the Investigator or funding organization to avoid potential harm  
to participants should be reported immediately (within 48 hours) whenever 
possible. 
 
NOTE: Subsite Institutions are not permitted to report directly to the 
OSU IRB. All subsite SAEs are to be reported to the Principal 
Investigator and Subsite Coordinator. The Subsite Coordinator will 
submit subsite SAEs to the OSU IRB. 
 
7.5.2 Reporting to Coordinating Center (Ohio State University), NCCN 
(National Comprehensive Cancer Network) and Novartis. 
 
Member Institution shall report only SAEs arising during the Study in 
subjects exposed to the Novartis Study Drug(s) to Ohio State University, 


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NCCN and Novartis within twenty-four (24) hours of first becoming aware 
of the event. Neither Ohio State University, NCCN nor Novartis require non- 
serious AEs to be reported, as they will be reviewed by local institution’s IRB 
and/or DSMB. 
 
SAE’s should be reported using MedWatch forms 
(http://www.fda.gov/Safety/ MedWatch/HowToReport/ucm085568.htm) 
 
Send MedWatch forms to Ohio State University (ATTN: Jennifer Sexton) at 
Fax: 614-366-4721 or secure email Jennifer.sexton@osumc.edu. 
 
Send MedWatch forms to the oncology Novartis DS&E department with the 
appropriate fax cover sheet via Fax # 1-877-778-9739 (Should the designated 
SAE Fax# be non-functional please send SAEs to the designated SAE 
mailbox: usdrugsafety.operations@novartis.com). 
You must include the Novartis study identifier on the form or cover 
sheet: CDRB436DUS17T. 
 
Send MedWatch forms to NCCN at fax # 215-358-7699 or email 
ORPreports@nccn.org. Please include the NCCN study identifier: 
NCCNGSK20008. 
 
7.5.3 Reporting to Food and Drug Administration (FDA) 
Coordinating site (Ohio State University) team will send SAE report to FDA 
using MedWatch form to the FDA in accordance with applicable regulations. 
Note: Subsite Institutions are NOT permitted to report directly to the FDA. 
Subsite SAEs are to be reported to the Principal Investigator and Subsite 
Coordinator.  The Subsite Coordinator will submit subsite SAEs to the FDA. 
 
 
7.6 
Specific Reporting of Pregnancy 
 
7.6.1. 
Time period for collecting pregnancy information: Pregnancies in female 
subjects and female partners of male subjects will be collected after the start of 
dosing, and until at least 30 days after the last dose of study medication. The time 
period for collecting information on whether a pregnancy occurs is from the Screen 
Visit to the Final Study Visit. Information on pregnancies identified prior to study 
drug administration does not need to be reported to the project contact for pregnancy 
receipt. Pregnancies detected between the first dose of study drug and the Final Study 
Visit will be followed to determine the outcome of the pregnancy. 
 
7.6.2. Action to be taken if pregnancy occurs in a female subject: The investigator 
will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this study. The subject will also be followed to determine the 
outcome of the pregnancy. Generally, follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any premature termination of the pregnancy 
will be reported. While pregnancy itself is not considered to be an AE or SAE, any 


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pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE. A spontaneous abortion is always considered to be 
an SAE and will be reported as such. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of a 
SAE through spontaneous reporting. Any female subject who becomes  pregnant 
while participating will discontinue study medication or be withdrawn from the study. 
7.6.3. Action to be taken if pregnancy occurs in a female partner of a male study 
subject: The investigator will attempt to collect pregnancy information on any female 
partner of a male study subject who becomes pregnant while participating in this 
study. The partner will also be followed to determine the outcome of the pregnancy. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any premature termination of the pregnancy will be reported. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7. 
 
8.1 
Dabrafenib (BRAFi) 
 
8.1.1 Pharmaceutical Description 
 
Dabrafenib Capsules are supplied as 50 mg and 75 mg capsules for oral 
administration. The 50 mg capsule is a dark red capsule imprinted with ‘GS TEW’ 
and ‘50 mg’. The 75 mg capsule is a dark pink capsule imprinted with ‘GS LHF’ and 
‘75 mg’. 
 
The product is packaged into white, opaque, high density polyethylene 
(HDPE) bottles with child-resistant closures. 
 
8.1.2 Physical and Chemical Properties of the Drug 
 
Approved Name: Tafinlar (Dabrafenib) 
 
Chemical and Structural Formula: Dabrafenib mesylate is a kinase inhibitor. The 
chemical name for dabrafenib mesylate is N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1- 
dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, 
methanesulfonate salt. It has the molecular formula C23H20F3N5O2S2●CH4O3S and 
a molecular weight of 615.68. 
Physical Form: Dabrafenib mesylate is a white to slightly colored solid with three 
pKas: 6.6, 2.2, and -1.5. It is very slightly soluble at pH 1 and practically insoluble above 
pH 4 in aqueous media. 
8.1.3 Storage Requirements 
The recommended storage conditions, and expiry date where required, are 
stated on the product label. 


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8.1.4 Route of administration 
The route of administration is oral. 
 
Drug-drug interactions/ Drug-food interactions 
Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, Pgp or Bcrp 
transporters, are prohibited because they may increase or decrease, respectively 
Dabrafenib concentrations (Appendix B). Mild or moderate inhibitor/inducers of  
these enzymes/transporters should be used with caution. 
 
Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. Drugs 
such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH 
may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical 
study has been conducted to evaluate the effect of pH on dabrafenib 
pharmacokinetics. In adhoc analysis, no differences in Cmax and AUC were noted 
between subjects who reported taking pH-elevating products relative to other  
subjects. Due to the theoretical risk that pH-elevating agents may decrease oral 
bioavailability and exposure to dabrafenib, these medicinal products that increase 
gastric pH should be used with caution when administered with dabrafenib. See 
section 5.2.2 re: supportive care when necessary. 
 
Patients should take Dabrafenib at least one hour prior to or two hours after a meal 
due to a potential food effect on Dabrafenib absorption. Subjects should abstain from 
ingestion of Seville oranges, grapefruit or grapefruit juice, pummelos, or exotic citrus 
fruits or grapefruit hybrids while on the study, and avoid ingestion of such fruit(s) for 
at least 24 hours prior to the start of the first dose due to potential increased plasma 
Dabrafenib concentrations due to inhibition of intestinal CYP3A4. 
 
 
8.2 
Trametinib (MEKi) 
 
8.2.1 Pharmaceutical Description 
 
Trametinib Tablets are supplied as, 0.5 mg, and 2 mg (as free base) tablets for oral 
administration. Trametinib 
 
Trametinib Tablets, 0.5 mg are yellow, modified oval, biconvex, film-coated tablets. 
 
Trametinib Tablets, 2 mg (as free base) are pink, round, biconvex, film-coated tablets. 
Trametinib Tablets are packaged into a high density polyethylene (HDPE) bottle that 
contains desiccant with a child-resistant closure that includes an induction seal liner. 
 
8.2.2 Physical and Chemical Properties of the Drug 
 
Novartis Code: TMT212-NXA The suffix NXA denotes the dimethyl 
sulfoxide solvate form. 


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Approved Name: Mekinist (Trametinib) dimethyl sulfoxide (USAN) 
 
Other Names: JTP-74057, JTP-78296, JTP-75303 
 
Chemical and Structural Formula: GSK1120212B, a MEK 1/2 inhibitor, is 
a polycyclic, nitrogen containing heterocycle also possessing aromatic 
halide and amide functionality, and is a dimethyl sulfoxide solvate. 
Molecular formula: C26H23FIN5O4C2H6OS 
Molecular weight: 693.53 
 
Physical Form: White to almost white solid 
 
Solubility: Practically insoluble in the pH range of 2-8 in aqueous media. 
8.2.3 Storage Requirements 
Trametinib is to be refrigerated at 36-46°F. The recommended storage 
conditions, and expiry date where required, are stated on the product label, 
and on the storage and dosage cards dispensed to the patient with their 
medication. 
 
8.2.4 Route of administration 
The route of administration is oral. 
 
 
9. CORRELATIVE STUDIES 
 
9.1 Tumor pharmacodynamics (PD) evaluation (Tumor Biopsies pre-study and on-study) 
 
9.1.1 Collection and Handling of Specimen(s): Fine needle aspiration (FNA) or core 
biopsy of tumor will be obtained at baseline and on C1D15 (+/- 5 days), for 7 
patients in each arm of the study (14 patients total: "Biopsy cohort") who provide 
informed consent and have tumor lesions that are deemed by the study 
investigators to be accessible for biopsy. If funding permits, pre-study and on- 
study (C1D15) biopsies can be done in additional 6 patients on the trial. Optional 
biopsy/FNA will also be performed at progression in up to 5 patients in each arm 
of the FNA cohort who provide informed consent and who demonstrate initial 
radiographic response to therapy followed by radiographic progression. While 
these FNA/biopsies are invasive and will be done for research purpose, such 
procedures are routinely done for diagnostic purpose in clinical setting and are 
well tolerated in patients with thyroid cancer. 
 
Biopsy/FNAs of accessible tumor will only be obtained under ultrasound or CT- 
guidance (unless palpable tumors) by medical personnel (e.g. cytologist, 
endocrinologist, surgeon, radiologist) with expertise in performing biopsy/FNA. 
Clinical trial research team member will be present bedside at time of biopsy to 
collect and process biopsy material. Detailed instructions describing  this 
procedure will be included in a separate Study Lab Manual. 


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To assure that 10 evaluable paired FNA/biopsies are obtained from patients on 
each ARM of the study (total 20 patients), each participating center (total of 4 
centers) will be required to enroll at least 5 patients who have paired biopsies. It  
is possible that 10 patients have pre-study biopsies but some of these patients 
might not be able to have 2nd on-study biopsy. Such case will be considered in- 
evaluable and additional patients will be recruited. 
 
9.1.2 Shipping of Specimen(s): Frozen FNA samples will be batch shipped on dry ice 
to the Solid Tumor Translational Science (STTS) Resource at The Ohio State 
University Comprehensive Cancer Center along with the whole blood specimen 
and the frozen plasma samples collected for BRAF mutation testing. After the 
C2D1collection time point. Shipping address and days of shipment details will be 
provided in the Lab Manual. 
 
9.1.3 Site(s) Performing Correlative Study: Laboratory of Dr. Daniel A. Haber at 
Massachusetts General Hospital Cancer Center. 
 
9.1.4 Methods for Analysis of Tumor Pharmacodynamics studies: Prior to staining, 
tumor biopsy samples will be thawed and deposited onto at least 3 glass slides by 
centrifugation (Cytospin), and briefly dried. Slides can be stored at 4oC covered  
in PBS until staining. The samples with be stained with antibodies to anti- 
thyroglobulin antibodies (thyroid cancer cells), CD45 (white blood cells), 
panCytokeratins, DAPI (nuclei), and one PD biomarker (pERK, NIS, pAKT, p- 
p70S6K or Ki67), followed by appropriate secondary antibodies, utilizing 
immunofluorescence staining protocols developed by S. Michael Rothenberg in 
Daniel Haber's laboratory at Massachusetts General Hospital Cancer Center. 
Additional 
proteins 
that 
provide 
information 
on 
tumor 
biology 
or 
pharmacodynamics may be tested as deemed appropriate by investigators. 
Immunofluroescence based cellular analysis has the primary advantages over 
traditional immunohistochemistry of: multiplexed analysis (e.g. simultaneous 
staining with three-four markers); sensitivity to scant samples; and the potential 
ability to quantify the results. Stained slides will be scanned within 48 hrs of 
staining on a Duet-3 automated scanning system (Bioview). Candidate tumor cells 
will be automatically scored according to pre-defined thresholds (e.g. CD45- 
negative, DAPI-positive, Cytokeratin-positive), and then visually inspected to 
confirm both cell morphology and specificity of staining. For pharmacodynamic 
analysis of the FNAs, the distribution of fluorescence intensities corresponding to 
pERK, pAKT, p-p70S6K, NIS and Ki67 will be determined and compared in pre- 
and on- treatment samples. The percentage change of tumor cell pERK, pAKT, p-
p70S6K, NIS and Ki67 levels from pretreatment levels (both mean fluorescence 
intensity and number of pixels above predefined thresholds as assessed by 
antibody staining) will be calculated. When patient-derived samples are analyzed, 
control cell lines, to consist of cultured BRAF-mutant thyroid cancer cells 
untreated or treated with the same agents, will be analyzed simultaneously and in 


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parallel. Day to day variations in assay performance will be accounted for by 
comparing the data derived from such control samples. 
 
9.2 
BRAF mutation quantification in circulating plasma DNA (Peripheral Blood 
pre-study, on-study and at progression): 
 
9.2.1 Collection and handling of Specimen(s): All patients with a documented BRAF 
mutation at enrollment (up to 52 patients) will have 10 mL of whole blood 
collected in EDTA tubes on day 1 of each cycle for the first 6 cycles and then 
every other cycle (alternating with CT/MRI scan) after that while patients remain 
on study (C8D1, C10D1 etc.). If a patient goes off study due to disease 
progression, a sample will be collected at that time. Details on the processing of 
these samples are included in the Study Lab Manual. 
 
9.2.2 Shipping of Specimen(s): Frozen plasma samples for cycles 1-2 will be shipped 
on dry ice to the Solid Tumor Translational Science (STTS) Resource at The Ohio 
State University Comprehensive Cancer Center along with FNA tumor biopsies  
(if applicable) and whole blood specimens. Specimens collected at cycle 3-7 will 
be held and batch shipped after cycle 7. The remaining samples will be stored at 
the individual sites and batched shipped either every 6 months or when the patient 
goes off study. Shipping address and days of shipment details will be provided in 
the Study Lab Manual. 
 
9.2.3 Site(s) Performing Correlative Study: Solid Tumor Translational Science 
Resource (STTS) at the Ohio State University Comprehensive Cancer Center.   
For method validation, one sample of plasma may be shipped to Molecular 
Diagnostics Co. 
 
9.2.4 Methods for Analysis of BRAF mutation quantification in circulating plasma 
DNA: DNA will be extracted from 1 mL of plasma, using the QIAamp 
Circulating Nucleic Acid kit (Qiagen) and quantitated using the Nanodrop 3300 
Fluorospectrometer with PicoGreen (Thermo Scientific). The BRAF V600E 
mutation will be detected in purified plasma DNA by running a highly sensitive 
allele-specific TaqMan assay on the 7500 FAST Real Time PCR System (Applied 
Biosystems). DNA concentration will be normalized across samples using the 
delta-Ct value of the wild-type BRAF allele. Copy number of the BRAF V600E 
allele will be determined by comparing plasma samples results to a standard curve 
for BRAF V600E consisting of eight dilutions (100%, 50%, 20%, 10%, 1%, 
0.1%, 0.02% and 0% mutated alleles) obtained by mixing purified wild-type and 
mutant linearized plasmid DNA. 
 
9.3 Tumor mutation screening/Mechanisms of drug-resistance (Tumor biopsy at 
Progression) 
 
9.3.1 Collection and handling of Specimen(s): Tumor mutational analysis to 
determine mechanisms of drug-resistance will be performed in at least 5 patients 


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in each arm of the study (10 patients total) who 1) provide informed consent 2) 
demonstrate initial radiographic response followed by documented disease 
progression while on study and 3) have biopsy/FNA accessible tumors. DNA will 
be extracted from tissue taken at the time of progression and compared to DNA 
extraction from baseline tissue. Ideally these samples would be from patients 
enrolled in the "Biopsy cohort" for PD biomarker evaluation (section 9.1.1) in 
order to obtain the status of these biomarkers at progression; however, this may 
not be possible given the limited number of these patients. Baseline tissue can be 
from either the FNA samples taken at baseline (if the patient was in this cohort 
and sufficient material is available) or from archival formalin-fixed paraffin- 
embedded (FFPE) tumor tissue. FNA samples will be collected and processed as 
described in section 9.1.1 and 9.1.2. For archival tumor samples, please see 
section 9.4. 
 
9.3.2 Shipping of Specimen(s): 
From archival tumor sample shipment, please see section 9.4. Frozen FNA 
samples will be shipped on dry ice to the Solid Tumor Translational Science 
(STTS) Resource at The Ohio State University Comprehensive Cancer Center 
with any remaining frozen plasma samples for BRAF mutations analysis. 
Shipping address and days of shipment details will be provided in the Study Lab 
Manual. 
 
9.3.3 Site(s) Performing Correlative Study: Solid Tumor Translational Science 
Resource (STTS) at The Ohio State University Comprehensive Cancer Center. 
 
9.3.4 Methods for Analysis of Tumor Mutation/Mechanisms of resistance studies: 
For DNA purification from archival FFPE tissue, an H&E slide will be prepared 
and tumor percentage and location will be determined by a pathologist. Tumor 
tissue will then be macro dissected from several matching 4-5 micron unstained 
slides and DNA will be extracted using the Recover All Total Nucleic Acid 
Isolation Kit for FFPE (Ambion) according to the manufacturer protocol. For the 
FNA/biopsy samples, cells will pelleted by centrifugation, supernatant removed, 
and DNA extracted using the same kit listed above minus the deparaffinization 
step. Quality and quantity of DNA will be assessed using the Nanodrop 1000 
Spectrophotometer. The status of >700 hot spot mutations across 46 common 
cancer genes, including MEK and members of the PI3K pathway, will be 
determined using the Ion AmpliSeq Cancer Panel on the Ion PGM sequencer. 
Sequence variants will be evaluated using the Torrent Suite Software. 
 
9.4 
Predictive markers of response (Archival Tumor Blocks): 
 
9.4.1 Collection and handling of Specimen(s): Archival formalin-fixed paraffin- 
embedded (FFPE) tumor tissue if available from prior surgery or biopsy will be 
collected for all patients on the study. Tumor blocks will be collected and at least 
5 unstained slides containing 4-5 micron sections of tumor block or part of tumor 
block will be provided. 


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9.4.2 Shipping of Specimen(s): From archival tumor sample, at least 5 unstained slides 
containing 4-5 micron sections of tumor block or part of tumor block will be 
shipped at room temperature. This can be shipped with the first shipment after 
cycle 2 samples are collected (plasma, blood and tumor biopsies, as applicable) to 
the Solid Tumor Translational Science (STTS) Resource at The Ohio State 
University Comprehensive Cancer Center. Shipping address and  days  of 
shipment details will be provided in the Study Lab Manual. 
 
9.4.3 Site(s) Performing Correlative Study: Solid Tumor Translational Science 
Resource (STTS) at the Ohio State University Comprehensive Cancer Center. 
 
9.4.4 Methods for Analysis of predictive biomarkers: If significant clinical response 
is demonstrated in the study, we will perform immunohistochemistry and/or 
tumor genotyping studies to examine levels of relevant protein expression (such 
as pERK, pMEK) and/or microRNA profile or tumor genetics. 
 
9.5 Pharmacokinetics (PK) (Peripheral Blood/plasma) 
 
9.5.1 Collection and handling of Specimen(s): First 7 patients enrolled on each arm of 
the clinical trial (14 patient’s total) at the times specified below for 
pharmacokinetic assessment. 
 
Two mL of whole blood into tubes containing K2EDTA as an anticoagulant will 
be collected from subjects at the time points specified below. If a cannula is 
used, the cannula will be inserted into an arm vein within sufficient time 
prior to dosing, will be kept patent with normal saline or heparin solution, 
and will be removed after the last blood sample is collected or earlier if the 
subject requests. Importantly, in order to avoid artificial dilution of the PK 
samples by the saline or heparin, 1 mL of whole blood will be collected  
and discarded before each whole blood PK sample is collected. 
Immediately after collection, gently invert (DO NOT SHAKE)  the 
evacuated blood collection tube 8-10 times to mix the K2EDTA 
anticoagulant with the whole blood and place the sample(s) on ice or in a 
refrigerator. Within 1 hour of sample collection, separate the plasma by 
refrigerated (4 C) centrifugation at 1,500 to 2,000 x g for a minimum of 10 
minutes. Transfer 400-500 microliters (0.4 - 0.5 mL) of plasma into one (1) 
1.8-mL NUNC tubes. 
If vital signs, safety ECGs and PK sample collection are scheduled for the same 
nominal time, the ECG will be obtained first, followed by vital signs, and then PK 
sample collection. Collect each PK sample as close as possible to the 
planned time relative to dosing. 
 
Store the plasma samples within 60 minutes of the sampling time* at -20°C or 
lower, in an upright position, to keep the plasma in the bottom of the tube. Keep 
the samples frozen in a freezer set at approximately -20°C or lower until shipped. 


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* It is acceptable to store the plasma samples within 90 minutes of collection 
provided that the collection tube was stored on wet ice until centrifugation. 
 
Pre-labeled collection and transport tubes will be supplied in kits. 
 
Time Points for PK Blood Collection: 
Samples will be drawn on: 
 
 
Cycle 1, Day 1: Prior to drug administration and at 1, 2, 3, 4, 6, 8±1 and 22±2 
hours after drug administration. 
 
Cycle 1, Day 15:  Pre-dose sample 
 
Cycle 2, Day 1: Prior to drug administration and at 1, 2, 3, 4, 6, 8±1 and 22±2 
hours after drug administration. 
 
C4D1, C6D1 and C12D1 – Pre-dose specimen. 
 
Patients will be instructed NOT to take their study drugs on the day of the clinic 
visit so the pre-dose samples on (C1D1, C1D15, C2D1, C4D1, C6D1, and 
C12D1) can be drawn. Patients who are selected  for  pharmacokinetics (PK) 
blood draws will take Dabrafenib (BRAFi) only once in the morning (instead of 
twice) on C1D1 and C2D1. On these days, patients on ARM B will take their 
daily dose of Trametinib (MEKi) in the morning. Dabrafenib and Trametinib 
should be taken under fasting conditions with 8 fluid ounces of water (either one 
hour before a meal or 2 hours after a meal). If a patient were to eat before their 
appointment, there should be at least a 2-hour time lapse between the food ingestion 
and the administration of the study medication(s). 
9.5.2 Shipping of Specimen(s): Frozen plasma samples for PK analysis will be 
shipped on dry ice to Covance. 
Refer to the study Lab manual for specific shipping schedule and directions on 
shipping. 
 
9.5.3 Site(s) Performing Correlative Study: Pharmacoanalytical Shared 
Resource at the Ohio State University Comprehensive Cancer Center will perform 
the pharmacokinetic analysis of plasma concentration-time data. 
 
9.5.4 Methods for Analysis of Pharmacokinetics: A liquid chromatography- 
tandem mass spectrometry assay for simultaneous quantification of Dabrafenib 
and Trametinib will be done by methods standardized and validated by team at 
Novartis. 
9.6 
Pharmacogenetics (PGx) 
 
9.6.1 
Collection and handling of Specimen(s): A 6-mL whole blood sample 
will be collected into an EDTA containing tube prior to dosing on day 1 of cycle 1 
from all patients enrolled in the clinical trial. After collection, the whole blood 
samples will be split into two 2-3 mL cryovials,   immediately frozen and stored  
at -70oC or -80 oC until shipping. 
 
9.6.2 
Shipping of Specimen(s): Frozen blood samples will be shipped on dry 


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ice to the Solid Tumor Translational Science (STTS) Resource at The Ohio State 
University Comprehensive Cancer Center along with tumor biopsies (if 
applicable) and with frozen plasma for BRAF mutation analysis.  Shipping 
address and days of shipment details will be provided in the Lab Manual. 
 
9.6.3 
Site(s) Performing Correlative Study: Pharmacoanalytical Shared 
Resource at the Ohio State University Comprehensive Cancer Center 
 
 
9.6.4 
Methods for Analysis of Pharmacogenetics: DNA will be extracted from 
frozen blood. Analysis for polymorphisms in drug metabolizing enzymes and 
transporter genes will be done using appropriate drug disposition (absorption, 
distribution, metabolism, elimination) genotyping panel(s). Dabrafenib is a 
substrate and inducer of CYP3A4 and information on the clearance pathways for 
Trametinib is limited. 
 
 
 
 
10. 
STUDY CALENDAR: 


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Pre- 
therapya 
(Days -28
to Day 0) 
 
On-therapyb 
Off- 
therapyc 
 
 
Day 1 
Cycle 1l 
 
 
Day 7 
Cycles 
1,2,3,4 
 
 
Day 15 
Cycles 1, 2 
Day 1 
Cycles 
2, 4, 6l 
Only first 
18 
Cyclesp 
 
Day 1 
Cycles 
3, 5, 7lp 
Study Drug (s) 
 
 
See Section 5.0 for details 
 
History/Physical Exam 
X 
X 
 
X 
X 
X 
X 
Vital signs/Weight 
X 
X 
 
X 
X 
X 
X 
Concurrent Medications 
X 
X 
 
X 
X 
X 
X 
Adverse Event Evaluation 
 
X 
 
X 
X 
X 
X 
Patient diary Submission 
 
 
 
 
X 
X 
X 
CBC w/diff, plateletsm 
X 
Xa 
 
X 
X 
X 
X 
Serum Chemistryd 
X 
Xa 
 
X 
X 
X 
X 
Serum -HCGe 
X 
 
 
 
 
 
 
Serum Thyroglobulin (Tg), 
anti-Tg antibody and TSH 
X 
 
 
 
 
X 
X 
Dermatology Exam 
Xj 
 
 
 
 
Xj 
 
Ophthalmologic Exam 
Xk 
 
 
 
 
 
 
Electrocardiogram (EKG)q 
X 
 
 
 
 
X 
 
CT or MRI scan of 
neck/chest/abdomenf 
Xf 
 
 
 
 
Xf 
 
PET scan (only if clinically 
indicated)g 
Xg 
 
 
 
 
Xg 
 
Transthoracic
Echocardiogram or MUGAh 
Xh 
 
 
 
 
Xh 
 
Phone Call Visito 
 
 
X 
 
 
 
 
 
 
Following Correlative tests may be done in selected group of patients ONLY. (See Section 9 and Lab Manual) 
6-mL blood for
Pharmacogenetics 
(Section9 .6)n 
 
X 
 
 
 
 
 
2-mL blood per time point for  
 
 
Please see Section 9.5 for details of time points 
 
pharmacokinetics
(Section 9.5)n 
 
Paraffin tumor block (Section 
9.4) 
X 
 
 
 
 
 
 


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10-mL blood for BRAF 
mutations in circulating 
plasma (Section 9.2) 
 
 
X 
 
 
 
Xr 
X 
(Cycles 3 
and 5 only) 
X 
Only if PD 
Tumor Pharmacodynamics 
Tumor Biopsy(Section 9.1) 
X 
 
 
Xi +/- 5 
days 
 
 
 
Tumor Mutation Screening 
Tumor Biopsy (Section 9.3) 
 
 
 
 
 
 
X 
Only if PD 


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a. If pre-study labs (CBC/diff, Chemistry) are drawn within 14 days of study entry, such labs do not have to 
be repeated on C1D1. 
 
b. All on-study visits can be performed within +/-3 days. For cycles 8 to 18, please follow same schedule as 
for even and odd cycles as Cycles 2, 4, 6 or Cycles 3, 5, 7 respectively. Please review all footnotes as some 
testing is not required as frequently after 1st 6 cycles. 
c. Off-therapy evaluations are to be conducted within 4 weeks after last dose of study drug (s). Labs do not 
need to be repeated if done within 2 weeks. 
 
d. Sodium, Potassium, Chloride, Bicarbonate, Creatinine, BUN, Glucose, Calcium, Phosphorus, Total 
protein, Albumin, Total bilirubin, SGOT (AST), SGPT (ALT), Alkaline phosphatase, lactate 
dehydrogenase (LDH). 
 
e. Pregnancy test (sensitivity of at least 50 mIU/mL) will be performed for all women of childbearing 
potential before beginning study drug (s). 
 
f. CT or MRI scans as determined by investigators to assess the response per RECIST v1.1 criteria. CTs or 
MRIs with IV contrast are encouraged but will be done per investigator’s discretion. Scans can be done 
within 7 days prior to day 1 of cycles 3, 5, 7 and subsequent odd number of cycles. If CT abdomen is 
negative at baseline, they only need to be repeated if clinically indicated during the study period. 
 
g. PET scans are performed only as clinically indicated at pre-study, every 8 weeks and off study as 
determined by treating physicians. 
 
h. Echo or MUGA will be done pre-study and every 2 cycles for 6 cycles and then every 4 cycles x 18 
months and then only if clinically indicated. Scans can be done within 7 days prior to day 1 of cycles 3, 5, 7 
and subsequent odd number of cycles. 
 
i. This can be done any time +/- 5 days from C1D15.  Not required during C2D15 time point. 
 
j. Patients on both ARMs must have a dermatologic exam to monitor and manage side effects on the skin. 
k. All patients must have ophthalmologic exam at pre-therapy. Patients randomized to or crossed over to 
ARM B (combination treatment arm) should have these as clinically indicated. Patients are required to 
have a standard ophthalmic exam performed by an ophthalmologist at baseline, and as clinically 
warranted per protocol’s guidance (Refer to Section 6.2.2 for visual changes stopping criteria).  The  
exam will include indirect fundoscopic examination, visual acuity (corrected), visual field examination, 
tonometry, and direct fundoscopy, with special attention to retinal abnormality that are predisposing 
factors for RVO or CSR. For patients with clinical suspicion of RVO or CSR, fluorescein angiography 
and/or optical coherence tomography are highly recommended. 
 
l. Each cycle start is allowed a +/- 3 day window 
 
m. Patients taking Antiplatelets or Anticoagulants need to have a CBC every 2 weeks for the first 4 months. 
 
n. Patients that cross over from ARM A to ARM B are not eligible for the PK or PGx correlative studies. 
 
o. All patients will receive a follow up phone call a week after each clinic visit for the first 4 months of 
treatment. The team will confirm with the patient that they are taking the correct amount of study 
medication, and that they have enough study medication to last until their next clinic visit. 
 
p. After the completion of the 18th cycle, visits will be extended to every 8 weeks. All exams, tests, and scans 
listed for the odd cycle visits will be completed. 
 
q. Electrocardiogram (EKG) will be done pre-study and every 2 cycles for 6 cycles and then every 4 cycles x 
18 months and then only if clinically indicated. 
 
r. After completion of the 18th cycle, visits will be extended to every 8 weeks. BRAF research labs will be 
drawn at every other visit (every 16 weeks) and at time of progression. 


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Baseline evaluations are to be conducted within 4 weeks prior to start of protocol 
therapy. Four weeks (28 days) is considered one cycle.   A member of  the study 
team will be making a follow up phone call to each patient a week after each 
clinic visit for the first 4 months of treatment. The team will confirm with the 
patient that they are taking the correct amount of study medication, and that they 
have enough study medication to last until their next clinic visit. 
 
In general, patients are followed every 2 weeks for the first 8 weeks and then 
every 4 weeks until the completion of cycle 18 at which time visits will be 
extended to every 8 weeks while on study. Off therapy visit is done within 4 
weeks after last dose of study drug. Additionally, patients will be seen in the 
clinic, or contacted by phone every 3 months for 1 year post study treatment. 
Follow up data to be collected: 
 Survival status 
 Disease status (progressed/stable) 
 If any additional cancer therapy was initiated (name & start date) 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated for response every 8 
weeks. Subsequent scan done at 8 weeks will serve as confirmatory scans following 
initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with Dabrafenib (ARM A) or from the time of their first 
treatment with Dabrafenib and Trametinib (ARM B). 


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Evaluable for objective response. Only those patients who have  measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for objective response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions. 
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray or as >10 mm with CT scan, MRI, or calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or  
might not be considered measurable unless there is progression (per RECIST  
v1.1) in tumor lesions in the irradiated field and if radiation therapy is more than 8 
weeks prior to study entry. 
 
Malignant lymph nodes. To be considered pathologically enlarged  and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 


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Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any  
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of  
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to  
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination  
unless the lesion(s) being followed cannot be imaged but are assessable by  
clinical exam. 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules). 
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, CT is 
preferable. 
 
Conventional CT and MRI This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion  should  be  twice the  slice  thickness.   MRI  is  also  acceptable  in certain 


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Protocol Version Date: 10/03/2017
 
situations (e.g. for body scans). 
 
PET-CT At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements. However, if the site can document that the  CT  
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic  
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used  
for RECIST measurements and can be used interchangeably with conventional  
CT in accurately measuring cancer lesions over time.  Note, however, that the  
PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not  
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
FDG-PET While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 'new' 
disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic 


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images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought 
to represent fibrosis or scarring. The use of FDG-PET  in  this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false 
positive 
CR 
due 
to 
limitations 
of 
FDG-PET 
and 
biopsy 
resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
11.1.4 Response Criteria (Modified to define Minor Response and progressive 
disease category) 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance  of  all  target  lesions. 
Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Minor Response (MR): 
20%-29%   decrease   in   the   sum   of   the 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition to  the  
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 
5 mm. (Note:  unequivocal  diagnosis  of 
new 
non-bony 
tumor 
lesion 
is 
also 
considered progression. This is because it 
has been challenging to diagnose bony 
metastasis 
response/progression 
while 
patients are treated with such new class of 
drugs-i.e.:   sometimes   necrosis   caused by 


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study drug is interpreted as ‘progression of 
lytic component). 
 
Stable Disease (SD): 
Neither  sufficient  shrinkage  to  qualify  for 
MR or PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum 
diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):   Disappearance  of  all  non-target  lesions  and 
normalization of tumor marker level. All 
lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Note: If tumor markers are initially above 
the upper normal limit, they must normalize 
for a patient to be considered in complete 
clinical response. 
 
 
Non-CR/Non-PD: 
Persistence   of   one   or   more   non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):      Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions. Unequivocal 
progression should not normally trump 
target lesion status. It must be 
representative of overall disease status 
change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
 
11.1.4.3 
Evaluation of Best Overall Response (Modified with confirmation of 
response required at 8 weeks rather than 4 weeks) 
 
The best overall response is the best response recorded from the start of  
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).   The patient's best response assignment will depend on 


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the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR
CR
No
CR
>8 wks. Confirmation**
CR 
Non- 
CR/Non-PD
No 
PR 
 
 
 
 
 
>8 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non- 
CR/Non- 
PD/not 
evaluated
No 
PR 
MR 
Non- 
CR/Non- 
PD/not 
evaluated
No 
MR 
SD 
Non- 
CR/Non- 
PD/not 
evaluated
No 
SD 
 
Documented at least once 
>8 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, MR, PR or 
CR 
Any 
PD*** 
Yes or 
No
PD 
Any
Any
Yes
PD
* 
See RECIST 1.1 manuscript for further details on what is evidence  of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression  in  non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression   at   that   time   should   be   reported   as   “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated 
No 
not evaluated 
Unequivocal PD
Yes or No
PD
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since


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11.1.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR or MR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the  
smallest measurements recorded since the treatment started, including the baseline 
measurements. 
 
 
11.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. 
 
11.1.7 Response Review 
 
Objective response review will be done by radiologists from each site where 
patient was treated. 
 
12. 
DATA REPORTING REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised


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12.1.1 Method 
 
This study will be monitored by Ohio State University (Coordinating site) per 
their institutional guidelines for Multicenter Trials. Cumulative protocol- and 
patient-specific data will be submitted via Case Report Forms to The Ohio State 
University within 2 weeks of patient completion of each cycle/study time point. 
 
12.1.2 Case Report Forms: 
 
Case Report forms will be provided by OSU. In addition to case report forms, 
relevant reports on source documents will be requested to verify objective 
response. Actual CT or MRI images might be requested to verify objective 
response. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Study Overview 
This is a randomized phase II study designed to screen two different regimens and 
identify which one is the more promising candidate for subsequent testing in a 
Phase III trial in metastatic, radioiodine-refractory differentiated thyroid cancer 
(DTC) patients with mutated BRAF. To determine this, this study will assess the 
proportion of patients who have any response (minor, partial, or complete) within 
6 cycles of therapy. Patients will be randomized to receive one of the two 
treatment regimens with equal allocation. Randomization will be done  using 
block randomization with varying block sizes. 
13.1.2 Primary Endpoint 
The primary endpoint for each of the treatment arms of this trial is overall 
objective response rate, defined as the proportion of patients who have a minor 
response (MR), partial response (PR), or complete response (CR) within the first  
6 cycles of therapy. All randomized patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be evaluable for 
response. 
Complete response (CR) and partial response (PR) will be defined by RECIST 
1.1, and minor response (MR) will be defined as 20-29% decrease in the sum of 
diameters of target lesions, taking as reference the baseline sum diameters. Any 
patients who have received at least one dose of treatment will be considered 
evaluable for these analyses. Patients will be analyzed in the treatment arm to 
which they were randomized. If a patient progresses, they will have met the 
primary endpoint classification for the purposes of this protocol (i.e. they will 
have had a response prior to progression or not). Patients’ statuses prior to 
progression will be used in the assessment of response rates when evaluating the 


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primary endpoints for the treatment arms. Data on patients who cross over and 
receive treatment per another arm after progression will not be used in the  
decision analyses. 
Rationale for using minor response as a part of objective response: Currently, 
many targeted therapy trials show clinically meaningful responses that are most 
evident only when reviewing waterfall plots that show % of tumor shrinkage in 
each patient. We have learned that PR and CR do not provide accurate assessment 
of clinical benefit. While stable disease is included as part of objective response in 
many solid tumors, it is not interpretable in patients with thyroid cancer due to 
overall slow-growing nature of cancer in many patients. Per RECIST 1.1, > 20% 
increase in tumor target lesions is considered significant and objective response in 
this case is defined as progressive disease. We therefore believe that 20-29% 
shrinkage of tumor represents true shrinkage that is clinically meaningful and is 
not by chance or measurement variation. Thus, we include MR as a part of 
objective response even though MR is not conventionally included. 
 
13.1.3 Statistical Design 
To both evaluate whether or not each of these experimental treatment regimens  
are sufficiently active in this patient population as well as to screen these 
regimens for the most promising regimen to be carried forward to the phase III 
setting, this study utilizes a flexible screening design developed by Sargent and 
Goldberg (Statistics in Medicine, 2001). Overall, we have developed this study to 
be able to determine that one regimen is decidedly worth pursuing further over 
another if the true differential in the overall response rates between arms is 0.20. 
Overall, we have developed this study to be able to determine that one regimen is 
decidedly worth pursuing further over another if the true overall response rates are 
15% versus 35%. This study design has 90% power to identify the correct  
regimen as most promising and thus the regimen to bring forward into larger and 
confirmatory studies. Based on these assumptions and constraints, 26 evaluable 
patients will be accrued to each arm to evaluate the regimens under the  
parameters specified. If our underlying assumptions regarding the true response 
rates associate with each of these arms is a little lower (e.g. 10% 
vs.  30%),  we 
will have additional power for these analyses (i.e. >90%). Even if our true 
response rates corresponding to the treatment regimens being evaluated 
here 
are higher (e.g. 40% vs. 60%), we will still have sufficient power (>88%) to 
determine that one arm is more promising than another if it truly is with this 
number of patients per arm and the same rule for observed differential described 
below. The main decision rule is based on differential, and the above assumptions 
show a flexibility and sufficient power for identifying the most promising  
regimen even if our hypotheses regarding response rates are slightly off. 
As part of this design, we define one treatment arm to be more promising than 
another if the actual observed overall response rate for each of the arms differ by 
10% or more, in which case the regimen with the higher overall response rate will 
be recommended for further testing. If these rates differ by less than 10%, factors 


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other than the overall response rate will be considered. 
 
If one treatment arm has an overall response rate that is at least 0.10 
higher than the other, then it will be deemed the most promising and 
carried forward to the phase III setting. 
 
If the rates of the arms fall within d = +/- 0.10 of each other, the results of 
the study are considered statistically ambiguous and the regimens are 
considered similar with respect to their respective overall response rates. 
In this case, other factors are allowed to be taken into consideration when 
deciding on which regimen to bring forward into definitive Phase III 
testing. For this trial, we will specifically evaluate differences in the 
toxicity, PR+CR rate, progression-free survival, and correlative markers 
that indicate if the inhibitor therapeutic agents are hitting their respective 
targets. 
 
In the event that the success rates fall within .10 of each other, this study 
design assumes that there is a 50/50 chance of choosing the correct 
regimen. However, the choice of “d” used to determine whether or not 
other factors are considered is decidedly wide in order to allow the 
incorporation of the toxicity, translational, and other efficacy endpoints to 
be taken into consideration in this complex patient population. If one is 
clearly more promising than the other regimens and thus surpasses the 
other by the stated “d”, then it is less relevant to utilize other factors in this 
determination. The only potential exception is if the clearly most  
promising regimen has substantially more toxicity than the other 
regimen(s). 
 
 
 
 
13.2 
Sample Size/Accrual Rate 
 
13.2.1 Sample Size 
The one-stage screening design to be utilized as described in Section 13.1. A 
maximum of 26 evaluable patients will be accrued to each arm unless undue 
toxicity is encountered. Overall, a total of 52 patients will be accrued to this trial 
(26 to each of the two treatment arms). 
13.2.1 Accrual Time and Study Duration 
Based on previous studies conducted through this group in this patient 
population, we expect the annual accrual rate to be approximately 7 
patients per quarter. Therefore, the accrual period for this  trial  is  
expected to be about 24 months. The total study duration is expected to be 
4 years, in order to fully evaluate clinical outcomes. 
The primary endpoint analysis will be done after the last accrued patient 


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has been followed for at 6 cycles. The primary endpoint analysis will be 
done after the last accrued patient has been followed for at 6 cycles. 
 
13.3 
Stratification Factors 
None 
 
13.4 
Analysis of Secondary Endpoints 
 
The MR+PR+CR response rate will be estimated for each treatment arm. In 
determining this rate, the number of patients with RECIST-based MR, PR or CR will 
be divided by the number of evaluable patients. All evaluable patients will be used for 
this analysis. Exact binomial 95% confidence intervals for the true PR+CR response 
rate will be calculated. 
 
The Kaplan-Meier method will be used to estimate progression-free and overall 
survival. Each of these variables will be measured from the date of registration to the 
date of the event (i.e., death or disease progression) or the date of last follow-up to 
evaluate that event. We will also evaluate the proportion of patients who are 
progression-free and alive at one year. 
 
Toxicity and Tolerability: Frequency and severity of adverse events and tolerability 
of the regimen in each of the treatment arms will be collected and summarized using 
descriptive statistics. As per NCI CTCAE v4.0, the term toxicity is defined  as  
adverse events that are classified as either possibly, probably, or definitely related to 
study treatment. The maximum grade for each type of toxicity will be recorded for 
each patient, and frequency tables will be reviewed to determine toxicity patterns. In 
addition, we will review all adverse event data that is graded as 3, 4, or 5 and 
classified as either “unrelated” or “unlikely to be related” to study treatment in the 
event of an actual relationship developing. The incidence of severe (grade 3+)  
adverse events or toxicities will be described. We will also assess tolerability of the 
regimens through assessing the number of patients who required dose modifications 
and/or dose delays. In addition, we will also capture the proportion of patients who go 
off treatment due to adverse reactions or even those who refuse further treatment for 
lesser toxicities that inhibit their willingness to continue participation on the trial. 
These tolerability measures will be assessed within each of the treatment arms and we 
will explore differences in these measures between the arms. All patients who have 
received at least one dose of any of the therapeutic agents in a treatment arm will be 
evaluable for toxicity and tolerability. 
 
In addition to the clinical outcomes of interest, we will also evaluate several 
correlative markers as well. Specifically, we will evaluate the serum thyroglobulin 
and assess how these levels correspond with achievement of response to treatment. 
We will assess this as between and across treatment arms; change in serum 
thyroglobulin levels will be evaluated between arms, and the impact of this change 
and how it is associated with response will be assessed using logistic regression 
analyses; we will look at how treatment arm and thyroglobulin levels are associated 


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with incidence of response. We will also evaluate differential levels using graphical 
methods (e.g. side-by-side boxplots) and two-sample t-tests (or nonparametric 
equivalent as necessary). We will also evaluate pharmacokinetic, pharmacogenetic, 
and pharmacodynamic markers. Differences in these markers and factors between 
patients who do vs. do not achieve response will be evaluated using chi-square 
statistics and two-sample t-tests depending on the type of marker/factor being 
compared based on clinical outcome group. Graphical analyses will also be used to 
assess potential trends and relationships between clinical response and these 
markers/factors. 
 
 
13.5 Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment with Dabrafenib on ARM A and from the time of their 
first treatment with Dabrafenib and Trametinib on ARM B. 
 
13.5.2 Evaluation of response – All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible. Each patient will be assigned one of the following  
categories: 1) complete response, 2) partial response, 3) minor response, 4) 
stable disease, 5) progressive disease, 6) early death from malignant disease, 7) 
early death from toxicity, 8) early death because of other cause, or 9) unknown 
(not assessable, insufficient data). [Note: By arbitrary convention, category 9 
usually designates the “unknown” status of any type of data in a clinical 
database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main 
analysis of the response rate. Patients in response categories 5-9 above should  
be considered to have a treatment failure (disease progression). Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion 
from the analysis of the response rate. 
 
All conclusions should be based on all eligible patients. Subanalyses may then 
be performed on the basis of a subset of patients, excluding those for whom 
major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.). 
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also  
be provided. 


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


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APPENDIX B 
 
Prohibited Medications: Strong CYP2C8/3A/Pgp/Bcrp Inhibitor/Inducers of Dabrafenib 
 
Strong CYP2C8/3A/Pgp/Bcrp Inhibitor/Inducer 
Therapeutic Area 
Clarithromycin, telithromycin, rifamycin class agents 
(e.g.  rifampin, rifabutin, rifapentine), troleandomycin, 
anti-retrovirals (ritonavir, indinavir, nelfinavir, 
saquinavir, amprenavir,atazanavir, efavirenz),
 
 
Antibiotics 
Itraconazole, ketoconazole, posaconazole, voriconazole 
Antifungals 
Nefazodone 
Antidepressants 
Gemfibrozil 
Hyperlipidemia 
Amiodarone, Bosentan, mibefranil, conivaptan, 
ethosuximide, St John’s Wort, grapefruit juice/extract
 
Miscellaneous 
Cyclosporine 
Immunosuppressive agents 
Carbamazepine, oxcarbazepine phenobarbital, 
phenytoin, s-mephenytoin
 
Anticonvulsant 


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APPENDIX C 
 
Cautionary Medications: Listed medications should be used cautiously with Dabrafenib 
 
 
USE WITH CAUTION: Concentrations of these drugs may be altered (increased or decreased) by 
GSK2118436. 
CYP2C8/C9/C19/Substrate 
Therapeutic Area 
Cerivastatin 
HMG-CoA Reductase Inhibitors 
Tolbutamide, nateglinide, repaglinide 
Antidiabetics 
Amitriptyline, clomipramine, imipramine 
Antidepressants 
USE WITH CAUTION: Potential for inhibitors of CYP3A, CYP2C8, Pgp and Bcrp since concentrations 
of Dabrafenib may be increased 
Mild/Moderate Inhibitor 
Therapeutic Area 
Erythromycin 
Antibiotic 
Fluconazole 
Antifungal 
diltiazem, verapamil 
Antiarrhythmics 
aprepitant, cimetidine, montelukast 
Miscellaneous 
USE WITH CAUTION:  Monitor for loss of efficacy or substitute another medication 
Substrates of CYP3A4/CYP2B6/CYP2C8/CYP2C9/CYP2C19 that may 
be affected by induction 
 
Therapeutic Area 
chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Antibiotics 
Caspofungin, Fluconazole, terbinafine 
Antifungals 
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil
 
Antihypertensives 
aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone, amitriptyline, clomipramine, imipramine
Antidepressants and 
Antipsychotics Agents
glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, repaglinide, 
rosiglitazone
 
Antidiabetics 
Lamotrigine, valproate, divalproex, zonisamide, 
Anticonvulsants 
alfentanil, 
oxycodone
buprenorphine, 
celecoxib, 
codeine, 
fentanyl, 
methadone,  
Analgesics 
aprepitant, cisapride, darifenacin, disopyramide, leflunomide, methohexital, 
oral contraceptives, quinine, ranitidine, solifenacin, sulfasalazine, tramadol, 
tolvaptan, 
chloroquine, 
zopiclone, 
dexlansoprazole, 
esomeprazole, 
famotidine, ilaprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
 
 
Miscellaneous 
alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone
 
Hypnotics and Sedatives 


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NCCN protocol no. NCCNGSK20008
Protocol Version Date: 10/03/2017
 
Diergotamine, ergotamine, eletriptan 
Antimigraine agents 
Everolimus, sirolimus, tacrolimus 
Immunosuppressive agents 
astemizole, chlorpheniramine, ebastine 
Antihistamine 
oral budesonide, methylprednisolone, dexamethasone 
Corticosteroids 
sildenafil, tadalafil, vardenafil 
Erectile Dysfunction agents 
Eplerenone 
Selective Aldosterone Blockers 
Disopyramide, dronedarone, mexiletine, propafenone, quinidine 
Antiarrhythmics 
lovastatin, atorvastatin, simvastatin 
HMG-CoA Reductase Inhibitors 
cilostazol, warfarin(excluded as therapeutic dosage), aspirin/anticoagulants 
Anticoagulants and Antiplatelets


Page 90 of 92
NCCN protocol no. NCCNGSK20008
Protocol Version Date: 10/03/2017
 
 
OSU 12064
Pre-therapy testing 
History, Physical Exam, Skin exam, and Eye* Exam 
Blood tests, EKG, Echo, CT or MRI scan 
Tumor biopsy*; PET scan* 
Obtain cancer specimen from prior biopsy or surgery 
1  Cycle 1 Day 1 
History 
Physical Exam 
Blood tests 
Blood tests up to 8 hours* 
2  Cycle 1 Day 2 
Blood tests* 
3 
4
5
6
7
8
9
10
11 
12 
13 
14 
9 
Cycle 1 Day 15 
History 
Physical Exam 
Blood tests 
Tumor biopsy*
16 
17 
18
19
20
21
22
23
24
25 
26 
27 
28 
29 
Cycle 2 Day 1 
History 
Physical Exam 
Blood tests 
Submit pill diary 
Blood tests up to 8 hours*
30  Cycle 2 Day 2 
Blood tests* 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43   Cycle 2 Day 15 
History 
Physical Exam 
Blood tests 
44 
45 
46 
47 
48 
49 
50- 56
CT or MRI scan, Echo*, PET scan*, Skin Exam 
Notes: 
1. Tests/items marked *will  only be done when/if applicable to you. 
2. Study drug (s) should be taken under fasting conditions, either one hour 
before a meal or 2 hours after a meal. It should be taken with 
approximately 240 mL (8 fluid ounces) of water. 
3. Please fill out pill diary and bring it to every clinic visit. 
57 Cycle 3 Day 1 
History 
Physical Exam 
Blood Tests 
EKG 
Submit pill diary 
58 
59 
Appendix D: Sample Calendar 


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NCCN protocol no. NCCNGSK20008
Protocol Version Date: 10/03/2017
 
Appendix E: Patient Pill Diary. [Note: Be sure to bring this pill diary and the pill bottles with you to your next study visit. Sign 
below.  Thank you] 
Study #:
Patient ID:
Patient Name
 
 
Patient Signature 
Date 
Day 1 of Cycle:
 
*If you have any questions 
 
 
Tafinlar (Dabrafenib) 
Morning Dose (mg)
 
Tafinlar (Dabrafenib) 
Evening Dose (mg)
 
Mekinist (Trametinib) 
Once daily dose (mg)
regarding your study
medication, or if you feel you are 
going to run out of study 
medication, please call the study 
team right away. 
 
Comments: 
Day 
Number
Day of 
Week 
Date
Time/Dose
Time/Dose
Time/Dose
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
 
 
 
 
 
 


Instructions for taking study drug 
Mekinist (Trametinib) 
Keep Trametinib refrigerated at 36-46°F. 
1. Take Trametinib at approximately the same time each 
day. 
2. Take Trametinib either one hour before or two hours 
after a meal. 
3. Take the amount of study drug indicated on the bottle 
once a day with approximately 8 ounces of water. 
4. Trametinib should be taken within a two hour window 
of the scheduled dose. If you miss the dose (falls 
outside of the scheduled 2 hour window) for some 
reason, you should just skip that dose and should take 
the next scheduled dose. 
5. If you vomit after taking study drug, do not retake the 
dose.  Take the next dose as scheduled. 
 
Appendix F: Novartis provided Storage & Dosing Instruction Cards to be dispensed to patients with Trametinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCCN protocol no. NCCNGSK20008 
Page 92 of 92 
Protocol Version Date: 10/03/2017 
 
 
 
 
 
Novartis Study 
Patient Dosing Instructions 
V1.0 Nov 2010