Clinical trial NCT02367859
Conditions: Ameloblastoma BRAF Gene Mutation
Keywords: ameloblastoma BRAF odontogenic cancer adamantinoma
Sponsor: Stanford University
Start date: 2017-07-17; Completion date: 2019-06-26
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies dabrafenib and trametinib in treating patients with ameloblastoma and a specific mutation (change) in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To observe the response rate of ameloblastoma to dabrafenib and trametinib at 6 weeks.

SECONDARY OBJECTIVES:

I. Feasibility and safety in this patient population. II. Response will be assessed pathologically. III. Two main histologic assays for treatment response will be used: tumor necrosis and phosphorylated-mitogen-activated protein kinase kinase 1 (MEK), phosphorylated-extracellular signal-regulated kinase (ERK), and Ki-67 levels as measured by immunohistochemistry.

OUTLINE:

Patients receive dabrafenib orally (PO) twice daily (BID) every 12 hours and trametinib 2 mg daily PO for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients whose disease is judged to be not amenable to resection will continue dabrafenib and trametinib indefinitely as long as there has not been tumor progression.

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

Arms: arm 1: Patients receive dabrafenib PO BID every 12 hours plus trametinib daily PO for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients whose disease is judged to be not amenable to resection will continue dabrafenib and trametinib indefinitely as long as there has not been tumor progression.
Interventions: intervention 1: Dabrafenib intervention 2: Trametinib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
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TITLE:  A pilot study of Dabrafenib and Trametinib for patients with BRAF-mutated 
ameloblastoma 
NCT02367859 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive, Stanford, CA 94305 
Protocol Director 
A Dimitrios Colevas, MD, Professor in Medicine 
Stanford University Medical Center 
Blake Wilbur Drive, Stanford, CA 94305-5826 
 
 
colevas@stanford.edu 
Co-Investigators 
Robert West 
Professor in Pathology Pathology  
Stanford, California 94305-5324 
 
 
Jonathan Pollack 
Professor in Pathology 
269 Campus Drive, Stanford, California 
94305-5176 
 
 
Davud Sirjani 
Clinical Assistant Professor 
 
 
Biostatistician 
Alex McMillan 
Sr Res Scientist-Basic Ls 
HRP (Redwood) Building  
Stanford, California 94305 
 
 
Study Coordinator 
Elizabeth Winters 
 
 
Protocol Amendment 8:  21 August 2018 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ................................................................................................................... 4 
SCHEMA ............................................................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................... 6 
1.0 OBJECTIVES ............................................................................................................................ 7 
1.1 
Primary Objectives ..................................................................................................................................... 7 
1.2 
Secondary Objectives ................................................................................................................................ 7 
2.0 BACKGROUND ........................................................................................................................ 7 
2.1 
Study Disease ............................................................................................................................................... 7 
2.2 
Study Agents/Device/Procedure .......................................................................................................... 9 
2.3 
Rationale ...................................................................................................................................................... 10 
2.4 
Study Design ............................................................................................................................................... 11 
2.5 
Correlative Studies Background ......................................................................................................... 11 
3.0 PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ............................ 12 
3.1 
Participant Eligibility Checklist ........................................................................................................... 12 
3.2 
Informed Consent Process ..................................................................................................................... 18 
3.3 
Study Timeline ........................................................................................................................................... 18 
4.0 TREATMENT PLAN .............................................................................................................. 18 
4.1 
General Concomitant Medication and Supportive Care Guidelines ....................................... 19 
4.1.1 
Permitted Medications and Non-Drug Therapies ................................................................................ 19 
4.1.2 
Prohibited Medications and Non-Drug Therapies ............................................................................... 20 
4.1.3 
Medications to be used with Caution ......................................................................................................... 21 
4.2 
Criteria for Removal from Study ......................................................................................................... 22 
5.0 STUDY AGENT INFORMATION ........................................................................................ 22 
5.1 
Study Agents: .............................................................................................................................................. 22 
5.2 
Availability .................................................................................................................................................. 23 
5.3 
Agent Ordering .......................................................................................................................................... 23 
5.4 
Agent Accountability ............................................................................................................................... 23 
6.0 DOSE MODIFICATIONS ...................................................................................................... 23 
6.1 
Dose Modification for General Toxicities ......................................................................................... 23 
6.2 
Dose Reductions for AEs of interest in patients taking dabrafenib and  trametinib ....... 24 
6.2.1 
Plantar-Palmar Erythrodysesthesia ........................................................................................................... 24 
6.2.2  
Pancreatitis ........................................................................................................................................................... 25 
6.2.3 
Uveitis and ocular events ................................................................................................................................ 25 
6.2.4 
Hyperglycemia .................................................................................................................................................... 27 
6.2.5 
Pyrexia .................................................................................................................................................................... 27 
6.2.6 
Malignancies ........................................................................................................................................................ 29 
6.2.7 
New Primary Melanoma ................................................................................................................................. 29 
6.2.8 
Non-Cutaneous Malignancies ....................................................................................................................... 29 
6.2.9 
Renal Insufficiency ............................................................................................................................................ 29 
6.2.10 Gudielines for Prolonges QTc........................................................................................................................ 31 
6.2.11 Guidelines for Pneumonitis ........................................................................................................................... 32 
6.2.12 Guidelines for Cardiomyopathy ................................................................................................................... 32 
6.2.13 Treatment of Study Treatment Overdose ................................................................................................ 34 
7 
ADVERSE EVENTS AND REPORTING PROCEDURES ................................................ 34 
7.1 
Potential Adverse Events ....................................................................................................................... 34 
7.1.1 
Dabrafenib potential adverse effects ......................................................................................................... 34 
7.1.2 
Trametinib potential adverse effects ......................................................................................................... 38 
7.2 
Adverse Event Reporting ....................................................................................................................... 42 


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8 
CORRELATIVE/ SPECIAL STUDIES ................................................................................ 44 
8.1 
Laboratory Correlative Studies ........................................................................................................... 45 
8.1.1 
Collection of Specimen(s) ............................................................................................................................... 45 
8.1.2 
Handling of Specimens(s) ............................................................................................................................... 45 
8.1.3 
Shipping of Specimen(s) ................................................................................................................................. 46 
8.1.4 
Site(s) Performing Correlative Study ........................................................................................................ 46 
8.1.5 
Coding of specimens for privacy protection ........................................................................................... 46 
9 
STUDY CALENDAR ............................................................................................................... 47 
10 
MEASUREMENTS .................................................................................................................. 49 
10.1 Primary and Secondary Outcome measures ................................................................................... 50 
10.1.1 Measurement Definition ................................................................................................................................. 50 
10.1.2 Measurement Methods .................................................................................................................................... 50 
10.1.3 Measurement Time Points ............................................................................................................................. 50 
10.2 Secondary Outcome ................................................................................................................................. 50 
10.2.1 Tumor necrosis ................................................................................................................................................... 50 
10.2.2 Measurement Definition ................................................................................................................................. 50 
10.2.3 Measurement Methods .................................................................................................................................... 50 
10.2.4 Measurement Time Points ............................................................................................................................. 51 
10.2.5 Response Review ............................................................................................................................................... 51 
10.3 Secondary Outcome – Proliferation index ....................................................................................... 51 
10.3.1 Measurement Definition ................................................................................................................................. 51 
10.3.2 Measurement Methods .................................................................................................................................... 51 
10.3.3 Measurement Time Points ............................................................................................................................. 51 
10.3.4 Response Review ............................................................................................................................................... 51 
10.4 Secondary Outcome – Phosphorylation of MEK/ERK .................................................................. 51 
10.4.1 Measurement Definition ................................................................................................................................. 52 
10.4.2 Measurement Methods .................................................................................................................................... 52 
10.4.3 Measurement Time Points ............................................................................................................................. 52 
10.4.4 Response Review ............................................................................................................................................... 52 
11 
REGULATORY CONSIDERATIONS .................................................................................. 52 
11.1 Institutional Review of Protocol ......................................................................................................... 52 
11.2 Data and Safety Monitoring Plan: ....................................................................................................... 52 
11.3 Data Management Plan ........................................................................................................................... 53 
11.3.1 Data Collection .................................................................................................................................................... 53 
11.3.2 Data Submission responsibility ................................................................................................................... 53 
11.3.3 Multicenter Guidelines .................................................................................................................................... 53 
12 
STATISTICAL CONSIDERATIONS ................................................................................... 53 
12.1 Statistical Design and primary analysis ........................................................................................... 53 
12.2 Secondary Analysis .................................................................................................................................. 54 
12.3 Sample Size ................................................................................................................................................. 54 
12.4 Accrual estimates ..................................................................................................................................... 54 
12.5 Feasibility and safety assessment....................................................................................................... 54 
13 
REFERENCES ......................................................................................................................... 55 
Appendix A:  Medication guide for patients .................................................................................. 58 
Appendix B:  Stanford Cancer Institute Serious Adverse Event Reporting ............................... 58 
Appendix C:  ECOG Performance Status ...................................................................................... 59 
Appendix D:  Cockcroft-Gault Formula......................................................................................... 60 
Appendix E:  Ophthalmic exam source sheet ................................................................................ 60 


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PROTOCOL SYNOPSIS 
In the table below summarize the basic aspects of this research.  This is to be used as a quick 
reference guide.   
 
TITLE 
A pilot study of Dabrafenib and Trametinib for 
patients with BRAF-mutated ameloblastoma  
STUDY PHASE 
Pilot 
INDICATION 
Ameloblastoma 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Dabrafenib and trametinib 
PRIMARY OBJECTIVE(S) 
Tumor response rate 
SECONDARY OBJECTIVE(S) 
Feasibility, safety, pathological response, 
evidence of molecular pathway inhibition 
TREATMENT SUMMARY 
Dabrafenib 150 mg po q 12 hours plus 
trametinib 2 mg once daily. 
SAMPLE SIZE  
17 evaluable patients 
STATISTICAL CONSIDERATIONS 
Simon Optimal 2 stage design 
 
IRB application number:  IRB-32275 
By determination of the Principal Investigator and the IRB, this study is considered IND-Exempt. 
 


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SCHEMA 
 
  
 
  
 
                        
 
 
 
                                             SD, PR, or CR
                    
Progression or intolerable AEs
 
                                          
 
                        YES 
 
No
                                        
 
   
   
 
 
 
                                                                
 
                                                                  
 
                                             
                                  
 
                                            
                        
 
                                                                                                              
 
                                                                                                                
 
 
 
Pathologically-documented ameloblastoma with BRAF-V600E or other known 
Dabrafenib-sensitive BRAF mutation in tumor by any CLIA-certified lab 
Confirmation of eligibility and documentation of informed consent 
Baseline biopsy, imaging, staging and clinical assessment by  
both ENT / oral surgeon and medical oncologist. 
Dabrafenib 150 mg PO q12hr plus 
Trametinib 2 mg daily PO  x 6 weeks 
Response and AE assessment q3 weeks x 2  
(see below for later assessment intervals) 
Assessment at 6 weeks: 
Surgically resectable? 
Biopsy and evaluation of 
pathological endpoints 
Resection and evaluation of pathological endpoints.  
No additional dabrafenib or trametinib 
Biopsy and evaluation of 
pathological endpoints 
Off-study 
Continue dabrafenib and trametinib, evaluate 
for DLT and response every 6 to 9 weeks 
with dose modifications per protocol 
SD, PR, or CR without 
intolerable AEs 
Progression or 
intolerable AEs 
Off-study 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HTN 
Hypertension 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
 


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1.0 OBJECTIVES 
1.1 
Primary Objectives 
To observe the response rate of ameloblastoma to dabrafenib plus trametinib at 6 weeks. 
1.2 
Secondary Objectives 
Secondary endpoints will include feasibility and safety in this patient population.  
Additionally, response will be assessed pathologically.  Two main histologic assays for 
treatment response will be used:  tumor necrosis and phosphorylated-MEK;  
phosphorylated-ERK;  and Ki-67 levels as measured by immunohistochemistry.   
2.0 BACKGROUND 
2.1 Study Disease 
Ameloblastoma is a rare, benign, slow-growing but locally-invasive neoplasm of 
odontogenic origin involving the mandible (80%) and maxilla with a high recurrence rate 
attributed to conservative treatment.  The neoplasm was first described by Cusack in 1827. 
{Cusack, 1827}  Etymologically, the name derives from the old French word "amel" which 
means enamel and the Greek word "blastos" meaning germ or bud.  Over time, this tumor 
has been referred to by many different names including “cystosarcoma,” 
“adamantine epithelioma,” “adamantinoma,” and finally “ameloblastoma.” {Ivy, 1930;  
Malassez, 1885;  Wedl, 1870;  Brazis, 1995]  
Ameloblastoma shows variable geographic prevalence, being the most common benign 
odontogenic tumor in China {Lu, 1998;  Wu, 1985} and Africa {Anand, 1967;  
Mosadomi, 1975;  Barnes, 2005}, while it is the second most common in the United States 
and Canada {Daley, 1994;  Regezi, 1978} (odontoma being most common).  Racial bias 
has also been observed, with African Americans at an overall five-fold increased risk of 
disease versus Caucasians. {Regezi, 1978}  Global incidence has been estimated at 0.5 
cases per million person years, with most cases diagnosed in the age range of 30 to 60 
years. {Larsson, 1978}  
Up to 80% of ameloblastoma cases occur in the mandible, with a particular predilection for 
the posterior mandibular region. {Reichart, 1995}  Rare cases have been reported as 
primary to the sinonasal cavities. {Schafer, 1998}  Often ameloblastoma can be associated 
with unerupted third molar teeth {Stanley, 1965;  Gerzenshtein, 2006;  Becelli, 2002} 
particularly in the unicystic type.  Desmoplastic ameloblastomas often occur in the anterior 
or premolar regions of the mandible or maxilla.  Ameloblastic carcinomas also favor the 
mandible (~2/3) over the maxilla. {Slootweg, 1984}  Maxillary ameloblastomas also 
mostly occur in the posterior molar region. 
Histopathologically, ameloblastoma resembles normal odontogenic/enamel epithelium and 
ectomesenchyme.  Odontogenesis consists of chronographic and reciprocal interactions 
between the ectomesenchymal cells, which are derived from the neural crest, and the oral 
cavity lining epithelium. {Chai, 2000}  The exact origin of ameloblastic epithelium has 
been hypothesized to arise from:  (1) cells from the rests of enamel organ, (2) cells of the 
sheet of Hertwig’s or epithelial cell rest of Malassez, (3) epithelial boundary of an 
odontogenic cyst, particularly a dentigerous cyst, (4) basal cells of the oral mucosa, and (5) 


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heterotrophic epithelial from other parts of the body, perhaps pituitary. {Ritchie, 1990;  
Bhasker, 1981}  
Until recently, little was known about the molecular aberrations driving ameloblastoma, 
due to the tumor’s rarity and the fact that technologies to query the tumor genome do not 
work as efficiently in formalin-fixed paraffin-embedded tissue.  However, in 2014, three 
separate reports, including one form our group at Stanford, profiling ameloblastoma via 
DNA sequencing were published, all showing the vast majority of tumors to contain 
somatic mutations impacting the mitogen-activated protein kinase (MAPK) signaling 
pathway (FGFR2-> RAS -> BRAF) that controls cell proliferation. {Kurppa, 2014;  
Sweeney, 2014;  Brown, 2014}  
In particular, all three studies reported a high frequency of BRAF-V600E (valine to 
glutamic acid substitution at amino acid 600) activating mutations at high allele frequencies 
in ameloblastomas.  In each of these reports, the BRAF-mutated neoplasms were almost 
exclusively located in the mandible.  Two of the three reports went on to characterize the 
sensitivity of BRAF-mutated ameloblastoma cells to vemurafenib, a V600E targeted small 
molecule inhibitor FDA-approved for metastatic melanoma.  Both studies showed that 
AM-1, a mandibular-derived ameloblastoma cell line harboring the BRAF-V600E 
mutation, was exquisitely sensitive to vemurafenib at concentrations similar to 
BRAF-V600E mutated melanoma and colorectal cancer cell lines.   
Surgery is the standard treatment for ameloblastomas.  Historically, the extent of resection 
has been controversial, comprising of two surgical options:  “conservative” vs.  “radical”.  
The former involves enucleation/curettage of the bony cavity, while the latter involves a 
radical operation with proper margins.  Advantages of enucleation include the fact that it is 
an outpatient procedure able to be performed by many different service providers (Oral 
Surgeons and ENT), since it requires no reconstruction.  Despite these facts, historical data 
on simple enucleation demonstrate recurrence rates 60 to 90% and this treatment modality 
is currently believed to play no role in the management of multicystic ameloblastomas. 
The “radical” surgical option is the current standard of care for ameloblastoma, which 
includes enbloc resection with 1 to 2cm bone margins {Sham, 2009;  Carlson, 2006;  
Gardner, 1980;  Williams, 1993;  Gortzak, 2006;  Becelli, 2011;  Pandya, 1972} and 
immediate bone reconstruction to help with speech and swallowing. {Sham, 2009;  
Vayvada, 2006;  Tsai, 2006;  Urken, 1991;  Urken, 1998}  
The bony margin is defined as the distance away from the radiographic margin predicted to 
be disease free and oncologically safe to perform osteotomies.  Data from 82 
ameloblastoma specimens showed microscopic tumor extension 2 to 8mm (mean of 
4.5mm) beyond the radiographic boundaries of the tumor. {Carlson, 2006}  Hence, the 
recommended bone margins are1 to 1.5cm for unicystic and 1.5 to 2cm for 
solid/multicystic histological types providing increased cure rates. {Wenig, 2007;  Becelli, 
2002;  Carlson, 2006;  Zwahlen, 2002;  Ueno, 1989;  Vayvada, 2006}  Ameloblastic 
carcinoma requires 2 to 3cm bone margins with an elective neck dissection. {Ndukwe, 
2010}  Therefore surgery for ameloblastoma, when possible, tends to be radical and 
disfiguring. 
Systemic chemotherapy has been attempted a number of times, with numerous agents and 
combinations being employed (see Table 1) {Gall, 1975;  Eliasson, 1989;  Ramadas, 1990;  


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Grunwald, 2001;  Campbell, 2003;  Amzerin, 2011;  Van Dam, 2010}.  Anecdotal reports 
have suggested that ameloblastoma may be sensitive to platinum based agents {Amzerin, 
2011} although occasional reports highlight lengthy survival without chemotherapy. 
{Ciment, 2002;  Hasim, 2007}  Chemotherapy may also have a role in improvement of 
clinical symptoms in non-surgical patients. {Ciment, 2002}  Much like radiotherapy 
though, only with continuous reporting of empirical case-based data will the role of 
systemic chemotherapy be evaluable in this rare entity. 
Table 1:  Anecdotal reports of Chemotherapy in Ameloblastoma 
Case 
Regimen 
Response 
Reference 
1 
Cyclophosphamide, Methotrexate, 
5-Fluorouracil 
None 
Gall, et al, 1975 
2 
Vinblastine, Cisplatin, Bleomycin 
PR 
Eliasson, et al, 1989 
3 
Adriamycin, Cisplatin, 
Cyclophosphamide 
PR 
Ramadas, et al, 1990 
4 
1st line:  5-Fluorouracil and Cisplatin;     
2nd line:  Paclitaxel-Carboplatin 
PR 
Grünwald, et al, 2001 
5 
Cyclophosphamide 
None 
Campbell, et al, 2003 
6 
Doxorubicin and Cisplatin 
PR 
Amzerin, et al, 2011  
7 
Gemcitabine and Carboplatin 
PR 
Van Dam, et al, 2010 
2.2 Study Agents 
Dabrafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or 
metastatic melanoma with BRAF-V600E mutation as detected by an FDA-approved test.  
Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 
values of 0.65, 0.5, and 1.84 nM for BRAF-V600E, BRAF-V600K, and BRAF-V600D 
enzymes, respectively.   It is manufactured in 50 and 75 mg capsules.   
According to the FDA approved package insert, the safety of dabrafenib has been evaluated 
in 586 patients with BRAF-mutant melanoma, including 181 patients treated for at least 6 
months and 86 additional patients for 12 months.  The most commonly occurring adverse 
reactions in these patients treated with dabrafenib  were, in order of decreasing frequency 
hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar 
erythrodysesthesia syndrome (PPES).  The most frequent adverse reactions leading to dose 
reduction of dabrafenib were pyrexia (9%);  PPES (3%);  chills (3%);  fatigue (2%);  and 
headache (2%). 
Dabrafenib has been demonstrated to induce response rates of 52% with a duration median 
of 5.6 months, in patients with BRAF-mutant melanoma.  There are presently no safety or 
efficacy data for dabrafenib in patients with BRAF-mutant ameloblastoma.  Dabrafenib is 
not FDA approved for treatment of patients with ameloblastoma, therefore conduct of this 
study will be under either an IND or FDA authorized IND exemption.  
Trametinib is a kinase inhibitor of MEK1 and MEK2 FDA-approved for use in patients 
with metastatic V600E mutated melanoma based upon a randomized control trial (RCT) of 
trametinib vs chemotherapy in which PFS (4.8 vs 1.5 mo) and RR (22% vs 8%) were 


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higher in patients treated with trametinib. {Flaherty, 2012}  In January 2014, the 
combination of dabrafenib and trametinib was approved  for the treatment of patients with 
BRAF-V600E mutant melanoma.  This approval was based upon a RCT which 
demonstrated an improvement in survival in the combination (25.1 mo median OS 
) vs dabrafenib alone (18.7 mo median OS) with corresponding response rates of 
69 vs 53% respectively. {Long, 2015}  Treatment-related adverse events occurred in 181 
(87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients 
in the dabrafenib only group;  the most common was fever (108 patients, 52%) in the 
dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib 
only group.  Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib 
and trametinib group and 66 (31%) patients in the dabrafenib only group.  Another RCT 
compared the combination of dabrafenib and trametinib vs vemurafenib, another  TKI 
active against V600E mutant melanoma. {Robert, 2015}  In that trial, the combination 
demonstrated improved PFS (11.4 vs 7.3 months), with similar AE and drug 
discontinuance rates. 
Therefore, it appears that in melanoma with BRAF-V600E mutations, the combination is 
active and provides clinical benefit.  More recently, this combination has also been shown 
to be active in other cancers with this BRAF mutation. {Williams, 2015;  Brastianos, 2016;  
Escandell, 2015}  Most relevant is a report of a dramatic  response in a patient with 
BRAF-mutant ameloblastoma. {Kaye, 2015}  Earlier this year we treated an 
ameloblastoma patient who declined major surgical resection off-label with single agent 
dabrafenib.  After 2 months of treatment the patient decided to have the resection.  We 
observed massive amounts of tumor necrosis in the specimen, a finding very atypical for 
untreated ameloblastoma (report accepted for publication, Oral Surgery, Oral Medicine, 
Oral Pathology, Oral Radiology, 14 December 2015). 
2.3 Rationale 
Present accepted standard of care treatment for patients with ameloblastoma is limited to 
surgical resection and reconstruction.  These operations for patients with advanced disease 
are morbid and disfiguring.  There is no defined role for radiation or chemotherapy 
treatment for ameloblastoma patients at any stage. 
Based on the recent discovery of potentially relevant BRAF mutations in ameloblastoma 
and preclinical data which suggest that BRAF-mutant ameloblastoma may respond to 
relevant mutant BRAF tyrosine kinase inhibition, we propose to ask in a pilot trial whether 
there is any evidence of anti- tumor activity against ameloblastoma in patients with 
advanced disease.  Because of robust data with combined BRAF and MEK inhibition in 
BRAF-mutant melanoma, we plan to use  dabrafenib and trametinib in combination.  
Novartis has agreed to supply both agents for this investigator-initiated study.  Because 
most patients with advanced disease have significant mandibular bone involvement but do 
not have metastatic disease, we are proposing a trial which will focus on this group of 
patients.  This allows us to ask in a preliminary way whether there is clinical, pathological, 
or microbiological evidence of anti-cancer activity of a relevant TKI, dabrafenib in 
combination with a MEK inhibitor, trametinib, in this situation.  The design of the trial will 
facilitate collection of tissue at baseline and after 6 weeks of treatment to allow for 
assessment of the pathological and microbiological endpoints, but will also not unduly 
delay attempts at definitive surgical treatment for appropriate patients.   


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2.4 Study Design 
This will be a single-group, single-arm, 2-stage, open non-randomized treatment study 
whose primary endpoint is tumor response rate with feasibility, safety, pathological and 
molecular biological secondary endpoints.   
2.5 Correlative Studies Background 
Activation of the Ras/Raf/MAPK signaling pathway begins with the binding of ligands to 
receptor-linked tyrosine kinases, such as epidermal growth factor receptor or fibroblast 
growth factor receptor.  This leads to phosphorylation of tyrosine residues on the receptor 
that then recruits adaptor proteins (eg, GRB2 and SOS).  This protein complex allows SOS 
to switch to an activated state that in turn leads to activation of Ras proteins by binding 
GTP.  This turns on the activity of Raf serine/threonine kinases, including B-Raf (BRAF).  
The signaling transduction cascade then continues with the phosphorylation and activation 
of MEK1 and MEK2 tyrosine/threonine kinases.  Through phosphorylation, the MEKs 
activate the Erk MAPKs which regulate transcriptional factors that influence 
differentiation, senescence, survival, and proliferation. 
Mutations in the Ras/Raf/MAPK pathway are essential in a number of cancers including 
the majority of melanomas with ~50% exhibiting BRAF mutations and ~ 20% exhibiting 
NRAS mutations.  In melanoma, these mutations appear at an early stage in tumorigenesis, 
including precursor lesions like benign nevi, and are preserved through progression.  These 
are activating mutations which result in the Ras/Raf/MAPK pathway constitutively 
signaling for proliferation and survival.  Inhibition of this pathway in tumors with BRAF 
mutations turns off this pathway and shuts down essential survival pathways resulting in 
cell death.  BRAF inhibitor (dabrafenib;  formerly GSK2118436) showed promising results 
with an approximately 2-fold increase in progression-free survival in a phase III trial, 
which is in a similar range as that of vemurafenib. {Hauschild, 2012}  
Recent studies on ameloblastoma have found BRAF-V600E mutations to be present in the 
majority of cases arising in the mandible.  Two studies have demonstrated that cell lines of 
ameloblastoma are responsive to V600E targeted small molecule inhibitors in cell 
proliferation assays.   
Two main histologic assays for treatment response will be used:  tumor necrosis and 
phosphorylated-MEK, phosphorylated-ERK, and Ki-67 levels as measured by 
immunohistochemistry.  As mentioned above, since the activation of the Ras/Raf/MAPK 
pathway promotes cell proliferation and survival, blockade of this pathway will result in 
cell decrease in proliferation, death and necrosis.  Furthermore, activation of the 
Ras/Raf/MAPK pathway leads to phosphorylation of several of the pathway components, 
including MEK and ERK.  These assays for treatment response thus examine both early 
and late effects of Ras/Raf/MAPK pathway inhibition. 
Routine Hemotoxylin-Eosin stained slides from both the pre-treatment biopsy as well as 
definitive resection specimens will be scored for the presence of tumor necrosis, which will 
be quantified.  Additionally, unstained slides from both pre- and post- specimens from 
participating institutions will be sent to Stanford University for analysis of 
phospho-MEK/ERK and Ki-67 staining.  Tumors will be scored, by at least two 
pathologists using percentage positive cells as the primary metric.  The results of the 


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immunohistochemical analysis will be expressed as both raw data in addition to a ratio 
between pre- and post- treatment 
We will also be consenting patients  for permission to sequence the genome of their tumor, 
to publish in public databases anonymized sequence data and to attempt to establich cell 
cultures of tumor specimens if there is sufficient material to do so.  These studies are 
exploratory and will only be done should there be sufficient specimen from the planned 
biopsies remaining after  the  tumor material for tumor necrosis and phosphorylation assays 
has been obtained.  
3.0 PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
In order to reduce redundancy, we have incorporated the actual eligibility checklist into the 
body of the protocol.  
3.1 Participant Eligibility Checklist  
A Participant Eligibility Checklist must be completed in its entirety for each subject prior 
to registration.  The completed, signed, and dated checklist must be retained in the patient’s 
study file and the study’s Regulatory Binder.  
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records.  A description 
of the eligibility verification process should be included in the EPIC or other Electronic 
Medical Record progress note or a signed version of the eligibility checklist must be 
available in EPIC or other Electronic Medical Record for review.  
 


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Eligibility criteria in checklist form 
I:  Trial information 
Protocol Title: 
A pilot study of dabrafenib and  trametinib for patients with 
BRAF-mutated ameloblastoma. 
Protocol Number: 
IRB-32275 / ENT0043 
Principal Investigator: 
A Dimitrios Colevas 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria 
Inclusion Criteria 
Yes 
No 
Supporting documents 
1. Histological diagnosis of ameloblastoma.  All 
stages are eligible.  Patients must have evaluable 
disease by RECIST criteria 
 
 
      
2. BRAF-V600E or other known dabrafenib 
sensitive BRAF mutation in tumor by any 
CLIA-certified lab.  May include, for example, 
Sanger sequencing, SNaPshot platform, 
immunohistochemistry, Foundation One tests, etc) 
 
 
      
3. At least 18 years old  
 
 
      
4. Life expectancy > 3 months 
 
 
      
5. ECOG performance status ≤ 2 (see Appendix C)  
 
 
      


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6. Lab values: 
 ANC > 1.5 x 109/L 
 PLT > 99 x 109/L 
 Hemoglobin > 8 g/dL 
 Tbili < 1.6 x ULN  
o Except subjects with known Gilbert’s 
syndrome 
 AST, ALT and alk phos < 2.6 x upper limit of 
normal (ULN) 
 Serum creatinine ≤ 1.5 mg/dL, or if serum 
creatinine is > 1.5 mg/dL, creatinine 
clearance must be  50 mL/min (calculate 
creatinine clearance using the Cockcroft-Gault 
formula (see Appendix D).  
 
PR / INR and PTT ≤ 1.3 X ULN.  Subjects 
receiving anticoagulation treatment may be 
allowed to participate with INR established 
within the therapeutic range prior to 
randomization 
 
 
 
 
 
      
7. Ability to understand and the willingness to sign a 
written informed consent document 
 
 
      
8. Patients of childbearing potential must agree to 
use effective contraception until at least 6 months 
after treatment with dabrafenib and trametinib.  
See exclusion criteria re pregnancy testing 
 
 
      
9. Able to swallow and retain oral medication and 
must not have any clinically significant 
gastrointestinal abnormalities that may alter 
absorption such as malabsorption syndrome or 
major resection of the stomach or bowels   
 
 
      
10. Left ventricular ejection fraction equal to or 
greater than normal within 1 month of enrollment.  
ECHO scans must be used throughout the study.  
 
 
 
Exclusion Criteria 
 
1. No prior  treatment with agents targeting 
BRAF-mutant tyrosine kinases or MEK inhibitors 
or radiation of target lesions 
 
 
      


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2. Invasive malignancy other than ameloblastoma 
within 3 years,  excluding curatively treated basal 
cell carcinoma, and other highly curable cancers 
such as  early stage cutaneous squamous cell 
carcinoma (T1 NO) cervical CIS, early stage 
prostate cancer, thyroid cancer, breast cancer or 
history of malignancy with confirmed activating 
RAS mutation at any time 
 
 
      
3. Uncontrolled hypertension (systolic blood 
pressure > 140 mm Hg and diastolic blood 
pressure of > 90 mm Hg which cannot be 
controlled by anti-hypertensive therapy), CHF, or 
other major medical illness. 
 
 
      
4. Prior allergic reactions attributed to compounds of 
similar chemical or biologic composition to 
dabrafenib or trametinib. 
 
 
      
5. Concomitant use of strong inhibitors 
(eg, ketoconazole, nefazodone, clarithromycin, 
gemfibrozil) or strong inducers (eg, rifampin,  
phenytoin, carbamazepine, phenobarbital, St 
John’s wort) of CYP3A4 or CYP2C8 .  For a full 
list of  excluded drugs see Section 4.1.2 of the 
protocol 
 
 
      
6. Concomitant use of proton pump inhibitors, 
H2-receptor antagonists, antacids 
 
 
      
7. Known G6PD deficiency 
 
 
      
8. Pregnant or nursing patients.  Women of 
childbearing potential must have a negative 
SERUM pregnancy test within 14 days of 
enrollment.  Women of child-bearing potential 
must agree to use effective contraception for 
14 days prior to enrollment, throughout the 
treatment period and for 4 to 6 months after the 
last dose of study treatment. 
 
 
      
9. EKG with QTcB (Bazett’s formula) > 480 ms 
done within 14 days of enrollment 
 
 
      
10. Interstitial lung disease or pneumonitis. 
 
 
      
11. A history of retinal vein occlusion (RVO).   
 
 
      


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12. Congestive heart fauilure NYHA Class III or 
worse (Marked limitation of physical activity.  
Comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, or dyspnea.) 
 
 
      
13. A history of acute coronary syndromes (including 
myocardial infarction or unstable angina), 
coronary angioplasty, or stenting within 6 months 
or a history or evidence of current clinically 
significant uncontrolled arrhythmias or 
intra-cardiac defibrillators or abnormal cardiac 
valve morphology (≥ Grade 2) documented by 
echocardiogram.  Subjects with Grade 1 
abnormalities (ie, mild regurgitations/stenosis) 
may be entered.  Subjects with moderate valvular 
thickening are not eligible. Subjects with atrial 
fibrillation controlled for > 30 days prior to 
dosing are eligible. 
 
 
      
14. Prior systemic anti-cancer treatment 
(chemotherapy, immunotherapy, biologic therapy, 
vaccine therapy or investigational treatment 
within 3 weeks preceding first dose of study 
treatment, or chemotherapy without delayed 
toxicity within 2 weeks preceding first dose of 
study treatment. 
 
 
      
15. Any serious or unstable pre-existing medical 
conditions, psychiatric disorders or other 
conditions which could interfere with the 
subject’s safety, obtaining informed consent, or 
compliance with study procedures. 
 
 
      
16. A history of Hepatitis B virus (HBV) or 
Hepatitis C virus (HCV) infection.  Subjects with 
laboratory evidence of cleared HBV and/or HCV 
will be allowed.   
 
 
      


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V.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute 
Scientific Review Committee, the Stanford IRB, and has finalized financial and contractual 
agreements as required by Stanford School of Medicine’s Research Management Group.   
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 


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3.2 Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any 
study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained in 
the medical record or research file.   
3.3 Study Timeline 
Primary Completion: 
We estimate the study will reach primary completion 27 months from the time the study 
opens to accrual. 
Study Completion: 
The study will reach study completion 36 months from the time the study opens to accrual. 
4.0 TREATMENT PLAN 
All patients will have  a diagnosis of ameloblastoma  pathologically confirmed  by the 
participating institution’s department of pathology.  The mutational status of BRAF in the 
tumor must be determined  by any CLIA-certified lab using standard techniques .  These 
may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, 
Foundation One tests, etc.).  While we are primarily expecting  to identify V600 E 
mutations, other BRAF mutations known to confer sensitivity to  dabrafenib  are acceptable 
if approved by the study principal investigator. 
Every patient must have baseline blood chemistries and counts and other eligibility criteria 
as defined in Section 3 done according to the schedule defined in the study calendar in 
Section 9.  Baseline imaging used to define RECIST v1.1 {Eisenhauer, 2009} 
measurements are at the discretion of the local investigator.  These will typically be either a 
contrast  enhanced CT or MRI of the relevant anatomy, but PET-CT is also appropriate if 
the  lesion is evaluable by PET-CT per RECIST v1.1 criteria.  To maintain consistency of 
data and quality of science, whatever imaging modality is used at baseline for each patient 
should be used throughout the trial.  Photographic documentation is encouraged but cannot 
substitute for imaging. 
The starting dose for all patients will be:   
Dabrafenib, 150 mg orally twice daily taken at least 1 hour before or at least 2 hours 
after a meal.  Dabrafenib comes as 75 mg and 50 mg capsules.  Therefore the initial dose 
will be two 75 mg capsules as specified above.  The second dose of dabrafenib (150 mg) 
should be administered approximately 12 hours after the morning dose.  
Trametinib 2 mg once daily.  
Take the once-daily dose of trametinib at approximately the same time each day with either 
the morning dose or the evening dose of dabrafenib.  Study medications should be taken 
orally with approximately 200 mL of water under fasting conditions, either 1 hour before 
or 2 hours after a meal.  


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If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled.  
If administration of trametinib is interrupted or permanently discontinued, administration of 
dabrafenib may be continued.  If administration of dabrafenib is interrupted or permanently 
discontinued, administration of trametinib may continue.  
If a subject misses a dose of dabrafenib, the subject may take the dose immediately if the 
next dose is scheduled for at least 6 hours later.  If the next scheduled dose of dabrafenib is 
due in less than 6 hours, the subject should skip the dose and resume dabrafenib dosing at 
the next scheduled dose.  If a subject misses a dose of trametinib, the subject may take the 
dose immediately if the next dose is scheduled for at least 12 hours later.  
Patients whose tumors are amenable to surgical resection will continue dosing continuously 
for at least 6 weeks  and proceed to surgery between weeks 6 and 7, without dose 
interruption.  Patients undergoing surgical resection will continue dabrafenib and 
trametinib until it is necessary to take nothing by mouth  in the hours preceding surgery, 
but ideally the patients will be dosed with dabrafenib and trametinib within 12 hours 
of the surgical resection.   Patients whose tumors are grossly completely resected will not 
resume dabrafenib and trametinib.  Patients whose tumors are not resected  completely 
have the option to resume the dabrafenib and trametinib at the dose they were receiving 
immediately prior to surgery  if  ALL of the following criteria  are met:  
1. Prior to surgery the patient  did not have AEs or progression which necessitated  
dabrafenib or trametinib cessation.  
2. The patient has recovered from surgery without unexpected complication.  
3. At least 1 week has passed since surgery.  
4. The patient has evaluable residual tumor.  
5. No more than 6 weeks has elapsed since surgery.  
Patients whose disease is judged to be not amenable to resection will continue dabrafenib 
and trametinib indefinitely as long as there has not been tumor progression either by 
RECIST v1.1 or clinical progression criteria, there have not been unacceptable adverse 
events and  the patient has not decided to discontinue for other reasons.  
Clinical evaluations  for protocol purposes will take place according to the schedule 
defined in Section 9.  Dose modifications will be according to the guidelines in Section 6.  
4.1 General Concomitant Medication and Supportive Care Guidelines 
4.1.1 
Permitted Medications and Non-Drug Therapies 
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of investigational drug administration.  Documentation of  
concomitant medication(s), including dietary supplements, taken during the study will be 
recorded in the  patient medical record according to the schedule specified in  Section 9.  
The minimum requirement is that drug name, dose, and the dates of administration are to 
be recorded.  
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 


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guidelines.  Use of anticoagulants such as warfarin is permitted however, caution should 
be exercised and additional International Normalized Ratio (INR) monitoring is 
recommended when dabrafenib is used concomitantly with warfarin.  See Section 4.1.3 for 
guidelines concerning concomitant warfarin and dabrafenib administration. 
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation.  It 
is recommended that dabrafenib and trametinib be held for 7  days before and 2 days after 
XRT.  
Medicinal products that increase gastric pH should be used with caution when 
administered with dabrafenib.  See Section 4.1.3 for details.  
4.1.2 
Prohibited Medications and Non-Drug Therapies  
The use of certain medications  (see Table 2 below) and illicit drugs within 28 days or 
5 half-lives, whichever is shorter, prior to and during  dabrafenib study treatment. will not 
be allowed.  
The following medications or non-drug therapies are prohibited while on treatment in this 
study:  
 Other anti-cancer therapies;  
 Other investigational drugs;  
 Herbal remedies (eg, St John’s wort);  
 Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4.  
Co-administration of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or with 
gemfibrozil, a CYP2C8 inhibitor, resulted in increases in dabrafenib AUC of 71% and 
47%, respectively.  Drugs that are strong inhibitors or inducers of CYP3A and CYP2C8 
(see list in the table below) may only be used under special circumstances (e.g.  as a 
single use for a procedure) while treatment with study drug is interrupted as they may 
alter dabrafenib concentrations;  consider therapeutic substitutions for these 
medications.  Approval of the protocol principal investigator is required and must 
be documented in these situations.  


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Table 2 :  Prohibited Medications 
PROHIBITED – Strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib 
may be decreased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Rifamycin class agents (eg, rifampin, rifabutin, rifapentine),  
Anticonvulsant 
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, 
s-mephenytoin  
Miscellaneous 
bosentan, St-John’s wort 
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib 
may be increased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Clarithromycin, telithromycin, troleandomycin 
Antidepressant 
Nefazodone 
Antifungals 
Itraconazole, ketoconazole, posaconazole, voriconazole 
Hyperlipidemia 
Gemfibrozil  
Antiretroviral 
ritonavir, saquinavir, atazanavir 
Miscellaneous 
Conivaptan  
 
4.1.3 
Medications to be used with Caution 
The following medications should be used with caution as their concentrations may be 
altered by dabrafenib or they may alter dabrafenib concentrations: 
 Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may 
alter concentrations of dabrafenib. 
 Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using midazolam 
(CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  Dabrafenib is an in vitro 
inducer of CYP2B6 and other enzymes such as CYP2C8, CYP2C19, UDP-glucuronyl 
transferases.  Transporters may also be affected.  Co-administration of dabrafenib and 
medications which are affected by the induction of these enzymes (including warfarin) 
and transporters 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.  A partial list of these medications is 
provided in Table 2 above.   
 Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by 
the site.  Warfarin exposure has been shown to decrease (37% decrease) due to 
dabrafenib-mediated enzyme induction.  Conversely, if dabrafenib dosing is reduced, 
interrupted, or discontinued, warfarin exposure may be increased.  Thus, warfarin 
dosing may need to be adjusted based on PT/INR during and after treatment with 
dabrafenib.  Prophylactic low dose warfarin may be given to maintain central catheter 
patency.   


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  InfromDabrafenib 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 an ad-hoc 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. 
4.2 Criteria for Removal from Study 
Patients should have dabrafenib discontinued for unacceptable adverse events, clinically 
unacceptable or RECIST v1.1 defined progression, or patient withdraws of consent.  For 
patients who stop dabrafenib because of unacceptable AEs or progression of disease, 
providers may proceed to surgical resection as clinically indicated.  Patients who have not 
withdrawn consent to be studied should have all planned restaging  and secondary tissues 
analyses performed per protocol  prior to surgery and  on the surgical specimens resected at 
the time of surgery.  Patients should be followed for protocol related AEs for 4 weeks after 
the last dabrafenib dose unless another systemic anti- cancer agent has been initiated. 
5.0 STUDY AGENT INFORMATION 
5.1 Study Agents  
Dabrafenib is a kinase inhibitor FDA approved for the treatment of patients with 
unresectable or metastatic melanoma with BRAF-V600E mutation as detected by an 
FDA-approved test.  It comes  in 50 mg and 75 mg capsules.  Active ingredient:  
dabrafenib.  Inactive ingredients:  colloidal silicon dioxide, magnesium stearate, 
microcrystalline cellulose.  Capsule shells contain:  hypromellose, red iron oxide (E172), 
titanium dioxide (E171). 
Trametinib is a FDA-approved kinase inhibitor for the treatment of patients with 
unresectable or metastatic melanoma with BRAF-V600E or -V600K mutations as detected 
by an FDA-approved test.  Tablets are supplied as 0.5 mg and 2 mg tablets for oral 
administration.  Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide 
equivalent to 0.5 mg of trametinib non-solvated parent.  Each 2 mg tablet contains 
2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated 
parent.  The inactive ingredients are tablet core:  mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (vegetable source), sodium 
lauryl sulfate, colloidal silicon dioxide;  and coating:  hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80 (2 mg tablets), iron oxide yellow (0.5 mg tablets), iron 
oxide red (2 mg tablets). 
Dabrafenib and trametinib will be dosed as specified in Section 4 of this protocol, with 
dose modifications in Section 6. 


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5.2 Availability 
Dabrafenib and trametinib will be obtained  from Novartis and distributed to all 
investigational sites according to  a pharmacy appendix to be developed prior to protocol 
activation. 
5.3 Agent Ordering 
Dabrafenib and trametinib will be ordered by site investigational pharmacies according to  
guidelines to be developed prior to protocol activation and included in the pharmacy 
appendix section.   
5.4 Agent Accountability 
Access to dabrafenib and trametinib will be restricted according to the standard operating 
procedures of the investigational pharmacies of each collaborating institution’s pharmacy.  
Drug accountability will similarly be according to each institution’s standard operating 
procedures. 
5.5 Combination Dosage and Administration and Handling and Storage Guidelines 
Dabrafenib and trametinib must be dispensed and administered in accordance with the 
protocol, and only to subjects enrolled in the study.  Dabrafenib and trametinib must be 
stored in a secure area under the appropriate physical conditions for the product.  Study 
medication is to be stored at the temperature specified on the label.  Maintenance of a 
temperature log (manual or automated) is required.  Access to and administration of 
dabrafenib and trametinib will be limited to the investigator and authorized site staff.   
6.0 DOSE MODIFICATIONS 
6.1 Dose Modification for General Toxicities 
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and for which specific 
guidelines do not apply are provided in the table below.  These guidelines are intended 
primarily for toxicities not easily managed with routine supportive care.  For example, 
alopecia is not an indication for dose modification, nor is grade 2 nausea and vomiting that 
can be easily managed with anti-emetics.   
Table 3:  Recommended dabrafenib and trametinib dose level reductions 
DABRAFENIB 
TRAMETINIB 
Dose Level 
Dose/Schedule 
Dose Level 
Dose/Schedule 
Full dose 
150 mg twice daily 
Full dose 
2 mg once daily 
First reduction 
100 mg twice daily 
First reduction 
1.5 mg once daily 
Second reduction 
75 mg twice daily 
Second reduction 
1 mg once daily 
Third reduction 
50 mg twice daily 
Third reduction 
0.5 mg once daily 


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Table 4:  Dose Modification Guidelines - General 
CTCAE Grade 
Occurance 
Action and Dose Modification a,b 
Grade 1 or 
Grade 2 
(tolerable) 
N/A 
Continue study treatment at same dose level (no dose 
modification) and monitor as clinically indicated 
Grade 2 
(Intolerable) or  
Grade 3 
1st, 2nd or 
3rdoccurrence 
Interrupt study treatment until toxicity resolves to ≤ grade 1 
then restart at next lower dose level 
4th or greater 
occurrence  
Discontinue treatment 
Grade 4 
1st occurrence 
Interrupt study treatment until toxicity resolves to ≤ grade 1 
or baseline then restart at next lower dose level or 
discontinue at discretion of investigator 
2nd occurrence 
Interrupt study treatment until toxicity resolves to ≤ grade 1 
or baseline then restart at two dose levels lower than the 
starting dose or discontinue at discretion of investigator and 
after discussion with the medical monitor. 
3rd occurrence 
Discontinue treatment 
a. 
Treatment should be discontinued if more than 3 dose reductions are required 
b. Approval from the protocol PI is required to restart study treatment after  ≥ 21 days  
When an individual’s adverse reactions are under effective management, dose re-escalation 
following the same dosing steps as de-escalation may be considered.  
These are general guidelines and investigators should always use clinical judgment in 
determining dose adjustments for any individual patient.  Some toxicities may require 
hospitalization for stabilization, additional work-up, and consultation with a specialist 
before treatment can be restarted.  Specific adverse events and recommended management 
include the following:  
6.2  
Dose reductions for AEs of interest in patients taking dabrafenib and trametinib 
6.2.1 Plantar- Palmar Erythrodysesthesia (Hand foot syndrome, PPES) – Measures for 
PPES should include:  
Lifestyle modification:  avoidance of hot water;  traumatic activity;  constrictive 
footwear;  or excessive friction on the skin.  Adopt the use of thick cotton socks and 
gloves, and shoes with padded insoles.  
Symptomatic treatments:  apply moisturizing creams frequently;  topical keratolytics 
(eg, urea 20 to 40% cream;  salicylic acid 6%;  tazarotene 0.1% cream;  
fluorouracil 5% cream), clobetasol propionate 0.05% ointment for erythematous areas;  
topical lidocaine 2%;  and/or systemic pain medication such as nonsteroidal 
anti-inflammatory drugs (NSAIDs);  codeine;  and pregabalin for pain.  
Dose modification may also be required.  


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6.2.2 Pancreatitis   
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory 
samples should be collected for confirmation of the diagnosis.  Patients should be 
closely monitored when re-starting dabrafenib after an episode of pancreatitis. 
6.2.3 Uveitis and ocular events (see below for specific guidelines) 
Ophthalmological exams will be required at baseline, Week 6 and annually thereafter.  
Episodes of visual changes have been observed in subjects receiving trametinib, 
dabrafenib, and combination therapy.  An ophthalmologist should be consulted if 
changes in vision develop.  However, if the visual changes are clearly unrelated to study 
treatment (eg, allergic conjunctivitis), then monitor closely as it may be reasonable to 
defer ophthalmic examination. 
Treatment with dabrafenib has been associated with the development of uveitis, 
including iritis.  Monitor patients for visual signs and symptoms (such as, change in 
vision, photophobia and eye pain) during therapy.  Special attention should be given to 
retinal findings (eg, retinal pigment epithelial detachment (RPED) or retinovascular 
abnormalities (ie, branch or central retinal vein occlusions (RVO).  Guidelines regarding 
management and dose reduction for visual changes and/or ophthalmic examination 
findings considered to be related to study treatment are provided in the below tables: 


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Table 5:  Management and Dose Modification Guidelines for Visual Changes and/or 
Ophthalmologic Examination Findings 
CTCAE 
Grade a 
Adverse Event Management 
Action and Dose Modification 
  
Grade 1 b 
 
Consult ophthalmologist 
within 7 days of onset 
 
 
If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be 
excluded by retina specialist/ophthalmologist.  If 
subject is receiving trametinib/dabrafenib 
combination therapy dabrafenib may be 
continued 
 
If RPED and RVO excluded, continue (or 
restart) trametinib at same dose level 
 
If RPED suspected or diagnosed:  see RPED 
dose modification table Y below;  report as 
SAE if diagnosed 
 
If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE 
 
 Grade 2 and 
 Grade 3 
 
Consult ophthalmologist 
immediately 
 
Interrupt trametinib.  If 
subject is receiving 
trametinib/dabrafenib 
combination therapy 
dabrafenib may be continued 
 
If RPED and RVO excluded, restart trametinib at 
same dose level 
 
If RPED diagnosed, see RPED dose 
modification table below;  report as SAE 
 
If RVO diagnosed:  Permanently discontinue 
trametinib  and report as SAE 
  
Grade 4 
 
Consult ophthalmologist 
immediately  
 
Interrupt trametinib.  If 
subject is receiving 
trametinib/dabrafenib 
combination therapy 
dabrafenib may be continued  
 
If RPED and RVO excluded, may consider 
restarting trametinib at same or reduced dose 
after discussion with study medical monitor  
 
If RVO or RPED diagnosed, permanently 
discontinue trametinib and report as SAE 
c. 
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’ 
d. If visual changes are clearly unrelated to study treatment (eg, allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 


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Table 6:  Recommended dose modifications for trametinib for retinal pigment epithelial 
detachments (RPED) 
CTCAE Grade a 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic;  clinical 
or diagnostic observations only) 
 
Continue treatment with retinal evaluation monthly 
until resolution.  If RPED worsens follow instructions 
below  
 
Grade 2-3 RPED (Symptomatic with 
mild to moderate decrease in visual acuity;  
limiting instrumental ADL) 
 
 
Interrupt trametinib  
 
Retinal evaluation monthly  
 
If improved to ≤ Grade 1, restart trametinib at lower 
dose (reduced by 0.5 mg) or discontinue in patients 
taking trametinib 1 mg daily 
e. 
Refers to CTCAE Version 4.0 ‘Retinopathy’ 
6.2.4 Hyperglycemia 
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral therapy 
can occur with dabrafenib.  Monitor serum glucose levels as clinically appropriate during 
treatment with dabrafenib in subjects with pre-existing diabetes or hyperglycemia.  
Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or 
any increase in the volume or frequency of urination. 
Investigators should always err on the side of caution in these settings if treatment-related 
toxicity is a possibility.  
6.2.5 Pyrexia 
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy, 
and is increased in incidence and severity in subjects receiving dabrafenib in combination 
with trametinib.  In a minority of cases the pyrexia was accompanied by symptoms such 
as severe chills;  dehydration;  hypotension;  and dizziness or weakness.  
Subjects should be instructed on the importance of immediately reporting febrile 
episodes.  In the event of a fever, the subject should be instructed to take anti-pyretics 
(eg, ibuprofen or acetaminophen) as appropriate to control fever.  The use of oral 
corticosteroids should be considered in those instances in which anti-pyretics are 
insufficient.  Monitor serum creatinine and other evidence of renal function during and 
following severe events of pyrexia.  
Guidelines regarding management and dose modifications for pyrexia considered to 
be related to study treatment provided below.  


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Table 7:  Management and Dose Modification Guidelines for Pyrexia  
Adverse 
Event 
Adverse Event Management 
Action and Dose Modification 
Pyrexia: a 
All Events: 
 
Clinical evaluation for infection and 
hypersensitivity c  
 
Laboratory work-up c 
 
Hydration as required d 
1st Event b: 
 
Administer anti-pyretic treatment  as 
clinically indicated and initiate prophylactic 
treatment if associated with rigors, renal 
failure, dehydration or hypotension e 
2nd Event f 
 
Within 3 days of onset of pyrexia 
o Optimize anti-pyretic therapy 
o Consider oral corticosteroids (ie, 
prednisone 10 mg) for at least 5 days or as 
clinically indicated f 
Subsequent Events:   
 
Within 3 days of onset of pyrexia: 
o Optimize oral corticosteroid dose as 
clinically indicated for recalcitrant 
pyrexia f  
o If corticosteroids have been tapered and 
pyrexia recurs, restart steroids  
o If corticosteroids cannot be tapered consult 
medical monitor 
1st Event:   
 
Interrupt dabrafenib 
 
Continue trametinib 
 
Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level 
o If fever was associated with rigors, renal 
failure, dehydration or hypotension, 
reduce dabrafenib by one dose level g 
2nd Event: 
 
Interrupt dabrafenib 
 
Continue trametinib 
 
Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level 
o If fever was associated with rigors, renal 
failure, dehydration or hypotension, 
reduce dabrafenib by one dose level g 
Subsequent Events: 
 
Interrupt dabrafenib 
 
Continue trametinib 
 
Once pyrexia resolves to baseline, restart 
dabrafenib reduced by one dose level g 
 
If dabrafenib must be reduced to < 50 mg 
BID, permanently  discontinue 
dabrafenib.  Trametinib may be 
continued 
a. Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3ºFahrenheit.   
b. For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and laboratory work-up is 
mandatory for each event;  anti-pyretic treatment should be started immediately at the first occurrence and prophylactic 
anti-pyretic treatment is recommended 
c. Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required;  laboratory work-up 
should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein (CRP), 
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, 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 doses should be gradually increased for subsequent 
events. 
g.   Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, severe chills, etc., 
which cannot be managed by best supportive care and increasing doses of oral steroids.  Escalation of dabrafenib is allowed 
if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction. 


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6.2.6 Malignancies 
Cutaneous squamous cell carcinoma (cuSCC) 
Cases of cuSCC (which include those classified as keratoacanthoma or mixed 
keratoacanthoma subtype) have been observed in subjects treated with dabrafenib.  
Approximately 70 % of events occurred within the first 12 weeks of treatment with a 
median time to onset of 8 weeks.  These should be surgically removed according to 
institutional practices.  Dose modification or interruption of study treatment is not required 
for cuSCC or KA, however cuSCC should be reported as an SAE.  In addition, a biopsy of 
the lesion should be taken, where possible, and a summary of the results submitted to the 
PI.  Patients should be instructed to immediately inform their physician if new lesions 
develop.  Skin examination should be performed prior to initiation of dabrafenib and during 
treatment with dabrafenib, every 2 months throughout therapy.  Monitoring should 
continue every 2 months for 6 months following discontinuation of dabrafenib or until 
initiation of another anti-neoplastic therapy.   
6.2.7 New Primary Melanoma  
New primary melanomas have been reported in patients treated with dabrafenib.  These 
were identified primarily within the first 5 months of therapy and did not require treatment 
modification other than excision.  Monitoring for skin lesions should occur as described for 
cuSCC. 
6.2.8 Non-Cutaneous Malignancies 
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in 
BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors, which may 
lead to increased risk of non-cutaneous malignancies in patients treated with dabrafenib.  
Cases of RAS-driven malignancies have been seen with BRAF inhibitors.  Patients should 
be monitored as clinically appropriate. 
New non-cutaneous malignancies should be reported as a SAE.  A biopsy of the new 
malignancy should be taken, where possible, and submitted for further analyses with the 
results provided to the PI.   
6.2.9  Renal Insufficiency 
Cases of renal insufficiency have occurred in subjects receiving dabrafenib and the 
combination of dabrafenib and trametinib.  Prior to start of study treatment, concomitant 
medications should be reviewed for the potential risk of inducing nephrotoxicity and 
concomitant medications should be modified if clinically possible.  Guidelines regarding 
management and dose reduction for renal insufficiency considered to be related to study 
treatment by the investigator are provided below. 


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Table 8:  Management and Dose Modification Guidelines for Renal Insufficiency 
Serum Creatinine 
Level 
Adverse Event Management 
Action and Dose 
Modification 
Serum creatinine 
increase > 0.2 mg/dL 
(18 umol/L) but 
 0.5 mg/dL 
(44 umol/L) above 
baseline 
 Recheck serum creatinine within 1 week 
 Serum creatinine increase > 1 week:  contact Novartis 
Medical Monitor.  If elevation persists beyond 4 weeks, 
recommend evaluation (consider renal biopsy) for etiology;  
consider nephrology consultation. 
 If pyrexia is present, treat pyrexia as per guidelines a 
 Continue study 
treatment at the 
same dose level 
Serum creatinine 
increase > 0.5 mg/dL 
(44 umol/L) above 
baseline or  
serum creatinine 
>2 mg/dL 
(> 177 umol/L) 
 Monitor serum creatinine ≥ 2 times per week  
 Hospitalization may be necessary  if serum creatinine 
cannot be monitored frequently 
 If pyrexia is present, treat pyrexia per guidelines a  
 Consult nephrologist if clinically indicated 
 Perform renal biopsy if clinically indicated, for example: 
o Renal insufficiency persists despite volume repletion 
o Subject has new rash or signs of hypersensitivity (such as 
elevated eosinophil count) 
 Interrupt study 
treatment until 
serum creatinine 
recovers to 
baseline 
 Restart with study 
treatment b 
a. 
NSAIDs can induce renal insufficiency, especially in subjects with dehydration;  encourage oral fluids or 
consider intravenous fluids as clinically indicated.  See guidelines for pyrexia Section  
b. 
Investigator may restart at either the same or a reduced dose level.  Escalation of study treatment to previous dose 
level is allowed if another episode of renal insufficiency does not occur after 4 weeks of dose reduction.   


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6.2.10 Guidelines for Prolonged QTc 
Guidelines for dose modification and stopping criteria due to QTC-prolongation are below. 
Table 9:  Withholding and Stopping Criteria for QTcB-Prolongation 
QTc-
Prolongation a  
Action and Dose Modification 
 QTcB  
≥ 501 msec  or 
 Uncorrected 
QT > 600 msec  
or 
 
QTcB > 530 
msec for subjects 
with bundle 
branch block 
 Interrupt study treatment until QTcB prolongation resolves to Grade 1 or baseline 
 Test serum potassium, calcium, phosphorus and magnesium.  If abnormal, correct 
per routine clinical practice to within normal limits 
 Review concomitant medication usage for a prolonged QTc 
 If event resolves, restart study treatment at current dose level b 
 If event does not resolve, permanently discontinue study treatments.  Consider 
evaluation with cardiologist. 
 If event recurs, permanently discontinue study treatment 
 Consider evaluation with cardiologist 
Abbreviations:  msec = milliseconds; QTc = QT interval on electrocardiogram  
a. 
Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT 
interval, obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine if study treatments should be interrupted or discontinued. 
b. 
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the 
investigator and Novartis medical monitor agree that the subject will benefit from further treatment 


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6.2.11  Guidelines for Pneumonitis 
Pneumonitis has been observed in subjects receiving trametinib in combination with 
dabrafenib.  To reduce the risk of pneumonitis, subjects will be monitored closely for 
symptoms, evaluated with imaging and functional tests.  Dose modification and supportive 
care guidelines for pneumonitis are described below. 
Table 10:  Management and Dose Modification Guidelines for Pneumonitis 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
 
Grade 1 
 CT scan (high-resolution with lung windows) 
recommended 
 Clinical evaluation and laboratory work-up for 
infection 
 Monitoring of oxygenation via pulse-oximetry 
recommended  
 Consultation of pulmonologist recommended  
 Continue trametinib at current dose 
Grade 2 
 CT scan (high-resolution with lung windows) 
 Clinical evaluation and laboratory work-up for 
infection 
 Consult pulmonologist 
 Pulmonary function tests –if < normal, repeat 
every 8 weeks until ≥ normal 
 Bronchoscopy with biopsy and/or BAL 
recommended 
 Symptomatic therapy including corticosteroids 
if clinically indicated 
 Interrupt trametinib until recovery to 
grade ≤1 
 Restart with  trametinib reduced by one 
dose level 
 Escalation to previous dose level after 
4 weeks and consultation with medical 
monitor possible 
 If no recovery to grade ≤1 within 
4 weeks, permanently discontinue study 
treatment 
Grade 3 
 CT scan (high-resolution with lung windows) 
 Clinical evaluation and laboratory work-up for 
infection 
 Consult pulmonologist 
 Pulmonary function tests-if < normal, repeat 
every 8 weeks until ≥ normal 
 Bronchoscopy with biopsy and/or BAL if 
possible 
 Symptomatic therapy including corticosteroids 
as clinically indicated 
 Interrupt trametinib until recovery to 
grade ≤1 
 After consultation with medical monitor, 
study treatment may be restarted reduced 
by one dose level 
 If no recovery to grade ≤1 within 
4 weeks, permanently discontinue study 
treatment 
Grade 4 
 Same as grade 3 
 Permanently discontinue trametinib  
6.2.12 Guidelines for Cardiomyopathy 
Across clinical trials of trametinib at the recommended dose 11% of patients developed 
evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of  normal 
with an absolute decrease in LVEF ≥ 10% below baseline) and 5% demonstrated a 
decrease in LVEF below institutional lower limits of normal with an absolute decrease in 
LVEF of ≥ 20% below baseline. 


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Assess LVEF  before initiation of trametinib, one month after initiation and then at  
3-month intervals while on treatment.  Withhold treatment if absolute LVEF value 
decreases by 10% from pre-treatment values and is less than the lower limit of normal.  
Permanently discontinue for  symptomatic cardiomyopathy or persistent, asymptomatic 
LVEF dysfunction that does not resolve within 4 weeks 
Table 11:  Combination Dose Modification Guidelines and Stopping Criteria for 
LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
 
Asymptomatic 
 
Absolute decrease of 
> 10% in LVEF 
compared to baseline 
and ejection fraction 
below the institution’s  
LLN 
 
Interrupt trametinib and repeat ECHO within 2 weeks a,b  
 
If the LVEF recovers within 4 weeks (defined as LVEF 
≥ LLN and absolute decrease ≤ 10% compared to baseline)   
 Consult with Novartis medical monitor and request 
approval for re-start 
 If approved, re-start treatment with TMT reduced by 
one dose level 
 
Repeat ECHO at 2, 4, 8, and 12 weeks after re-start, 
continue at intervals of 12 weeks 
 
If  LVEF does not recover within 4 weeks 
    Consult with cardiologist 
 
Permanently discontinue trametinib 
 
Report as SAE 
 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks, or 
until resolution 
Symptomatic c Grade 3:  resting LVEF 
39 to 20% or > 20% 
absolute reduction from 
baseline 
 
Permanently discontinue trametinib 
 
Interrupt dabrafenib d  
 
Report as SAE  
 
Consult with cardiologist 
 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks, or until 
resolution b,d 
Grade 4:  resting 
LVEF < 20% 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower 
limit of normal; LVEF = left ventricular ejection fraction;  
a. 
If ECHO does not show LVEF recovery after 2 weeks, repear ECHO two weeks later. 
b. If recurrent episodes of LVEF reduction occur in subjets receiving DRB monotherapy, consult medical monitor. 
c. 
Symptoms may include:  dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and edema. 
d. 
Once LVEF recovers, including resolution of symptoms, restart of dabrafenib monotherapy only can be considered 
in consultation with Novartis medical monitor. 


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6.2.13 Treatment of Study Treatment Overdose 
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a 
single dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a 
trametinib overdose, defined as administration of more than 3.0 mg once daily the 
investigator should closely monitor the subject for AEs/SAEs and laboratory abnormalities.  
The investigator will use clinical judgment to treat any overdose.  Hemodialysis is not 
expected to enhance the elimination of either dabrafenib or trametinib as both are highly 
bound to plasma proteins. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the PI based on the clinical evaluation of the subject. 
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the case report  forms. 
7 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
7.1.1 Dabrafenib potential  adverse effects 
Please see the FDA package insert for dabrafenib.  Additional information can also be 
found in the Investigator Brochure section titled “Summary of Data and Guidance for the 
Investigator.”  Below are tables from the 2015 package summarizing anticipated AEs: 


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Table 12:  Selected Common Adverse Reactions Occurring in > 10% (All Grades) or ≥ 2% 
Grades 3 or 4) of Patients Treated with dabrafenib N = 187 
 
 
Table 13: Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a 
Higher Incidence in Patients Treated with dabrafenib (Tafinlar) in a single agent melanoma 
trial [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)]a 


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Other clinically important adverse reactions observed in < 10% of patients (N = 586) 
treated with dabrafenib were: 
 Gastrointestinal Disorders:  Pancreatitis.   
 Immune System Disorders:  Hypersensitivity manifesting as bullous rash 
 Renal and Urinary Disorders:  Interstitial nephritis. 


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Table 14: Select Adverse Reactions Occurring in ≥10% (All Grades) of 
Patients Treated with dabrafenib( tafinlar)  in Combination with Trametinib 
 


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Table 15: Select Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All 
Grades) of Patients Receiving dabrafenib (Tafinlar) in combination with trametinib. 
 
7.1.2 Trametinib potential adverse effects 
Please see the FDA package insert for trametinib.  Additional information can also be 
found in the Investigator Brochure section titled “Summary of Data and Guidance for the 
Investigator”.  Below are tables from the 2015 package insert summarizing anticipated AEs 


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Table 16:  Selected Adverse Reactions Occurring in ≥10% of Patients Receiving 
trametinib (Mekinist) and at a Higher Incidence (≥ 5%) than in the Chemotherapy 
Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions 
 
 
Other clinically important adverse reactions observed in less than or equal to 10% of patients 
(N = 329) treated with Mekinist (trametinib) were:  
Cardiac Disorders: Bradycardia  
Gastrointestinal Disorders: Dry mouth  
Infections and Infestations: Folliculitis, rash pustular, cellulitis  
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis  
Nervous System Disorders: Dizziness, dysgeusia  
Ocular Disorders: Blurred vision, dry eye  


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Table 17:  Percent-Patient Incidence of Laboratory Abnormalities Occurring at  
a Higher Incidence in Patients Treated With trametinib (Mekinist) in Trial 1  
[Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4) a] 
 


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Table 18: Incidence of Adverse Reactions Occurring in ≥10% (All Grades) of Patients 
Receiving trametinib (MEKINIST_ with Dabrafenib and at a Higher Incidence* than in 
Patients Receiving Single-Agent Dabrafenib 
 
Other clinically important adverse reactions for trametinib observed in less than 10% of patients 
receiving trametinib in combination with dabrafenib (N = 559) were:  
Cardiac Disorders: Bradycardia  
Musculoskeletal Disorders: Rhabdomyolysis 


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Table 19:  Treatment-Emergent Laboratory Abnormalities Occurring at ≥ 10% (All Grades) of 
Patients Receiving trametinib (Mekinsit) with Dabrafenib and at a Higher Incidence* than in 
Patients Receiving Single-Agent Dabrafenib 
 
7.2    Adverse Event Reporting 
For detailed guidance on reporting adverse events, refer to the adverse event SOP 
(Appendix B) 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided the main informed consent and until at least 30 days after the patient 
has stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 


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Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment.  Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information.  
An SAE occurring at a different time interval or otherwise considered completely unrelated 
to a previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report.  The investigator must assess and record the relationship of each SAE to 
each specific study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and send the completed, signed form by fax within 24 hours to the 
oncology Novartis Drug Safety and Epidemiology (DS&E) department - Fax: 
(877-778-9739).  The original copy of the SAE Report Form and the fax confirmation sheet 
must be kept with the case report form documentation at the study site.  Follow-up 
information is sent to the same contact(s) to whom the original SAE Report Form was sent, 
using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report.  Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless 
of when it occurs.  The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, an 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently 
require further information from the investigator for Health Authority reporting.  Novartis 
may need to issue an Investigator Notification (IN), to inform all investigators involved in 
any study with the same drug that this SAE has been reported.  Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as 
per national regulatory requirements in participating countries. 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence.  The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E).  
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment any pregnancy outcome.  Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific 
Case Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each 


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Adverse Event (AE) to determine whether it is unexpected according to Section 7.1 of the 
protocol and related to dabrafenib and trametinib.   
SAEs and all subsequent follow-up reports will be reported to the CCTO Safety Office 
regardless of the event’s relatedness to the investigation.  Following review by the CCTO 
Safety Officers, any events meeting the IRB definition of “Unanticipated Problem” will be 
reported to the IRB using eProtocol within 10 working days of the review, or within 5 
working days for deaths or life-threatening experiences.  SAEs will be relayed back to 
Novartis. 
7.2.1 SAE definitions 
Serious adverse event (SAE) is defined as one of the following: 
 Is fatal or life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Is medically significant, ie, defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 Requires inpatient hospitalization or prolongation of existing hospitalization,  
Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
7.3 Pregnancy 
Pregnancy Testing and Prevention 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
A female of non-childbearing potential (ie, physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy), bilateral tubal ligation or tubal occlusion, or is post-menopausal.   
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, eg, age appropriate, > 45 years in the absence of hormone-replacement 
therapy (HRT).  In questionable cases, the subject must have a follicle-stimulating 
hormone (FSH) value > 40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L). 


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A female of child-bearing potential is defined as any female who does not meet the criteria 
of non-childbearing potential as described in the previous paragraph.   
If a female subject is of childbearing potential, she must have a serum β-human chorionic 
gonadotropin (HCG) pregnancy test performed within 14 days prior to randomization.  
Subjects with a positive pregnancy test result must be excluded from the study.  Subjects 
with a negative pregnancy test result must agree to use an effective contraception method 
as described below throughout study treatment and until 4 months after the last dose of 
study treatment. 
Novartis acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows: 
 An intrauterine device with a documented failure rate of less than 1% per year. 
 Male partner sterilization prior to the female subject’s entry, and this male is the sole 
sexual partner for that female. 
 Complete abstinence from sexual intercourse for 14 days prior to enrollment, 
throughout study treatment, and for at least 4 months after the last dose of study 
treatment. Abstinence is only acceptable when in line with the preferred and usual 
lifestyle of the subject.  Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods, etc) and withdrawal are not acceptable 
methods of contraception. 
 Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). 
Note:  Hormonal-based methods (eg, oral contraceptives) are not permitted as 
contraception due to potential drug-drug interactions with dabrafenib.   
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for 4 months 
following the last dose of study treatment. 
If a subject becomes pregnant during the treatment period of the study, the study treatments 
should be stopped immediately.  
8 
CORRELATIVE/ SPECIAL STUDIES  
8.1 Laboratory Correlative Studies 
8.1.1 Collection of Specimen(s) 
Biopsy specimens will be collected per normal institutional methods for biopsy and 
surgical resection procedures. 
8.1.2 Handling of Specimens(s) 
At the time of the baseline biopsy, endpoint biopsy, and/or resection specimen, the tissue 
will be handled and processed by routine tissue protocol at the pathology laboratory of the 
institution performing the procedure.  Standard morphologic assessment of the tissue 
(including H&E stain) will be performed by the pathology laboratory of the institution 
performing the procedure with an emphasis to avoid decalcification of the tumor material, 
if possible. 


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8.1.3 Shipping of Specimen(s) 
The archived biopsy or representative portions of the resection specimen, including 
formalin fixed paraffin embedded block and matching H&E slide, will be sent to the 
laboratory of Dr Robert West at the Site Performing Correlative Study 
(Stanford Cancer Institute) by overnight courier at room temperature.  Once archived, the 
tissue is stable at room temperature. 
8.1.4 Site(s) Performing Correlative Study 
The Site Performing Correlative Study is the laboratory of Dr Robert West at the Stanford 
Cancer Institute at the Stanford University Medical Center.  Dr West’s laboratory will be 
responsible for all the correlative study tests. 
8.1.5 Coding of specimens for privacy protection 
The specimens will be coded at the time of receipt in the laboratory of Dr Robert West.  
The specimen will be given a 5-digit number with no relationship to the subjects’ HIPPA 
data.  The key for the coded specimens and the patient data will be kept by Dr Robert West 
in a locked office. 


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9 
STUDY CALENDAR 
 
Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 Off-Study d 
Dabrafenib 
 
Dabrafenib will be 
administered twice daily as 
specified in Section 4 until 
surgical resection 
FOR SUBJECTS 
NOT UNDERGOING 
SURGICAL RESECTION:  
dabrafenib will continue 
until disease progression or 
intolerance 
 
Trametinib 
 
Trametinib will be 
administered daily as 
specified in Section 4 until 
surgical resection 
FOR SUBJECTS 
NOT UNDERGOING 
SURGICAL RESECTION:  
trametinib will continue 
until disease progression or 
intolerance 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy of tumor for 
correlative studies 
X 
 
 
 
 
 
 
X g 
 
 
 
 
 
 
Surgical resection for 
patients with 
resectable tumors, and 
tissue collection for 
correlative studies 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
Concurrent meds 
X 
X 
X a 
 
 
Physical exam 
X 
 
 
X 
 
 
X 
 
 
X a 
 
 
X a 
X 
Vital signs 
X 
 
 
X 
 
 
X 
 
 
X a 
 
 
X a 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plts 
X 
 
 
X 
 
 
X 
 
 
X a 
 
 
X a 
X 
Serum chemistry b 
X 
 
 
X 
 
 
X 
 
 
X a 
 
 
X a 
X 
EKG within 14 days 
of enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO cardiogram 
within 1 month of 
enrollment 
X 
 
 
X 
 
 
 
 
 
 
 
 
X f 
 


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Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 Off-Study d 
Adverse event 
evaluation.  See 
Section 7 for expected 
AEs and Section 6 for 
dose modification 
rules. 
X 
 
 
X 
 
 
X 
 
 
X a 
 
 
X a 
X a 
Tumor measurements 
X 
Tumor measurements are repeated every 6 weeks.  After 
Week 7, tumor measurements are repeated every 
6 to 9 weeks. Documentation (radiologic) must be 
provided for patients removed from study for progressive 
disease. 
X d 
Radiologic evaluation 
(CT, MRI, X-ray) 
X 
Tumor measurements are repeated every 6 weeks.  After 
Week 7, tumor measurements are repeated every 
6 to 9 weeks. Documentation (radiologic) must be 
provided for patients removed from study for progressive 
disease. 
X d 
Serum Pregnancy 
testing within 14 days 
of enrollment 
X 
 
 
Ophthalmologic 
examination.  See 
Section 6 on 
guidelines for visual 
changes and exam 
source sheet in 
appendix 
X 
 
 
 
 
 
X e 
 
 
 
 
 
 
 
a: Only for patients continuing on dabrafenib and/ or  trametinib who have not undergone surgery.   
b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
phosphorus, potassium, total protein, AST, ALT, sodium. 
d: Off-study evaluation.   
e: Ophthalmologic exams to be repeated  annually. 
f: 
Every 3 months while on trametinib. 
g. For subjects not undergoing surgical resection. 
 
 
10 
MEASUREMENTS 
Primary Outcome Measure:  Response rate according to RECIST v1.1 at 6 weeks  
 RECIST v1.1 response rate, specifically, the sum of CR and PR per RECIST v1.1  
 Time Frame:  6 weeks 
 Safety Issue:  Not a safety issue primary endpoint 


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10.1 Primary and Secondary Outcome measures 
The primary endpoint will be tumor response rate (CR + PR)  at 6 weeks.  We intend to use 
modified RECIST v1.1 criteria {Eisenhauer, 2009}, knowing that since this patient 
population will include presurgical subjects, we will be unable to obtain response 
confirmation following the surgical resection of tumors. {Eisenhauer, 2009 #311} 
10.1.1 Measurement Definition 
The definition we will use for the primary endpoint of response will be per the 
RECIST v1.1 criteria, with the exception that for patients undergoing surgical resection 
there will be no confirmatory imaging as this would be irrelevant following surgical 
resection. CR, PR, SD, PR are all defined in the cited RECIST reference and are widely 
available and therefore will not be repeated here.  
10.1.2 Measurement Methods 
Standard CT or MRI scans and physical exam, per RECIST v1.1 criteria, will be used to 
measure tumors for purposes of response assessment.  To maintain consistency of data and 
quality of science, whatever imaging modality is used at baseline for each patient should be 
used throughout the trial.  
10.1.3 Measurement Time Points 
Initial response evaluation for the primary endpoint will be at 6 weeks.  For patients not 
undergoing surgical resection, follow-up imaging will be every 6 to 9 weeks, which we 
consider to be standard of care. 
10.2 Secondary Outcome 
10.2.1 Tumor necrosis 
One secondary outcome will be percent of tumor necrosis at the time of endpoint biopsy or 
surgical resection.  We intend to use this outcome with criteria established for treatment 
response in other tumors.   
10.2.2 Measurement Definition 
The definition we will use for the first secondary endpoint of response will be evaluation of 
extent of tumor necrosis by H&E slide review.  This will be performed on either the 
endpoint biopsy or the resection specimen.   
10.2.3 Measurement Methods 
Routine H&E slide review will be used to measure extent of tumor necrosis for purposes of 
response assessment.  Percentage of tumor necrosis by volume will be assessed as routinely 
done with other solid tumors such as osteosarcoma.  The biopsy slide or multiple slides of 
the resection specimen will be examined and the volume of the necrosis compared to the 
volume of the total tumor will be determined by the centrally reviewing pathologists and 
percentage readouts of tumor necrosis, in increments of 10%, will be determined.  In 
addition to measuring tumor necrosis the slide review will also estimate therapy effect on 
intact cells by estimating the percent cells with therapy-associated nuclear atypia. 


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10.2.4 Measurement Time Points 
Tumor necrosis evaluation for this secondary endpoint will be at the time of the endpoint 
biopsy or the surgical resection. 
10.2.5 Response Review 
Tumor necrosis evaluation will be centralized review by the study co-investigator, Robert 
West, and at least one designee with substantial experience with tumor necrosis evaluation.  
Disagreements concerning response assessment between the PI and the second reviewer 
will be adjudicated by a board certified pathologist with tumor necrosis evaluation 
experience. 
10.3 Secondary Outcome – Proliferation index 
A second secondary outcome will be proliferation index as measured by Ki67 percent 
positivity at the time of endpoint biopsy or surgical resection.  We intend to use this 
outcome as measured with immunohistochemistry with criteria established for assessment 
of proliferation index for other tumors.   
10.3.1 Measurement Definition 
The definition we will use for the second secondary endpoint of response will be evaluation 
of percent proliferation index by Ki67 immunohistochemistry.  This will be performed on 
the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. 
10.3.2 Measurement Methods 
Proliferation index evaluation will be performed in the laboratory of Dr.  Robert West on 
the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen.  
Ki-67 immunohistochemistry will be scored by at least two pathologists using percentage 
positive cells as the primary metric.  The results of the immunohistochemical analysis will 
be expressed as both raw data in addition to a ratio between pre- and post- treatment.  All 
pathological evaluations will be done centrally by the pathology co- investigators, Robert 
West and Jonathan Pollack or their designees. 
10.3.3 Measurement Time Points 
Proliferation index evaluation for this secondary endpoint will be at the time of the 
endpoint biopsy or the surgical resection. 
10.3.4 Response Review 
Proliferation index evaluation will be centralized review by the study co-investigator, 
Robert West and Jonathan Pollack and at least one designee with substantial experience 
with proliferation index evaluation.  Disagreements concerning response assessment 
between the PI and the second reviewer will be adjudicated by a board certified pathologist 
with proliferation index evaluation experience. 
10.4 Secondary Outcome – Phosphorylation of MEK/ERK 
A second secondary outcome will be expression of phosphorylation of MEK and ERK as 
measured by phospho-MEK/ERK positivity at the time of endpoint biopsy or surgical 
resection.  We intend to use this outcome as measured with immunohistochemistry using 
antibodies specific for phospho-MEK/ERK and total MEK/ERK (either phosphorylated or 


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un-phosphorylated) with criteria established for assessment of protein expression by 
immunohistochemistry for other tumors.   
10.4.1 Measurement Definition 
The definition we will use for the second secondary endpoint of response will be evaluation 
of protein expression by immunohistochemistry.  This will be performed on the initial 
pre-treatment biopsy and either the endpoint biopsy or the resection specimen. 
10.4.2 Measurement Methods 
Immunohistochemistry evaluation for MEK/ERK will be performed in the laboratory of 
Dr.  Robert West on the initial pre-treatment biopsy and either the endpoint biopsy or the 
resection specimen.  Immunohistochemistry will be scored by at least two pathologists 
using percentage positive cells and intensity of staining as the primary metrics.  The results 
of the immunohistochemical analysis will be expressed as both raw data in addition to a 
ratio between pre- and post- treatment.  All pathological evaluations will be done centrally 
by the pathology co- investigators, Robert West and Jonathan Pollack or their designees. 
10.4.3 Measurement Time Points 
Immunohistochemistry evaluation for MEK/ERK for this secondary endpoint will be at the 
time of the endpoint biopsy or the surgical resection. 
10.4.4 Response Review 
Immunohistochemistry evaluation for MEK/ERK will be centralized review by the study 
co-investigator, Robert West and Jonathan Pollack and at least one designee with 
substantial experience with protein expression evaluation.  Disagreements concerning 
response assessment between the PI and the second reviewer will be adjudicated by a board 
certified pathologist with protein expression evaluation experience. 
11 
REGULATORY CONSIDERATIONS 
11.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g.  advertisements used to recruit participants) will be reviewed and 
approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee 
(SRC).  Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation.  The Protocol Director will disseminate the 
protocol amendment information to all participating investigators.  All participating sites 
will similarly have the informed consent document and protocol reviewed and approved by 
their local IRB and scientific review committee.  There is to be only one version of the 
protocol to be used across all participating sites and no site can individually modify or 
amend the protocol at their site alone.  That is, all protocol amendments and modifications 
must be reviewed and approved by all institutions’ relevant review boards. 
11.2 Data and Safety Monitoring Plan:   
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This may 


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include review of the following types of documents participating in the study:  regulatory 
binders, case report forms, eligibility checklists, and source documents.  In addition, the 
DSMC will regularly review serious adverse events and protocol deviations associated with 
the research to ensure the protection of human subjects.  Results of the DSMC audit will be 
communicated to the IRBs of all participating institutions and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as needed. 
11.3 Data Management Plan 
11.3.1 Data Collection 
Data collection for this study will be via REDCap, a password protected HIPAA compliant 
web- based electronic data capture system.  Prior to opening this study at any site, case 
report forms for the collection of all relevant required data will be developed and relevant 
site staff trained on the access and use of REDCap.  Eligibility for each patient enrolled 
will be confirmed by the PI or designee centrally before authorization to enroll and patient 
number assignment is made via REDCap.  The Protocol Director, or his/her designee, will 
prepare and maintain adequate and accurate participant case histories with observations and 
data pertinent to the study.  At each participating site, that site’s PI or designee is 
responsible for collecting and storing in one central location copies of all primary clinical 
documents and be prepared to transmit these documents via secure electronic means  for 
remote audit and review.  All sites should also be able to readily access actual primary 
documentation, either electronically or in paper form, for on-site audit purposes. 
11.3.2 Data Submission responsibility 
It is the responsibility of each site PI to ensure that all investigators and designees at that 
site understand and are trained in all the relevant procedures for data collection and 
submission.  For the purposes of site data submission compliance, data will be considered 
delinquent and such delinquency reported to that site’s IRB if the data for any required 
routine evaluation is not submitted within 4 weeks after the relevant visit, test, or 
assessment has been completed or resulted. 
11.3.3 Multicenter Guidelines 
The overall PI is responsible for distribution of all IND action letters and safety reports to 
all participating institutions.   
12 
STATISTICAL CONSIDERATIONS 
12.1 Statistical Design and primary analysis 
We propose a two stage Optimal design per Simon, et al.  (Simon   R ,1989.  Controlled 
Clinical Trials.  10:1-10), and using the UNC calculator: 
http://www.cscc.unc.edu/cscc/aivanova/SimonsTwoStageDesign.aspx 
The null hypothesis that the true response rate is 0.05 will be tested against a one-sided 
alternative.  In the first stage, 9 evaluable patients will be accrued.  If there is less than one 
response (defined in Section 10.1) in these 9 patients, the study will be stopped.  If at the 
time of the 9th patient’s enrollment there has not been at least one centrally documented 
response, accrual will stop until responses have been centrally determined for the first nine 
patients.  Otherwise, 8 additional evaluable patients will be accrued for a total of 


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17 evaluable patients.  The null hypothesis will be rejected if 3 or more responses are 
observed in 17 patients.  We will allow for up to 11 patients in the first stage and up to 
10 patients in the second stage to account for patient drop-out / uneavaluable patients.  This 
design yields a type I error rate of 0.0466 and power of 0.8122 when the true response rate 
is 0.25.  We believe that anything below a response rate of 25% would not be clinically 
meaningful given the potential risks of dabrafenib and trametinib.  The likelihood of 
stopping early if the null hypothesis is true will be 0.63.  A response rate of 25% or higher, 
in the context of other promising secondary endpoint results such as a high % of tumor 
necrosis, would warrant further study. 
12.2 Secondary Analysis 
We will determine secondary responses for:  1) tumor necrosis;  2) proliferation index;  and 
3) ERK/MEK phosphorylation.  These assays will be exploratory and not subjected to a 
prospective statistical plan for analysis.  Tumor necrosis % will be estimated according the 
standard surgical pathology techniques.  Proliferation index will be measured  by 
percentage of cells in mitosis and Ki 67 staining per standard surgical pathiology assays.  
The ratio of unphosphorylated to phosphorylated ERK and MEK will be done using 
standard phosphorylation specific antibodies  on tumor tissue specimens in Dr West’s lab 
according to his lab’s SOPs.  See Section 10 for details. 
12.3 Sample Size 
11 to 21 patients (9 to 17 evaluable pateints).  See Section 12.1 
12.4 Accrual estimates  
We estimate 3 to 6 patients will be accrued among collaborating institutions annually.  This 
is a very rare disease, incidence 0.5/ million estimated.  Stanford sees and evaluates outside 
pathology on about 5 cases per year and our collaborating centers estimate about the same.  
12.5 Feasibility and safety assessment 
Because this is a very rare disease, our assumptions concerning the ability to accrue in a 
timely way are considerably uncertain.  Therefore, at each annual review, should the 
accrual in the preceding year be less than 3 patients, we will re-evaluate the feasibility of 
conducting this protocol and either modify the protocol or close the protocol.  Also as part 
of that annual review, if the cumulative rate of completion of 6 weeks of dabrafenib and 
trametinib treatment as specified in Section 4 is not achieved in at least 2/3 of all subjects , 
we will review the feasibility of administering treatment on this study and modify or close 
the protocol.  
Safety data, collected as specified in the study calendar in section nine, will be summarized 
in tabular form using the CTCAE v4.03 for AE description and grading.  Cumulative safety 
data and all SAE reports will be reviewed by investigators both annually and at the end of 
the first stage of accrual.  Should less than 2/3 of patients enrolled at any of these annual 
reviews or first stage analysis not complete the protocol treatment as stipulated in this 
protocol, the protocol will either be amended to address these safety issues or the protocol 
will be closed to further accrual.  High-grade AEs alone are not to be construed as an 
indication to stop accrual or amend the protocol as long as treatment of those AEs per 
standards of care and modifications per Section 6 allow for completion of treatment as 
specified in Section 4.  Reporting of SAEs is covered in Section 7.2. 


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Appendix A:  Medication guide / Patient Information for patients: 
Dabrafenib capsules 
The current Medication Guide for Tafinlar (dabrafenib) dated November 2015 is attached to the 
eProtocol IRB-32275 application.  
Trametinib Tablets 
The current Patient Information for  Mekinist (trametinib) is provided in the package insert dated 
November 2015, attached to the eProtocol IRB-32275 application.  
 
Appendix B:  Stanford Cancer Institute Standard Operating Procedures 
Standard Operating Procedures (SOPs) for the Stanford Cancer Institute (SCI) pertaining to risks 
to subjects and safety reporting are available on the SCI Cancer Clinical Trials Office website 
(http://med.stanford.edu/ccto/services/regulatory.html).  
 


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Appendix C:  ECOG performance status 
 
 
 


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Appendix D:  Cockcroft-Gault formula: 
CCr={((l 40–age) x weight)/(72xSCr)}x 0.85 (if female) 
Appendix E:  Ophthalmic exam source sheet 
Note to examiner:  Please assess particularly for visible retinal pathology. 
* Optical coherence tomography is highly recommended  For patients in whom retinal abnormalities are noted, 
color fundus photos, and fluorescein angiography if clinically indicated, are recommended.   
OPHTHALMIC EXAMINATION  Subject name/ MRN: 
1. Date of Examination: 
_ _/_ _ _ /_ _ _ _ 
   dd  /   mmm   /    yyyy 
VISUAL ACUITY 
Enter corrected visual acuity 
OD: 
OS: 
TONOMETRY 
Enter IOP (mmHg) 
OD: 
OS: 
INDIRECT FUNDOSCOPY 
Indirect Exam: Indicate 
normal or specify abnormalities 
OD: 
OS: 
CONFRONTATION VISUAL FIELD EXAM OR AUTOMATED PERIMETRY 
(eg, Humphrey 24-2 or 30-2 or equivalent if using a non-Humphrey instrument) 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
OPTICAL COHERENCE TOMOGRAPHY (strongly recommended) 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
COLOR FUNDUS PHOTOS (recommended if retinal abnormalities are noted)* 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
FLORESCEIN ANGIOGRAPHY (suggested if retinal abnormalities are noted and 
test clinically indicated)* 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
Were any of the following noted on ocular history or exam? 
Yes No 
 
History of CSR? 
 
 
 
Evidence of new optic disc cupping? 
 
 
 
Evidence of new visual field defects? 
 
 
EXCLUSION CRITERIA 
Yes No 
 
History of RVO? 
o If yes, patient is not eligible for the study. 
 
 
Signature of Examiner: _____________________________   
Printed Name: _________________________      Date: ______________