Clinical trial NCT01682213
Conditions: Melanoma
Keywords: Dabrafenib (GSK2118436) BRAFV600E/K Resected AJCC Stage IIIC 12-124
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2012-09-01; Completion date: 2019-05-01
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this study, the investigator's want to find out if dabrafenib can stop stage IIIC melanoma from coming back after surgery.

Detailed description:

Arms: arm 1: This is a single institution phase II trial assessing the efficacy of adjuvant dabrafenib (GSK2118436) in patients with surgically resected AJCC stage IIIC melanoma characterized by a BRAFV600E/K mutation.
Interventions: intervention 1: Dabrafenib
Intervention descriptions: intervention 1: Following definitive surgical resection, eligible patients will receive dabrafenib at 150 mg twice a day by mouth for 4 cycles (± 5 days). One cycle is 28 days.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
 
 
 
 
 
A Phase 2 Trial of Ad juvant Dabrafenib (GSK2118436) in Patients with Surgically 
Resected AJCC Stage IIIC Melanoma Characterized by a BRAFV600E/K Mutation 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Paul B. Chapman, MD 
Medicine/MSO 
Co-Principal Investigator(s)/Department: 
Jedd Wolchok, MD PhD 
Medicine/MSO 
Investigator(s)/Department: 
Ping Chi, M D, PhD 
Sandra D’A ngel o, MD 
Mark Dickson, MD 
Margaret Callahan, MD 
Jam es Harding, MD 
Michael Postow, M D 
Parisa Momtaz, MD 
Alexander Shoushtari, MD 
Charlotte Ariyan, MD, PhD 
Mary Sue Brady, MD 
Dani el G. Coit, MD 
Mario Lacout ure, M D 
Mark Bluth, MD 
Alyona Weinstein, RN, MSN, FNP-BC  
Yelena Sham es, MS, ANCP-BC, 
CNRN 
Nana Prem peh-Ket eku, MS, ANP-BC 
Mimma Errante, MS, NP-C, OCN 
Jacqueline Brom berg, MD, PhD 
Klaus J. Busam, MD 
Jasmine Francis, MD 
Murk-Hei n Hei nem ann, M D 
Brian P. Marr, MD 
David C. Lyden, MD, PhD 
Taha M erghoub, PhD 
Katheri ne Panageas, DrP H 
David Solit, MD 
Agnes Viale, PhD 
Ira J. Dunkel, MD 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Surgery/MSO 
Surgery/MSO 
Surgery/MSO 
Dermatol ogy 
Radi ology 
Nursi ng 
Nursi ng 
Nursi ng Nursi 
ng Medicine 
Pathology 
Ophthalmol ogy 
Ophthalmol ogy 
Ophthalmol ogy 
Pediatrics 
Medicine 
Epidemi ology and Biostatistics 
Medicine/GU 
Genomics Core Laboratory 
Pediatrics 
Consenting Professional(s)/Department: 
Paul B. Chapman, MD 
Jedd Wolchok, MD PhD 
Ping Chi, M D, PhD 
Sandra D’A ngel o, MD 
Mark Dickson, MD Michael 
Postow, M D Alexander 
Shoushtari, MD Ira J. 
Dunkel, MD 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Medicine/MSO 
Pediatrics 
Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
Page 1 of 38 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 2 of 38 
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA........................................................................3 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................3 
 
3.0 
BACKGROUND AND RATIONALE .......................................................................................4 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .............................................................. 8 
 
4.1 
Design..................................................................................................................................8 
 
4.2 
Intervention ..........................................................................................................................8 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS...............................................................................8 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY...............................................................................9 
 
6.1 
Subject Inclusion Criteria .....................................................................................................9 
 
6.2 
Subject Exclusion Criteria..................................................................................................10 
 
7.0 
RECRUITMENT PLAN .........................................................................................................11 
 
8.0 
PRETREATMENT EVALU ATION ........................................................................................11 
 
9.0 
TREATMENT/INTERVENTION  PLAN .................................................................................12 
 
10.0 EVALU ATION DURING TREATMENT/INTERVENTION....................................................19 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 22 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................25 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ........................................................................25 
 
14.0 BIOSTATISTICS ...................................................................................................................26 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES27 
 
15.1 Research Participant Registration .....................................................................................27 
 
15.2 Randomization...................................................................................................................27 
 
16.0 DAT A M AN AGEMENT ISSUES...........................................................................................27 
 
16.1 Quality Assurance..............................................................................................................27 
 
16.2 Data and Safety Monitoring ............................................................................................... 27 
 
17.0 PROTECTION OF HUMAN SUBJECTS..............................................................................28 
 
17.1 Privacy ............................................................................................................................... 28 
 
17.2 Serious Adverse Event (SAE) Reporting ..........................................................................29 
 
17.2.1 Definition of SAEs/Reporting to Novartis.......................................................................29 
 
18.0 INFORMED CONSENT PROCEDURES..............................................................................30 
 
19.0 REFERENCES ......................................................................................................................31 
 
20.0 APPENDICES .......................................................................................................................33 


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IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 3 of 38 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Inhibition of BRAFV600E kinase has emerged as effective therapeutic strategy for patients with 
metastatic melanoma harboring a BRAF
V600E  mutation.   It is reasonable to speculate that 
BRAFV600E   kinase inhibitors  will benefit molecularly  selected melanoma patients  at earlier 
stages of the disease.    Patients with stage IIIC melanoma are at an extremely high risk of 
disease recurrence and death despite definitive surgical resection.  Data from our Center 
indicate that the relapse-free survival (RFS) for stage IIIC disease is only 24% at 2 years.  In 
this single center phase II trial, patients with surgically-resected stage IIIC melanoma 
characterized by a BRAFV600E  or BRAFV600K mutation will be treated with 4 cycles of adjuvant 
dabrafenib  and  monitored  clinically  and  radiographically  for  disease  recurrence  for  24 
months following surgical resection.  We will test the hypothesis that adjuvant BRAF kin ase 
inhibition will improve RFS from 24% to 51% at 24 months.  The planned accrual is for 23 
patients.  The primary objective of the study will be to determine the RFS at 24 months.  The 
trial would  be considered positive if 9 or  more patients  are relapse-free  and alive at 24 
months.  The trial would be terminated early i f at any time 15 patients relapsed or died before 
24 months.   Secondary objectives  include the assessment  of dabrafenib toxicity and the 
determination  of  overall  survival  (OS).    In  an  exploratory  fashion,  pretreatment  tumors 
biopsies and biopsies at the time of relapse will be obtained to characterize the tumors 
genetically and to assess for mechanisms of resistance to BRAF inhibition.   Serial blood 
samples will also be obtained and used to determine if circulating tumor-derived exosomes 
can predict melanoma recurrence. 
 
STUDY SCHEMA 
 
 
Stage IIIC 
Melanoma 
• 
Age ≥ 18 
• 
ECOG performance 
= 0 
• 
Surgically resection 
within 6 weeks 
• 
No radiographic 
evidence of disease 
V600E/K 
 
 
 
Adjuvant 
Dabrafenib 
• 
150 mg BID 
orally 
• 
1 cycle = 28 
days 
• 
4 cycles total 
 
Observatio 
n 
Exam and 
appropriate 
radiographic 
evaluation q3 
months until 
disease relapse 
• 
BRAF 
mutation 
or end of study 
• 
No history of prior 
BRAF/MEK therapy 
• 
No history of prior 
ipilimumab 
• 
No concurrent 
adjuvant therapy 
• 
Adequate end organ 
function 
at 24 months 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 4 of 38 
 
 
 
 
 
2.1      Primar y Obje ctive 
 
To determine the RFS at 24 months for patients with Stage IIIC melanoma harboring a 
BRAF
V600E/K mutation who are treated with definitive surgical resection followed by four cycles 
of adjuvant dabrafenib administration. 
 
2.2 
Se condary Obje ctives 
To determine overall survival. 
To assess toxicity. 
2.3      Exploratory Objectives 
 
To characterize the genetic heterogeneity of BRAF-mutated melanomas and explore 
mechanisms of intrinsic and acquired resistance to dabrafenib. 
 
To  evaluate  the  ability  of  circulating  tumor-derived   exosomes   to  predict  melanoma 
recurrence. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1      Re gional me tastatic me lanoma 
 
It is projected that there will be 76,250 new cases of cutaneous melanoma in the Un ited 
States  in 2012  [1].   Ten to 13% of patients  with cutaneous  melanoma will present with 
regional metastatic disease. Regional metastatic melanoma [American Joint Commission on 
Cancer (AJCC) Stage III disease] is defined by the neoplastic involvement of the regional 
lymph nodes and/or regional cutaneous disease in-transit.   Independent  prognostic factors 
for this stage of disease include the depth of the primary tumor, the presence of ulceration in 
the primary  tumor,  the number  of tumor-bearing  lymph  nodes,  and the burden  of nodal 
disease [2].  Stages III patients are sub-classified into three groups (i.e. IIIA, IIIB and IIIC) by 
presence or absence of these important prognostic factors. 
 
Definitive  surgical  resection  is  the only  widely  accepted  modality  for  long-term  disease 
control and cure.   Even in the setting of a complete surgical resection, the risk of disease 
recurrence and death is extremely high, particularly for patients with stage IIIC disease.  Data 
from our Center show that the 5-year relapse-free survival for stage IIIC melanoma is 15%; 
the 5-year overall survival is only 11% [3].  This indicates that relapse is almost equivalent to 
death  in patients  with stage  IIIC  melanoma.    Preventing  disease  relapse  is  thus  a key 
objective. 
 
Patients with surgically resectable stage IIIC melanoma have few tolerable and effective 
systemic therapies available to alter the natural history of their disease.  Adjuvant high d ose 
and pegylated interferon therapy have been shown to offer a modest relapse-free survival 
benefit  in randomized studies  [4, 5].   Unfortunately,  interferon-based  adjuvant therapy  is 
poorly tolerated and no study has demonstrated an overall survival advantage [4-7].  As such 
interferon  is  not  uniformly  accepted  as  a standard  of care, despite  being  the only FDA 
approved agent for use in the adjuvant setting.  Clinical trials of adjuvant immunotherapies, 


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IRB Number: 12-124 A(14) 
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50 
 
 
 
vaccines and chemotherapies have also been disappointing and have not modified the risk of 
recurrence or death from melanoma after definitive surgical resection [8]. 
 
As surgically resectable stage IIIC melanoma has a high mortality with minimal effective 
treatments,  novel  adjuvant  and neoadjuvant  therapies  are clearly  necessary  to improve 
patient outcomes. 
 
 
 
 
 
 
 
 
3.2      Mutations in BRAF activate the MAPK pathway in me lanoma 
 
A subset of melanoma is driven by constitutive activation of the mitogen-activated protein 
kinase (MAPK) signaling cascade [9].  Fifty to sixty percent of melanomas harbor activating 
mutations in BRAF.  Ninety percent of these mutations occur at codon 600 [10].  The most 
common mutation at this position is a missense error resulting in a valine to glutamate 
substitution (i.e. BRAFV600E).   Other variants have also been observed and include V600K, 
V600R and V600D [11].  It is now well-established that melanomas with BRAFV600 mutations 
are dependent on signaling through the MAPK pathway for cellular proliferation and survival 
[12] and that blocking signaling through this pathway results in cell cycle arrest and apoptosis 
in vitro and in vivo [13]. These preclinical observations have led to the clinical development of 
two potent inhibitors of mutated-BRAF kinase: vemurafenib and dabrafenib. 
 
3.3       Ve murafenib and Dabrafenib 
 
In vitro studies indicate that vemurafenib and dabrafenib effectively block signaling through 
the MAPK pathway by inhibiting BRAF
V600 E  kinase activity [14, 15]. The IC 
of vemurafenib 
for BRAFV600E  kinase is 31nM [14].  Dabrafenib is a more potent inhibitor of this kinase in vitro 
with a corresponding  IC50 of 0.7nM [15].  Dabrafenib also effective ly inhibits BRAFV600K   and 
BRAFV600D   kinase  with an  IC50   of  0.5  and  1.8nM,  respectively.    Both  vemurafenib  and 
dabrafenib induce growth suppression, rapid cell cycle arrest, and apoptosis in melanoma 
cell lines characterized by a BRAFV600E  mutation [15, 16].  Likewise, administration of each of 
the agents  in  vivo  results  in profound  tumor  regression  in murine  xenograft  melanoma 
models [14, 15]. 
 
The completed phase I, II and III clinical trials of vemurafenib have confirmed that this agent 
is a safe and effective treatment modality for patients with metastatic melanoma [17-19].  The 
pivotal,  randomized,  open  label,  phase  III  trial  (BR IM 3)  comparing  vemurafenib  with 
dacarbazine in patients with previously untreated, BRAF-mutated metastatic melanoma led 
to FDA licencing of the agent in August of 2012 [18].  Forty-eight percent of patients treated 
with vemurafenib  had  a confirmed  objective  response  (2 CR  and 104 PR)  by RECIST 
criteria.  The median time to response was 1.5 months .  At the time of first interim analysis, 
the median follow-up for patients treated with vemurafenib and dacarbazine was 3.8 months 
and 2.3 months, respectively.  Importantly,  vemurafenib  was associated with a statistically 
significant relative risk reduction of 63% in the risk of death and of 74% in the risk of death or 
progression of disease when compared to dacarbazine. These beneficial effects on outcome 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 6 of 38 
 
 
 
 
 
were independent of disease stage [i.e. unresectable stage IIIC, Stage IV (M1a, M1b and 
M1c)].   In the phase  II trial of vemurafenib,  n early 90% of patients  achieved a maximal 
response by 4 months [19]. 
 
The safety and clinically efficacy of dabrafenib appears to be equivalent to vemurafenib.    A 
multicenter phase I/II trial assessed the tolerability and activity of dabrafenib in patients with 
previously-treated BRAF-mutated metastatic melanoma and other solid tumor [20].  Although 
a maximum  tolerated  dose  was  not  identified,  dabrafenib  at 150  mg twice  a da y was 
ultimately selected as the recommended phase II dose.   This schedule was comparable in 
antitumor activity, pharmacokinetic properties and pharmacodynamic effect to higher doses. 
Twenty-five of 36 (69%) BRAF-mutant metastatic melanoma patients who were treated with 
the recommend  phase  II achieved  an  unconfirmed  partial  or  complete  response.    The 
median duration of response was 6.2 months; the median progression-free survival was 5.5 
months.  Tumor biopsies were obtained prior to treatment and 7 (±4) days into treatment in 
12 patients.   Importantly,  a marked decrease in proliferation with associated necrosis and 
apoptosis  was observed in all samples.   Two phase  II studies  of dabrafenib have since 
confirmed its antitumor activity in melanoma [21, 22].  Response rates in these studies range 
from 31% to 58% and thus appear to be equivalent to those observed with vemurafenib, 
which range from 48 to 57% [17-19]. 
 
In a multicenter,  open label, randomized phase III clinical trial (BREAK-3)  in patients with 
unresectable stage IIIC or IV BRAF-mutated melanoma dabrafenib was found to improve 
progression-free survival compared dacarbazine [23].  Median progression-free survival was 
6.7 months for dabrafenib as compared to 2.9 months with dacarbazine with a hazard ratio 
for progression of 0.35.   These data are equivalent to the data obtained from BRIM-3, the 
randomized phase III study comparing vemurafenib to dacarbazine in patients with 
unresectable stage IIIC or IV BRAF-mutated melanoma.   In BRIM-3, the PFS for patients 
receiving vemurafenib was 6.9 months versus 1.6 months for dacarbazine (HR 0.38) [18, 24]. 
 
3.4      Study rationale 
 
Preclinical  in vitro  and  in vivo  data  with both  vemurafenib  and dabrafenib  indicate  that 
inhibitors of mutated-BRAF kinase induce cell death in melanoma cells harboring a BRAF 
mutation [14, 16].  Clinical data demonstrate that inhibition of mutated-BRAF kinase results in 
rapid and significant tumor shrinkage in more than 50% of patients with advanced melanoma 
characterized by BRAF
V600  mutations independent of disease stage [15, 17-19].  Correlative 
studies  show that apoptosis  and tumor necrosis  are apparent  within  one week after  the 
initiation  of  BRAF  kinase  inhibitors.  Anecdotally,  we  have  observed  several  patholog ic 
complete  responses   following  metastasectomy   after  best  response  to  BRAF  kinase 
inhibition.  This indicates that inhibitors of mutated-BRAF kinase have the ability to eradicate 
bulky metastatic disease. It is thus reasonable to speculate that inhibition of mutated-BRAF 
kinase will benefit molecularly selected melanoma patients at earlier stages of the disease. 
 
The underlying  hypothesis  of this trial is that  treatment of micrometastatic  disease for 4 
cycles will be sufficient to improve RFS in stage IIIC patients with BRAF mutations who are 
currently free of disease.     Based on our data at MSKCC [3], stage IIIC patients would be 
expected to have a RFS of only 24% at 24 months . We will test the hypothesis that 4 cycles 
of adjuvant dabrafenib will result in an improvement in RFS from 24% to 51% at 24 months. 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 7 of 38 
 
 
 
 
 
The duration of treatment (i.e. 4 cycles) was based on the time to maximal response in 
patients with bulky disease treated with BRAF inhibitor as well as the observation that 
resistance  to these  agents  generally  develops  after  month  six.    It was  also  felt  that  if 
continuous  adjuvant  treatment  with  dabrafenib  were  necessary  to  improve  relapse-free 
survival, then treatment at relapse would  likely be just as effective and the rationale for 
adjuvant therapy would be undercut. 
 
3.5      Corre lative studies 
 
Resistance to BRAF kinase inhibition 
 
Despite  the  major  success  of  BRAF  inhibition,  subsets  of  melanomas  are  intrinsically 
resistant to inhibitors of mutated BRAF kinase [25].  Fourteen percent of melanoma patients 
had  primary  progressive  disease  on  the  phase  II  trial  of  vemurafenib  [19].     Genet ic 
heterogeneity may in part explain de novo resistance.  Mutations in other signaling pathways 
and/or tumor suppressor genes may abrogate the cellular dependence on mutated-BRAF 
activity.  To  this  end,  concomitant  mutational  inactivation  of  PTEN  and  RB1  has  been 
observed in BRAF mutated cell lines and these co-mutations render these cell lines resistant 
to BRAF  kinase inhibition [26, 27]. 
 
Melanomas also appear to develop acquired resistance to BRAF inhibition. The median 
progression-free survival to vemurafenib is 5-7 months in the metastatic setting [18]; the 
progression-free survival to dabrafenib appears to be similar.   Investigators have proposed 
numerous candidate mechanisms  for acquired resistance [28-32], however, r eactivation of 
the RAS-RAF-MEK-ERK  pathway appears to be a prominent mode of resistance to BRAF 
kinase inhibition.  Acquired N-RAS (Q61K) and MEK (C121S) mutations [30-32] as well as a 
unique splice variant of BRAFV600E  [32] have been shown to up-regulate the MAPK signaling 
pathway and convey resistance to BRAF kinase inhibition. 
 
Additional mechanisms will likely be postulated in the months to come.   Unfortunately, few 
patient samples have actually been interrogated to date.  The proposed trial is uniquely 
positioned to acquire substantial tumor tissue.   Tumors obtained prior to treatment will be 
genetically characterized by whole exome sequencing to identify co-mutations in BRAF 
mutated  melanomas.    Tumor  will  also  be  obtained  in  virtually  all  patients  at  time  of 
progression since tissue confirmation of progression is a standard of care. Tumor biopsies at 
progression will allow discovery of resistance mechanisms in a prospective manner. 
 
Circulating tumor-derived exosomes as a marker of melanoma recurrence 
 
Exosomes   are  microvesicles   derived   from   the   luminal   membrane   of  the   endocytic 
compartment  in both normal and neoplastic  cells  [33].   These membrane-bound  particles 
range between 30 and 100 nanometers in size and are constitutively released into the 
extracelluar matrix after fusion of endosome with the cell membrane.   Exosomes contain a 
number of subcellular elements including messenger RNAs, micro-RNAs, DNA, and a variety 
of proteins involved in multiple cellular processes such as antigen presentation, cell targeting 
and adhesion, apoptosis, signal transduction, and cell proliferation.  Thus, exosomes play a 
critical role in mediating intercellular communication allowing for the horizontal transfer of 
information between cells [34]. 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
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Peinado and colleagues [34] recently isolated and characterized exosomes from the sera of 
patients with increasing stages of cutaneous melanoma.   Exosome size distribution and 
absolute number did not differ based on clinical stage.  Interestingly, exosomes isolated from 
patients with advanced stages of melanoma were qualitatively different from normal controls 
as well as individuals with earlier stages of the disease.  Specifically, exosomes from patients 
with Stage IV disease were characterized by both higher concentrations  of proteins and a 
unique protein signature including tyrosinase-related protein-2 (TYRP2), very late antigen 4 
(VLA-4), heat shock protein  70 (HSP70), and the MET oncoprotein.   Exosomal levels  of 
TYRP2 were also significantly higher in patients with Stage III disease and in a retrospective 
analysis of 29 patients correlated with disease progression.  In an exploratory fashion, we will 
obtain  serial  peripheral  blood  samples  from  all  patients  on  this  trial  to  measure  and 
characterize tumor-derived exosomes in patients with surgically resected stage IIIC disease. 
We will prospectively test the hypothesis that qualitative changes in circulating exosomes will 
be able to predict melanoma recurrence. 
 
4.0     OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1     Design 
 
This is a single institution, single arm, phase II trial of adjuvant dabrafenib  in patients with 
surgically-resected stage IIIC cutaneous melanoma characterized by a BRAF
V600E/K  mutation. 
 
4.2     Intervention 
 
Following definitive surgical resection, eligible patients will receive dabrafenib at 150 mg 
twice a day by mouth for 4 cycles.  One cycle is 28 days. 
 
. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1      Mechanism of Action 
 
Dabrafenib, a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is an orally bioavailable, 
small molecule, ATP-competitive inhibitor of BRAFV600  kinase.  Dabrafenib (IND # 105032) is 
an investigational agent manufactured and supplied by Novartis Pharmaceuticals.  Detailed 
information regarding the pharmacologic properties of dabrafenib can be found in the 
Investigator’s Brochure. 
 
5.2      Formulation, Storage and Packaging 
 
Dabrafenib will be provided as 50 mg and 75 mg capsules.  Each capsule contains 50 mg or 
75 mg as free base present as the mesylate salt.   The inactive ingredients include 
microcrystalline cellulose, magnesium stearate, gelatin, FDA red iron oxide and titanium 
dioxide.   The drug should be stored in a dry location at room temperature not exceeding 
25°C. 
 
5.3      Administration of Dabrafenib 


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Dabrafenib will be dosed at 150 mg twice a day by mouth.  Patients are instructed to take 
150 mg in the morning and 150 mg in the evening, approximately 12 hours apart. Dabrafenib 
should be administered under fasting conditions , either 1 hour before or 2 hours after a meal. 
If a study participant vomits after a dose, the patient should be instructed not to retake the 
dose and should take the next dose at its scheduled time.   If a dose is missed, it can be 
taken up to 6 hours prior to the next dose to maintain the twice daily regimen.  Instructions 
for dose modifications can be found in Section 9. 
 
 
 
 
 
 
 
 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1     Subject Inclusion Criteria 
 
6.1.1    AJCC (2009) stage  IIIC cutaneous  melanoma  rendered free of disease by 
surgical resection no greater than 90 days prior study enrollment.   Patients 
with unknown primaries will be eligible for this trial.  Patients with a history of 
resected stage I or II cutaneous melanoma who subsequently have their first 
disease recurrence  meeting the criteria  for stage  IIIC  disease will also be 
eligible for this trial. 
 
6.1.2    Patients  must  have  clear  margins  after  wide  local  excision.  Patients  with 
nodes that are palpable or detectable on radiologic imaging must have an 
adequate lymphadenectomy. 
 
6.1.3    Patients must be adequately recovered from surgery, radiation therapy, or any 
surgical complications prior to enrollment.  In general, this means patients will 
be off antibiotics from wound infections and drains removed.   However, if 
necessary, patients can be treated with a drain in place at the discretion of the 
PI if the 90 days window is about to expire. 
 
6.1.4 Histologic proof of melanoma reviewed and confirmed by MSKCC. 
 
6.1.5 A documented  BRAFV600E  or BRAFV600K  mutation by genotyping  or IHC [35] 
performed by a CLIA certified laboratory. 
 
6.1.6 Age > 16 years old. 
 
6.1.7 ECOG performance status = 0 or Karnofsky Performance Status equivalent 
(Appendix A). 
 
6.1.8 The ability to swallow pills. 
 
6.1.9 Patients must have adequate organ and marrow function as defined below: 


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IRB Number: 12-124 A(14) 
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Absolute neutrophil count                   >  1.5 K/mcL 
Platelets                                             >  100 K/mcL 
Hemoglobin                                        >  9.0 g/dL 
Total bilirubin                                       1.5 X institutional 
upper limit of normal (ULN) 
 
≤  3.0  X institutional  ULN  if  the 
patient  has  Gilbert’s   Syndrome 
AST (SGOT) and ALT (SGPT) 
 2.5 X institutional ULN 
Creatinine 
   1.5 X   institutional ULN   or 
creatinine  clearance  (calculated 
or measured) > 60 ml/min 
 
6.1.10  Women with child bearing potential and men with reproductive potential must 
be willing to practice acceptable methods of contraception. 
 
 
 
6.2 
Subject Exclusion Criteria 
 
6.2.1   Patients with a history of stage III melanoma (any primary melanoma with 
locoregional nodal/subcutaneous disease) treated with surgical resection who 
subsequently  have  disease  recurrence  meeting  the  criteria  for  stage  IIIC 
disease. 
 
6.2.2 Prior therapy with ipilimumab, other BRAF inhibitors, or MEK inhibitors . 
 
6.2.3 Concurrent adjuvant immunotherapy, chemotherapy, or radiotherapy. 
 
6.2.4    Current use of a prohibited medication  while on dabrafenib (See Section 9, 
Appendix B). 
 
6.2.5    Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption of drugs. 
 
6.2.6 A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency. 
 
6.2.7 Pregnant women and lactating women. 
 
6.2.8 A concurrent  second malignancy  even if it does not require active therapy. 
Patients with indolent B-cell malignancies will not be eligible. Prior malignancy 
will be allowed as long as the patient is known to be free of diseas e for at least 
3 years. 
 
6.2.9    Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection,  symptomatic  congestive  heart  failure,  unstable  angina  pectoris, 


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cardiac  arrhythmia,  or  psychiatric  illness/social  situations  that  would  limit 
compliance with study requirements. 
 
6.2.10  QTc interval > 500 msec, unless a bundle branch block is also present. 
 
6.3     Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited through the Melanoma Disease Management Team of the Memorial 
Sloan-Kettering Cancer Center.   Melanoma tumors are routinely genotyped for BRAF at 
MSKCC.  The Melanoma/Sarcoma service and the Melanoma Disease Management Team 
each hold weekly interdepartmental meetings to identify study participants for open clinical 
trials. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
The following procedures and assessments must be performed prior to treatment start: 
 
8.1      At any time prior to the start of the study 
 
• Histologic confirmation of melanoma by a MSKCC pathologist. 
• Assessment  of BRAF mutational status  (either primary or regional metastases)  by 
CLIA certified laboratory. 
 
8.2      Within 90 days of the start of study 
 
• Complete surgical resection of Stage IIIC disease. This can be completed either at 
MSKCC or at an outside institution. 
• Patients may have adjuvant radiation therapy but all treatment must be completed 
and patients adequately recovered before beginning dabrafenib. 
 
8.3      Within 4 we e ks of the start of the study 
 
• Written Informed Consent 
• A contrast-enhanced CT or MR I of the brain 
• ECG 
 
8.4      Within 2 we e ks of the start of the study 
 
• Updated medical history and physical examination 
• A complete skin examination by dermatology or a consenting medical oncologist. 
• An eye examination by ophthalmology 
• Laboratory studies including a CBC with differential; comprehensive metabolic panel; 
serum phosphorous, magnesium and LDH levels. 


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• A serum pregnancy test for woman of child-bearing potential. 
• Appropriate radiologic assessment to assure no evidence of disease.  In general, th is 
will involve a CT scan (with contrast) of the chest, abdomen and pelvis; if the patient 
is not able to undergo a CT scan, a MR I with and without gadolinium may be used. 
For patients  with a primary melanoma below  the knee,  a PET scan with a non - 
contrast chest CT will also be acceptable. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1      Adjuv ant Dabrafenib 
 
Treatment  will be  administered  on  an  outpatient  basis.    Reported  adverse  events  an d 
potential risks are described in Section 11.  Appropriate dose modifications for dabrafenib are 
described below in Section 9.2.  No investigational or commercial therapies other than those 
described below may be administered with the intent to treat the patient’s malignancy. 
 
If all eligibility criteria are met, study participants will self-administer dabrafenib by mouth at a 
dose of 150 mg twice a day. Four weeks of treatment is one full cycle.  After each cycle (± 5 
days) the study participant will be seen in clinic for a complete clinical evaluation as detailed 
in section 10.0.    A pill diary will be provided to the patient and will be reviewed  at th e 
completion of each cycle (Appendix C).   This will be used to assure compliance with th e 
regimen.    In the absence  of treatment  delays  due to  adverse  event(s),  dabrafenib  will 
continue for 4 cycles or until one of the criteria listed in Section 13 apply. 
 
 
 
9.2      Dose Modification 
 
9.2.1    Dose Modifications Algorithm 
 
Management   of  symptomatic   adverse   drug  reactions   may  require   temporary 
interruption and dose reduction of dabrafenib treatment.  Table 1 describes the dose 
levels to be used for any necessary dose modifications. 
 
Table 1: Dabrafenib Dose Reduction Algorithm 
 
Dose Level Dose /Schedule 
0 
150 mg BID 
-1 
100 mg BID 
-2 
75 mg BID 
-3 
50 mg BID 


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9.2.2    Dose Modifications/Interruption for Toxicity 
 
The severity of adverse events will be graded utilizing the CTCAE version 4.0. 
Guidelines for dose modifications and interruptions for management of toxicities 
associated with the study treatment other than fever, neutropenia, rash, hand-foot 
syndrome, renal dysfunction, and QTc elongation are provided in Table 2.  Dose 
modifications  for fever and neutropenia are provided in Table 3 and 4, respectively. 
Dose modifications  for rash and hand foot syndrome are provided in Table 5 and 
Table 6, respectively.   Table 7 contains guidelines for the management of renal 
insufficiency. 
 
Dabrafenib must be withheld if the QTc exceeds 530 milliseconds.  This will be based 
on the average QTc value of triplicate ECGs.  For example, if an ECG demonstrates 
a prolonged QT interval, obtain 2 more ECGs over a brief period, and then use the 
averaged QTc values of the 3 ECGs to determine whether the subjects should have 
study medication withheld. 
 
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started 
on the study medication if the Investigator and Novartis Medical Monitor agree that the 
subject will benefit from further treatment. 


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Table 2: Dose Modification for non-he matologic and he matologic toxicity (exce pt ne utrope nia) 
 
Non-he matol ogic an d 
hematol ogic Toxicity 
(exce pt ne utr ope nia) 
Dos e Modi ficati on Algorithms a, b, d, e 
Grade 1 
Continue dabrafenib at full dos e, monitor as clinica lly indicated. 
Grade 2 
For Gr ade 2 Di arrhe a wi th acc ompan ying ris k fact ors c Hold 
dabrafenib until return to  Grade 1, provide s upportive care. 
For all other toxicities :  Cons ider holding dabrafenib until res olution to 
Grade 1 or bas eline; provide s upportive care as clin ically indicated. 
Monitoring of laboratory values s hould occur as clinica lly indicated. 
For Gr ade 2 or higher res pir at ory s ymptoms (i.e . c ough, dys pne a, 
hypoxia etc. ), eva luation by a CT s can is reco mmended. 
Grade 3 
For Gr ade 3 toxicity, hold dabrafenib until to xicity is Grade 1 or bas eline 
then reduce dos e of dabrafenib by 1 dos e level. The s ubject may be 
continued at the s ame dos e if, in the judgment of the inves tigator, the 
toxicity is cons idered to be unrelated to dabrafenib.  Continue to monitor 
as clinica lly indicated. 
If any Gr ade 3 toxicity recurs , hold dos ing until Grade 1 or bas eline, 
then reduce current dos e of dabrafenib by one dos e level. 
Grade 4 
Dis continue dabrafenib.  Continue to monitor as clin ically ind icated, and 
provide s upportive care as needed 
If in the inves tigator’s judgment the toxicity is unlikely to recur then, hold 
until to xicity is Grade 1 or bas eline, then reduce dos e of dabrafenib by 1 
dose level.  If Grade 4 to xicity recurs after dos e reduction, dis cuss 
continuation of study drug with the Novartis Medical Monitor. 
a. 
The min imu m dos e is 50mg BID. If a s ubject requires dos e reduction below 50mg BID then the 
s ubject mus t be dis continued fro m s tudy medication. 
b. For advers e events of abdominal pa in or s us pected pancreatitis , amylas e and lipas e laboratory 
s amples s hould be collected. 
c. 
Ris k factors for cancer t reat ment-induced diarrhea include: fever, orthos tatic s ymptoms (i.e. 
dizzines s ), abdominal pain/cra mping, or wea knes s . 
d. If the s ubject has a Grade 3 or 4 laboratory abnormalities that, in the judgment of the inves tigator, 
is not cons idered clinica lly s ignificant, dos e modification is not required. 
e. 
For s ubjects who develop s ymptoms as sociated with uveitis including blu rry vis ion, eye pain o r 
erythema ophthalmo logic cons ult is required. 


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Table 3: Dose Modification and Guide lines for Manage me nt of Ne utrope nia 
 
Gr ade 
ANC val ue 
K/ mcl 
Manage ment of Ne utr openi a 
Dabrafeni b 
Dos e Adjus tme nt 
1 
1.5 to LLN 
• 
Monitor per protocol s tudy 
calendar. 
• 
Continue at current dos e 
2 
1.0 to <1.5 
• 
Re-check ANC in 1 week.  If 
improve ment to grade 1, 
continue to monitor per s tudy 
calendar. 
• 
If s table at grade 2, monitor 
ANC every 2 wee ks until 
res olution to grade 1 or until 
s table for 4 weeks 
• 
If wors ens to grade 3 or 4 follow 
below. 
• 
Any occurrence: continue at 
current dos e 
3 
0.5 to <1.0 
• 
Re-check ANC at leas t weekly 
during dos e interruption. 
• 
If res olved to grade 1, re -check 
ANC 3 days after rechallenge 
with dabrafenib and then 1 week 
later. 
• 
Any occurrence: hold until 
return to grade 1, then reduce 
one dos e level 
• 
1st recurrence:  d is continue 
dabrafenib or hold until return to 
grade 1, then reduce one dos e 
level 
• 
2nd recurrence:  d is continue 
dabrafenib. 
4 
< 0.5 
• 
Re-check ANC at leas t weekly 
• 
If res olved to grade 1, re -check 
ANC 3 days after rechallenge 
with  dabrafen ib and then 1 wee k 
later. 
• 
Dis continue or hold until return 
to grade 1, then reduce 
dabrafenib by one dos e level. 
• 
1st recurrence  dis continue 
dabrafenib 


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Table 4: Dose Modification and Guide lines for Manage me nt of Feve r 
 
Definiti on 
Dos e Modi ficati on 
Algorithms 
Dabrafeni b Dos e 
Adjus tment 
Co mplicated 
fever. 
(≥38.5⁰ C or 
101.3⁰ F ) 
Grade  3 or any grade 
with s igns and 
s ymptoms including; 
rigors , dehydration, 
hypotens ion, dizzines s 
or wea knes s 
• 
Subject mus t  be 
evaluated in clin ic 
• 
Labs : Obtain blood 
s ample to as s ess ANC, s 
erum creat inine and 
BUN if s amp le was not 
collected within 3 days 
of the fever. 
• 
Evaluate fo r s igns and 
s ymptoms of infect ion 
and cons ider work up as 
clin ically indicated. 
• 
If s igns and symptoms 
of dehydration occur, 
cons ider intravenous 
hydration. 
• 
When restarting drug, 
adminis ter 
acetaminophen 500 mg 
or ibuprofen 400 mg (or 
s uitable alternative) 
prophylactically BID 
with s tudy drug for 2-3 
days . 
• 
Re-check ANC 1 week 
after the s tart of fever; 
encourage s ubject to 
take oral te mperature 
daily fo r 4 weeks after 
res tarting dabrafenib. 
• 
Interrupt dabrafenib 
immed iately and hold 
until fever res olves to 
<38.0⁰ C  or 100.4⁰ F and 
accompanying 
s ymptoms res olve 
• 
At rechallenge reduce 
dose of dabrafenib by  
one dos e level. 
Uncomp licated 
Fever 
(≥38.5⁰ C or 
101.3⁰ F) 
defined as grade 2 
without s igns and 
s ymptoms as des cribed 
above 
• 
Encourage oral 
hydration. 
• 
If s ubject is s een in the 
clin ic, obtain blood 
s ample to as s ess ANC, s 
erum creat inine and 
BUN if s amp le was not 
collected within 3 days 
of the fever 
• 
Evaluate fo r s igns and 
s ymptoms of infect ion 
and cons ider work up as 
clin ically indicated. 
• 
If s igns and symptoms 
of dehydration occur, 
follow a lgorith m for 
complicated fever. 
• 
When restarting drug, 
adminis ter 
acetaminophen 500 mg 
or ibuprofen 400 mg (or 
s uitable alternative) 
prophylactically BID 
• 
Hold until fever res olves 
to <38.0 ⁰ C or 100.4⁰F . 
• 
Dabrafenib may be 
res tarted at the original 
dose level or reduced 
one dos e level as 
clin ically indicated. 


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with s tudy drug for 2-3 
days . 
• 
Re-check ANC 1 week 
after the s tart of fever; 
encourage s ubject to 
take oral te mperature 
daily fo r 4 weeks after 
res tarting dabrafenib. 
 
1. 
If fever does not recur after 3 days , prophylactic antipyretics may be dis continued or tapered. 
 
 
 
Table 5: Guide lines for Sk in Ras h Manageme nt 
 
S kin Toxicity 
Gr ade 
(CTCAE v 4.0 ) 
Gui deline for Manageme nt 
Dos e Re duc tion 
1 
Topical cort icos teroids (mo metas one, 
betamethas one, or fluocinonide 
crea ms ) 
None 
2 
As for grade 1, with the addition of 
diphenhydramine 50 mg bid, o ral 
prednis one (s hort cours e) 
None: if unacceptable to s ubject or medica lly 
concerning then hold until recovery to 
 Grade 1.   Res tart at s ame dos e. 
3 
Hold until recovery to  Grade 1.  Then 
reduce the dos e by one dos e level. 
 
 
Table 6: Guide lines for Hand-Foot Syndrome 
 
Grade 
Occurre nce 
Dose Modification 
Grade 1: Minimal skin 
changes or 
dermat it is (e.g., eryt hema, 
edema, or hyperkerat osis) 
wit hout pain 
Any occurrence. 
Continue treatment with dabrafenib and s tart topical 
therapy a for s ymptomatic relief. 
Grade 2: Skin changes 
(e.g., peeling, 
blist ers, bleeding, edema, or 
hyperkeratosis) with pain; 
limit ing instrument al ADL 
1s t occurrence. 
Continue treatment with dabrafenib and s tart topical 
therapy a for s ymptomatic relief.  Ins truction on life-s tyle 
modifications s hould als o be given .b 
If no improve ment within 28 days , s ee below 
No imp rovement 
within 28 days or 
additional 
occurrence. 
Interrupt dabrafenib treatment until to xicity res olves to 
Grade 0-1.c 
When resuming treat ment, decreas e dabrafenib dos e by 
one dos e level. Continue topical therapy a for 
s ymptomatic relief.  Ins truction on life-s tyle 
modifications s hould als o be givenb 
Grade 3 or intolerable 
grade 2: Severe skin 
changes (e.g., 
peeling, blist ers, bleeding, 
edema, or hyperkerat osis) 
wit h pain; limit ing self care 
ADL 
1s t or 2nd 
occurrence. 
Interrupt dabrafenib treatment until to xicity res olves to 
Grade 0-1.c 
When resuming treat ment, decreas e dabrafenib dos e by 
one dos e level. Continue topical therapy a for 
s ymptomatic relief.  Ins truction on life-s tyle 
modifications s hould als o be given.b 
3rd occurrence. 
Dis continue dabrafenib treatment. 
 
a. 
Topica l therapy includes the follo wing options ; keratolytics (e.g. urea 40%), high potency 
corticos teroids  
(fluocinonide, c lobetas ol)oral analges ia (non -s teroidal anti-infla mmatories or 
narcotics ) 
b. Lifes tyle modificat ions include; avoidance of exces s ive temperatures , e xe rcis e, and ill-fitting 
clothing/shoes . Us e of s oft s lippers (Tempurpedic or Crocs ), friction -re lieving meas ures (calfs kin, 


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gels ). 
c. 
HSFR us ually res olves within 2-4 weeks of drug ces s ation. 
 
 
 
 
Table 7: Renal Ins ufficie ncy Guide lines 
 
Creatinine 
Gui delines for Manage ment 
For s ubjects with s 
erum creat inine increas 
e > 0.2 mg/dL but  0.5 
mg/d L above bas eline: 
1. 
Continue dabrafenib and re-check s eru m c reatinine within 1 wee k 
2. 
If s ubject has fever (T >/= 38.5C): treat pyre xia as per guidelines (pleas e note 
NSAIDs can induce renal ins ufficiency, es pecially in s ubjects with 
dehydration); encourage oral fluids 
3. 
If e levation in s eru m creat inine pers is ts beyond 1 week, pleas e contact 
med ical monitor 
For s ubjects with 
s erum creat inine ris e 
>0.5 mg/dL above 
bas eline or s erum 
creatinine >2 mg/d L: 
1. 
Interrupt dabrafenib 
2. 
If s ubject has fever (T >/= 38.5C): treat pyre xia as per guidelines (pleas e note 
NSAIDs can induce renal ins ufficiency, es pecially in s ubjects with 
dehydration); cons ider IV hydration 
3. 
Follow s eru m creat inine at leas t twice weekly (or cons ider hospitalization if 
s erum creat inine cannot be monitored frequently) 
4. 
Cons ider renal cons ultation 
5. 
If s eru m c reatinine returns to bas eline, may res tart s tudy treatment at the s ame 
dose, or reduced by one dos e level at the inves tigator’s discretion. 
6. 
Cons ider renal b iops y if c lin ically indicated , for e xa mp le: 
a. 
Renal ins uffic iency pers is ts despite volume repletion 
b. Subject has new ras h or s igns of hypers ens itivity (s uch  as elevated 
eos inophil count) 
7. 
Prior approval of Med ical Monitor is required to re -init iate therapy if 
c. 
Subject’s s erum creat inine has not returned to bas eline 
d. There is evidence of thro mbotic microangiopathy 
 
 
9.3 
Drug Inte ractions 
 
9.3.1    Prohibited Medications 
 
The pathways for metabolism and elimination of dabrafenib are presently unknown in 
humans.  Preclinical in vitro data indicate that dabrafenib is primarily metabolized by 
CYP2C8, CYP3A4, and CYP2C19.   Dabrafenib is also a substrate of two cell 
membrane drug transporter proteins; human P-glycoprotein (PGP) and murine breast 
cancer  resistant  protein  1 (BCRP1)  in vitro.    Drugs  that  are strong  inhibitors  or 
inducers  of CYP3A, C YP2C8, PGP  or BCRP1, are prohibited because they may 
increase or decrease dabrafenib concentrations, respectively (see Appendix B). 
 
9.3.2    Cautionary Medications 
 
The following medications should be used with caution (see Appendix B): 
 
• Drugs that are mild/moderate inhibitors or inducers of CYP3A, CYP2C8, PGP 
or BCRP because they may alter dabrafenib concentrations. 


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• In  vitro   dabrafenib   inhibits   CYP2C8,   CYP2C9,   and  CYP2C19   activity. 
Concentration of medications metabolized by these enzymes may be altered 
by dabrafenib. 
 
 
• In  vitro  dabrafenib  induces  CYP3A4,  C YP2B6,  CYP2C8,  C YP2C9,  and 
CYP2C19.   Co-administration   of  dabrafenib   and  medications   which   are 
affected by the induction of these enzymes may result in loss of efficacy.   If 
co-administration of these medications is necessary, investigators should 
monitor subjects for loss of efficacy or consider substitutions of these medications. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1    Standard Ev aluation 
 
Study participants will be evaluated at the start of each 4 week cycle (± 5 days, see Table 8). 
At these visits, patients will be assessed clinically for melanoma recurrence, toxicity, and 
performance  status.  A full  physical  examination  with  standard  vital  signs  will  also  be 
performed in addition to an ECG and standard laboratories including a CBC, comprehensive 
metabolic panel, phosphorous, magnesium, and LDH.   Radiographic  evaluation of disease 
status will occur at the end of cycles 2 and 4.  Dermatological exams (to assess toxicity and 
to  screen  for  squamous  cell  carcinoma/keratoacanthomas)   will  also  be  done  at  the 
completion of cycles  2 and 4 or more frequently as indicated clinically.   Ophthalmologic 
exams  will be done at the completion of Cycle 1 and 3 or more frequently as indicated 
clinically.   Dabrafenib will be discontinued after 4 cycles of adjuvant therapy or sooner for 
disease recurrence or the development of any of the conditions listed in Section 13.0. 
 
After   the  completion   of  adjuvant   dabrafenib,   study  participants   will  undergo   active 
surveillance for disease recurrence.  Patients will present at 6 months for a medical history, 
physical examination with standard vital signs, standard laboratories, and a radiographic 
evaluation of disease status.    This assessment will be repeated every 3 months until the 
completion of the active follow-up period at 24 months from the date of surgical resection or 
at recurrence.   These assessments  and radiographic studies can occur 2 weeks earlier or 
later without being considered a protocol violation.   After 24 months, patients who remain 
free of disease will continue to undergo routine follow-up and disease assessment at the 
discretion  of  their  treating  physician.    Their  charts  will  be  reviewed  by  research  staff 
biannually to monitor for disease relapse and survival and data collection will be limited to 
survival status until the completion of the study. 


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Table 8: Pre tre atme nt Evaluation/Evaluation during Tre atme nt 
 
Screen 
i
 
Adjuvant Dabrafe nib 
j
 
Obse rvation 
h
 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Month 
6 
Ever y 3 
months 
24 
months/ 
End of 
S tudy 
Survi val 
(e ve ry 6 
months) 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
Pill D iary 
X 
X 
X 
X 
ECOG  Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
a
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Evaluation b, c 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
X 
Radiologic 
Evaluation d 
X 
X
k
 
X
k
 
X 
X 
X 
Dermatology 
Evaluation h 
X 
X 
X 
Ophthalmologic 
Evaluation h 
X 
X
X 
MRI Brain 
e
 
X 
X 
Tumor Biopsy 
f
 
X 
Research Bloods g 
X 
X 
X 
X 
X 
X 
X 
Surviva l Review 
X 
a: Co mplete phys ical e xa minat ion with s tandard vital s igns 
b: CBC, CM P, Phos phorous , Magnes ium and LDH 
c: Seru m β -HCG if applicab le 
d: CT -C/A/P with contras t (preferred) or M RI with and without gadolinium (if contras t allergy) or PET s can with non - 
contrast CT of the ches t (if below the knee me lanoma primary) 
e: Contras t enhanced CT-head is an acceptable alternative 
f:  Mandatory tumor b iops y at relaps e of dis eas e 
g: One 10cc lavender top , 2 ce ll-free DNA BCT tubes (Streck, Inc.), and 2 10 cc green top tubes at the firs t res earch 
blood draw; two 10cc green top tubes and 2 cell-free DNA BCT tubes (Streck, Inc.) thereafter as  indicated on the 
s tudy calendar. 
h: ± 2 wee ks 
i:  Re fer to Section 8.0, laboratories and ECG performed at s creening do not need to be performed at Cycle 1, wee k 1 if 
thes e s tudies were comp leted with in 7 days of Cycle 1, wee k 1. 
j:  Treat ment window ± 5 days for each cycle 
k: ± 1 wee k 


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10.2 
Corre lative Studies and Tumor Biopsies at Progression of Dise ase 
 
Pre-treatment  tumor material will be available  from the biopsy used to establish that the 
patient had stage IIIC melanoma or from the initial surgical resection of residual disease.  In 
patients who relapse, the standard of care is to obtain a biopsy to confirm progression.  This 
will also be available.  Biopsies will be performed either by the Principal Investigator or staff 
members from surgery, dermatology, or interventional radiology.  Tissue samples will either 
be collected  from  the  Tissue  Procurement  Service  (TPS)  after  appropriate  pathological 
review  or  directly  delivered  to  the Wolchok  Lab by a Research  Study  Assistant  or  lab 
member.  We shall coordinate samples within Pathology through Dr. Klaus Busam and/or 
any other appropriate members of the pathology service.   Tissue samples will be analyzed 
with the appropriate assays described in this protocol, and stored in the Immune Monitoring 
Facility in the Zuckerman Research Building under the supervision of Dr. Jedd Wolchok and 
Dr. Taha Merghoub. 
 
In addition, peripheral blood will be obtained on the first day of therapy and then ever y 3 
months for the duration of the study.   One 10cc lavender top tube and 2 10cc green top 
tubes of peripheral blood will be collected on the first day of treatment.   The lavender top 
tube will be utilized to extract germline DNA to serve a control for the genetic analyses 
described below. This tube of blood will be delivered by the research staff to the Wolchok 
Lab for storage and processing as described below. The green top tubes and all additional 
research bloods will be used for exosomes analysis.  These blood samples will be delivered 
to the laboratory of Dr. Jacqueline Bromberg for storage and processing as described below. 
 
DNA from pretreatment tumor, germline DNA from peripheral blood, and tumor DNA from 
progressing melanoma will be analyzed.  These studies will be performed in the laboratory of 
Dr. David Solit and Michael Berger using an exon capture assay.  This assay, designed by 
Dr. Berger, currently sequences all coding exons of 230 cancer-associated genes including 
PTEN, PIK3CA, AKT1, RB1, NF1, TP53, ERBB4 and others. In brief, tumor and normal DNA 
from each patient is used to generate a bar-coded library for sequencing analysis.  Libraries 
are then subjected to exon capture of all coding exons for the 230 gene panel using custom - 
designed probes generated using the Agilent SureSelect Target Enrichment system [31]. 
Hybridized DNA is then sequenced using Illum ina HiSeq 2000 instrumentation to generate 
paired-end 75-bp reads. Read pairs are assigned to the corresponding tumor samples 
according to the identity of each barcode and then aligned to the reference human genome 
(hg19) using the BWA algorithm [36], and performance metrics are calculated using the 
publically available suite of Picard tools (http://picard.sourceforge.net).  Sequence variants, 
sequence coverage, and copy number alterations in tumor samples are determined using 
additional  algorithms  developed  by  the  Medical  and  Population  Genetics  and  Cancer 
Genome  Analysis  groups  at the Broad  Institute,  including  the Genome  Analysis  Toolkit 
(GATK) [37, 38]. Both  tumor and matching normal DNA are analyzed simultaneously  to 
identify germline single nucleotide polymorphisms  (SNPs). In preliminary studies, we have 
generated  average  mean  read  coverage  of  over  500X  using  a  DNA  input  of  250-500 


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nanograms. Importantly, this assay can be carried in FFPE-derived DNA, underscoring the 
utility of exon capture sequencing in identifying genetic aberrations from FFPE tissue. 
 
Exosome analysis will be completed in the laboratories of Drs. David Lyden and Jacqueline 
Bromberg.   Exosomes will be purified and analyzed as previously described [34].   Briefly, 
fresh or frozen human plasma will be isolated by centrifugation followed by serial 
ultracentrifugation with or without filtration.  The L M10 nanoparticle characterization system 
(NanoSight)   will  be  used   for   real-time   analysis   of  particle   size,  concentration   and 
aggregation.   Exosomes will be further characterized by multiple methods including flow 
cytometry,   immunoblotting,   electron   microsc opy,   reverse   phase   high  pressure   liquid 
chromatography   with  mass  spectrometry   (HPLC-MS),   and  gene   expression   profiling 
analysis. Importantly, the concentrations of exosomal levels of TYRP2, VLA-4, HSP70, and 
the MET oncoprotein will be determined over time in each patient in an effort to prospectively 
evaluate exosomal content as biomarker of melanoma recurrence. 
 
Two tubes of blood (cell-free DNA BCT tubes (Streck, Inc.) or another appropriate tube for 
cFDNA)  will  be  collected  pre-treatment  and  every  time  research  bloods  are  collected 
thereafter as shown in Table 8, in order to measure circulating tumor-derived DNA.  Plasma 
will be stored until needed.  DNA will be extracted from plasma and analyzed by digital PCR 
in the Genomics Core Laboratory (Agnes Viale, head).   Probes will be used specific for both 
mutated and wild-type BRAF V600E or V600K to allow quantification of tumor-derived and 
non-tumor-derived D NA.  The hypothesis to be tested is that detection of circulating tumor - 
derived DNA will be an accurate measure of tumor recurrence. 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1    Adv erse Events 
 
An Adverse Event (AE) is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product or other protocol- 
imposed intervention, regardless of attribution. 
 
This includes the following: 
 
• AEs not previously observed in the patient that emerge during the protocol specified 
AE  reporting  period,  including  signs  or  symptoms  associated  with recur rence  of 
melanoma that were not present prior to the AE reporting period. 
 
• Complications   that  occur  during  the  study  as  a  result  of  protocol-mandated 
interventions (e.g., invasive procedures such as biopsies). 
 
• AEs that occur prior to assignment of study treatment that are related to a protocol- 
mandated intervention (e.g., invasive procedures such as biopsies or medication 
washouts). 
 
• Preexisting medical conditions that are judged by the investigator to have worsened 
in severity or frequency or changed in character during the protocol-specified AE 
reporting period. 


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11.2    Se rious Adverse Event 
 
Serious Adverse Events (SAEs) as defined by the FDA will be recorded and reported as 
detailed in section 17.2.   Recurrent melanoma will not be considered an SAE.   However, 
development of a new primary melanoma will be reported as a SAE. 
 
11.3    Asse ssment of Adv erse Events 
 
All adverse events  encountered  during the study will be evaluated according to the NC I 
Common  Toxicity  Grading  system  version  4.0.  Grade,  duration  and  treatment  will  be 
recorded.  Life  threatening  toxicities   and  serious   adverse  events   should  be  reported 
immediately to the Principal Investigator. 
 
11.4    Previously Reported Toxicities Associated with Dabrafenib 
 
The interim results of a phase I/II trial of the dabrafenib in patients with metastatic melanoma 
and other solid tumors were reported at ASCO in 2010 [15].  Dabrafenib was generally well 
tolerated with a manageable toxicity profile.  The majority of all AEs were reported as Grade 
1 and 2. Acute adverse events have been reversible upon discontinuation of dabrafenib and 
in most instances the drug can be re-started with a dose reduction. 
 
A comprehensive list of the previously reported drug-related toxicities associated with 
dabrafenib  as  well as  their  relative  frequencies  is  presented  below.  In addition,  a more 
complete  discussion  will  follow  regarding  a  subset  of  important  adverse  events  with 
guidelines for management and prevention. 
 
11.4.1  Likely Toxicities (>10%) 
• 
Anemia 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Anorexia 
• 
Constipation 
• 
Rash 
• 
Actinic keratosis 
• 
Hyperkeratosis 
• 
Squamous Cell Carcinoma (SCC) of the skin 
• 
Alopecia 
• 
Pruritus 
• 
Fatigue 
• 
Headaches 
• 
Pyrexia 
• 
Syncope 
• 
Arthralgias 
• 
Myalgias 
• 
Chills 


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11.4.2  Le ss Likely Toxicities (≥1% and <10%) 
• 
Leukopenia and Neutropenia 
• 
Hypophosphatemia 
• 
Abdominal Pain 
• 
Influenza-like Symptoms 
• 
Renal Dysfunction/Acute Renal Failure 
• 
Acrochordon 
• 
Cutaneous papillomas 
• 
Grover’s Disease 
• 
Palmar-Plantar Erythrodysesthesia (PPE) 
• 
Uveitis 
 
11.4.3  Rare But Serious (< 1%) 
• 
Pancreatitis 
• 
Drug Hypersensitivity Reactions 
• 
Uveitis/Iritis 
• 
Retinal Vein Occlusion 
 
11.5    Pyre xia 
 
Pyrexia has been observed in several patients on a number of ongoing clinical trials.  Fevers 
have occasionally been associated with hypotension, rigors, renal insufficiency/renal failure, 
weakness, dizziness, syncope, presyncope, dehydration, nausea, vomiting, and/or an 
influenza-like illness. Generally, this syndrome is observed within 30 days of initiating 
dabrafenib.  Study participants with pyrexia should be evaluated as detailed in Table 4. 
 
11.6    Acute Re nal Failure 
 
Acute renal failure and granulomatous interstitial nephritis have been reported in study 
participants receiving dabrafenib. In some cases, pyrexia may be associated with renal 
insufficiency/renal failure, possibly secondary to dehydration or hypotension. R enal function 
should be monitored carefully, especially in patients with pyrexia. Guidelines for the 
management of renal dysfunction can be found in Table 7. 
 
11.7    Squamous Ce ll Carcinoma of the Skin 
 
BRAF inhibition is associated with the development of squamous cell carcinoma (SCC) of the 
skin,  keratoacanthomas   (KA)  and  cutaneous   papillomas   [39].     The  median  time  to 
appearance is approximately 8 weeks into treatment.   All suspicious lesions should be 
completely  resected  by  a  dermatologist  and  submitted  for  pathologic  review.  A  dose 
reduction is not indicated for this adverse event. 
 
11.8    Ophthalmologic Effe cts 
 
Ophthalmologic effects including blurred vision (2%), uveitis and iritis (<1%), eye pain (<1%), 
visual impairment  (<1%) and reduced visual acuity (<1%) have been observed in clinical 
studies to date, with all events Grade 1 or 2. Retinal vein occlusions have also been reported 
with RAF inhibitors.  An ophthalmologic consult is required for subjects developing symptoms 
associated with uveitis including blurry vision, eye pain or erythema. 


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11.9    Re productive Risk 
 
Preclinical data indicate that dabrafenib is detrimental to the developing fetus.  Thus, fertile 
patients must not become pregnant or father a child while on study. Contraception should be 
utilized for the duration of the study and for at least 6 months after study completion.  Women 
should not breastfeed while on study. 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1    Asse ssment of Re lapse Free Surv ival 
 
Relapse free survival is defined as the time from surgical resection to the first recurrence or 
death as assessed by physical examination and radiographic evaluation.  All recurrences will 
be confirmed by biopsy and histologic evaluation. 
 
12.2    Asse ssment of Overall Survival 
 
Overall survival  is defined  as the time from  surgical resection to death or  last follow-up. 
Follow up will continue until the completion of the study. 
 
12.3    Asse ssment of Toxicity 
 
Toxicity will be graded by the NC I Common Toxicity Criteria (CTC) version 4.0 with e ach 
cycle of adjuvant dabrafenib. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
•    Recurrence of the underlying malignancy. 
 
 
• 
Unacceptable toxicity not improved with the recommended dose reductions will require 
cessation of the study drug. 
 
 
• 
Development of a secondary malignancy whose systemic treatment would interfere with 
the study.  This does not apply to the development of cutaneous SCC, a known adverse 
event associated with dabrafenib. 
 
• 
Development of an intercurrent medical illness in which further administration of the study 
drug, in the opinion of the Investigator and the treating physician, would be detrimental to 
the patient. 
  
•    Treatment delay of more than 14 days (longer delays must be approved by the Principal 
Investigator). 
 
 
•    Request of the patient to stop the study. 
 
 
• 
Inability of the patient to comply with the requirements  of the protocol for treatment or 
evaluation. 


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14.0 
BIOSTATISTICS 
 
This is a single institution phase II trial assessing the efficacy of adjuvant dabrafenib 
(GSK2118436) in patients with surgically resected AJCC stage IIIC melanoma characterized 
by a BRAFV600E/K  mutation.  The primary  endpoint  is  24 month  relapse-free  survival  rate. 
Patients will be enrolled within 90 days of surgical resection and monitored clinically and 
radiographically for relapse for recurrence for 24 months.  Data from our Center indicate that 
the relapse-free survival (RFS) for stage IIIC disease is only 24% at 2 years . 
 
A single stage design will be employed whereby a 24% relapse-free rate at 24 months is 
considered not promising, a 51% relapse-free rate at 24 months is considered promising, 
and the probabilities of a type I error (falsely accepting a non-promising therapy) and type II 
error (falsely rejecting a promising therapy) are set at 0.10 and 0.10, respectively.   Twenty- 
three patients will be accrued.  All patients will be followed for a minimum of 24 months.  At 
the end of the trial, if 9 or more patients are relapse-free at 24 months out of a total of 23 
patients then the treatment will be considered worthy of further investigation.   If 8 or fewer 
patients are relapse-free at 24 months in then the treatment will be declared negative.   The 
trial would be terminated early if at any time 15 patients relapsed or died before 24 months. 
This design yields a 0.90 probability of a positive result if the true relapse-free survival is at 
least 51% and yields a 0.90 probability of a negative result if the true relapse-free survival is 
24%. 
 
With  the exception  of those  patients  who  elect  to withdraw  consent,  all patients  will be 
followed with an intention-to-treat and will be evaluated for the primary endpoint as per the 
protocol study calendar. This includes patient who develop unacceptable toxicity from the 
agent, secondary malignancies, or an intercurrent illness as listed in section 13.0.  Patients 
who elect to withdraw  consent will be evaluated as follows.   If patients  relapse on study 
before withdrawing consent (failure), or if they withdraw consent after month 24 without 
relapsing (success), they are counted as events. If patients withdraw consent before month 
24 and before they relapse, then they are not events and will be replaced.  Patients, who are 
lost to follow up  at 24 months  or later, are counted  as successes  and will be censored 
beyond that point. 
 
Toxicities  will be tabulated according  to the NCI Common Toxicity  version 4.0.   Overall 
survival and relapse-free survival will be estimated using Kaplan-Meier methodology.  Overall 
survival  will be assessed  from  surgical  resection  to death  or  last follow-up;  relapse-free 
survival  will  be  assessed  from  surgical  resection  to  relapse,  death  or  last  follow-up. 
Explorative  correlative  studies   examining  the  genetic   heteroge neity  of  BRAF-mutated 
melanoma, genetic mechanisms of intrinsic and acquired resistance to dabrafenib, and 
circulating tumor-derived exosomes as a biomarker of disease recurrence will be reported in 
a descriptive manner. 
 
A total of 23 patients will be accrued to this study.  Enrollment is anticipated to take 6 to 12 
months and the study is expected to be completed in 30 to 36 months. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1    Re search Participant Re gistration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain  informed  consent,  by  following  procedures  defined  in  section  entitled  Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2    Randomization 
 
Not applicable. 
 
16.0 
DAT A M AN AGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. The data collected for this study will be entered into a secure 
database.  Source  documentation  will  be  available  to  support  the  computerized  patient 
record. 
 
16.1    Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow -up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random -sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
 
16.2    Data and Safety Monitoring 
 
The Data and Safety  Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address t he 
new policies set forth by the NC I in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.  The MSKCC  Data and 


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Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at: 
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring,   compliance  and  data  verification  audits,  therapeutic   response,  and  staff 
education on clinical research QA) and departmental  procedures  for quality control, p lus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored,  NC I cooperative group, etc.) Will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Participation  in the research  study  is  voluntary.  The patients  will be explained  the risk, 
benefits, toxicities/side  effects, treatment alternatives/options,  financial  costs/burdens  and 
the voluntary nature of the study. Informed consent will be obtained as detailed in section 
18.0. 
 
Benefits: It is possible that treatment with dabrafenib will result in improved relapse-free 
survival.  This could lead to improvement in overall survival. 
 
Costs: Dabrafenib is an investigational drug that will be provided by Novartis to all study 
participants.   Costs  for venipuncture  for  research bloods  will not  be billed to the patient 
unless part of by clinical blood t est venipuncture.  All other standard medical costs will be the 
responsibility of the study participants. Biopsies performed at progression of disease are a 
standard of care and will be billed to the patient.  Research testing on the tissue will not be 
charged to the subject.  BR AF testing, if not done prior to enrollment, performed to determine 
subject eligibility will not be billed to the patient. 
 
Incentives: No incentives will be provided to participants in the trial. 
 
Alternatives: Other treatment options are available for patients with stage IIIC melanoma who 
choose not to participate in this investigational study. Other alternatives include participation 
in another clinical trial, adjuvant high dose or pegylated interferon, adjuvant radiotherapy, or 
expectant observation. 
 
Confidentiality:  All research and medical records are confidential in accordance with He alth 
Insurance Portability and Accountability Act. Protected information will not be released or 
reported in any presentations or publications that may result from this study. 
 
17.1    Priv acy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 


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protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2    Se rious Adverse Event (SAE) Re porting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
•    Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
•    Medical record number 
•    Disease/histology (if applicable) 
•    Protocol number and title 
 
Data needing to be entered: 
 
•    The date the adverse event occurred 
•    The adverse event 
•    Relationship of the adverse event to the treatment (drug, device, or intervention) 
•    If the AE was expected 
•    The severity of the AE 
•    The intervention 
•    Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FD A assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FD A by the 
SAE staff through the IND Office. 
 
17.2.1  Definition of SAEs/Re porting to Nov artis and the National Comprehensive 
Cancer Network (NCCN) 
 
All AEs and SAEs will be collected from the initiation of the study drug until 28 days after 
discontinuation  of the last dose of the study drug.   Definitions for adverse events can be 
found in Section 11.  A serious adverse event is defined as any adverse event that: 
 
• Results in death 
• Is life-threatening 


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• 
Requires hospitalization or prolongation of an existing hospitalization 
• 
Results in disability/incapacity 
• 
Results in congenital anomaly or birth defect 
• 
Any event which requires intervention to prevent the previously stated outcomes 
 
In addition to standard institutional  practice and reporting,  all SAEs  must be reported to 
Novartis and NCCN within 24 hours.  The SAE should be recorded on an MSK CRDB SAE 
report and after de-identification faxed to the attention of: 
 
• 
Local Novartis Drug Safety and Epidemiology Safety Desk 
o Fax #: 877-778-9739 
o Should the designated SAE Fax# be non-functional please send SAEs 
to the designated SAE mailbox:  clinicalsafetyop.phuseh@novartis.com 
o Please include Novartis SAE report coversheet for any SAE report 
 
And: 
 
NCCN at ORPReports@nccn.org or fax to 215-358-7699 
 
Novartis may contact the PI/research staff for additional information, clarification, or current 
status of the subject for whom and adverse event was reported. 
 
 
 
18.0    INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals  will exp lain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are fr ee to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions  and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain  the aspects  of patient  privacy  concerning  research  specific  information.    In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 


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Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
  
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
 
 
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3. 
Romano, E., et al., Site and timing of first relapse in stage III melanoma patients: implications 
for follow-up guidelines. J Clin Oncol, 2010. 28(18): p. 3042-7. 
4. 
Kirkwood, J.M., et al., Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous 
melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol, 1996. 
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Eggermont, A.M., et al., Adjuvant therapy with pegylated interferon alfa-2b versus 
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Wheatley, K., et al., Does adjuvant interferon-alpha for high-risk melanoma provide a 
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Kirkwood, J.M., et al., A pooled analysis of eastern cooperative oncology group and 
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Verma, S., et al., Systematic review of systemic adjuvant therapy for patients at high risk for 
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Curtin, J.A., et al., Distinct sets of genetic alterations in melanoma. N Engl J Med, 2005. 
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Davies, H., et al., Mutations of the BRAF gene in human cancer. Nature, 2002. 417(6892): p. 
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Rubinstein, J.C., et al., Incidence of the V600K mutation among melanoma patients with 
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Solit, D.B., et al., BRAF mutation predicts sensitivity to MEK inhibition. Nature, 2006. 
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Bollag, G., et al., Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF- 
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Joseph, E.W., et al., The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell 
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Flaherty, K.T., et al., Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J 
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Chapman, P.B., et al., Improved survival with vemurafenib in melanoma with BRAF V600E 
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Sosman, J.A., et al., Survival in BRAF V600–Mutant Advanced Melanoma Treated with 
Vemurafenib. N Engl J Med, 2012(366): p. 707-717. 
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Falchook, G.S., et al., Dabrafenib in patients with melanoma, untreated brain metastases, 
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21. 
Long, G.V., et al., Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant 
melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. 
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22. 
Trefzer, U., D. Minor, and A. Ribas, BREAK-2: a Phase IIA trial of the selective BRAF kinase 
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Hauschild, A., et al., Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open- 
label, phase 3 randomised controlled trial. Lancet, 2012. 
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Chapman, P.B., et al. Updated overall survival results for BRIM-3, a phase III randomized, 
open-label, multicenter trial comparing BRAF inhibitor vemurafenib with dacarbazine in 
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mutation to the specific Raf inhibitor PLX4032. J Transl Med, 2010. 8: p. 39. 
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dependence in melanomas harboring (V600E)BRAF. Oncogene, 2012. 31(4): p. 446-57. 
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with the BRAF inhibitor GSK2118436 (GSK436). in ASCO Annual Meeting. 2011. J Clin 
Oncol 
28. 
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switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell, 
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RAS upregulation. Nature, 2010. 468(7326): p. 973-7. 
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Approval date: 20-Jun-2018 
Page 33 of 38 
 
 
 
 
 
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20.0 
APPENDICES 
 
Appendix A: ECOG/KPS Conversion Table 
 
Appendix B: Prohibited and Cautionary Medications 
 
Appendix C: Pill Diary 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 34 of 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A: ECOG/KPS Conversion Table 
 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Desc ription 
Perc ent 
Desc ription 
0 
Normal ac tivity. Full y ac tive , able to 
c arry on all pre-disea se per formanc e 
without restric tion. 
100 
Normal, no c omplaints, no e videnc e of 
disease. 
90 
Able to c arr y on normal ac tivi ty; minor 
signs or s ymptoms o f disea se. 
1 
Symptoms, bu t ambulator y. Res tric ted 
in ph ysic ally strenuou s ac ti vity, but 
ambulatory and able to c arr y out work of 
a light or seden tar y nature (e.g ., light 
housework, offic e work) . 
80 
Normal ac tivity with effor t; some signs or 
s ymptoms of disease . 
70 
Cares for self, unable to c arr y on normal 
ac tivity or to do ac ti ve work . 
2 
In bed <50% of the time. Ambulato r y 
and c apable of all sel f-c are, bu t unable 
to c arr y ou t an y wor k ac ti vitie s. Up and 
about more than 50% of waking hou rs. 
60 
Requires oc c asional assistanc e, bu t is 
able to c are for mos t o f his /her need s. 
50 
Requires c onsiderable assis tanc e and 
frequent medic al c are. 
3 
In bed >50% of the time. Capable of 
only limited self-c are, c onfined to bed or 
c hair more than 50% of waking hour s. 
40 
Disabled, requires spec ial c are and 
assistanc e. 
30 
Se verel y di sabled, ho spitali zation 
indic ated. Death no t imminent. 
4 
100% bedridden. Completel y disabled. 
Cannot c arr y on an y self -c are. T otally 
c onfined to bed or c hair. 
20 
Ve r y sic k, hospi taliza tion indic ated. 
Death no t imminent. 
10 
M oribund, fatal proc esses progres sing 
rapidly. 
Dead. 
Dead. 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 35 of 38 
 
 
 
 
 
5 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B:  Prohibited and Cautionary Medications 
 
PROHIBITED MEDICATIONS 
Strong CYP2C8/3A/PGP/BCRP1 Inhibitor/Inducer.  May alter levels of DABRAFENIB 
Therapeutic Area 
Clarithromyc in, telithromycin, rifamycin c lass agents (e.g.  rifampin, rifabutin, rifapentine), 
troleandomyc in 
Antibiotic s 
Itrac onazole, ketoc onazole, posac onazole, voric onazole 
Antifungals 
Nefazodone 
Antidepressants 
Gemfibrozil 
Hyperlipidemia 
Carbamazepine, phenobarbital, amiodarone, , phenytoin, s- mephenytoin, bosentan, 
mibefradil, c onivaptan 
M iscellaneous 
Cyc losporine 
Immunosuppressive agents 
 
 
CAUTIONARY MEDICATIONS 
CYP2C8/C9/C19 Substrates; these drugs may be altered (increased or decreased) by 
DABRAFENIB 
Therapeutic Area 
Cerivastatin 
HMG-CoA Reduc tase 
Inhibitors 
Tolbutamide, nateglinide, repaglinide 
Antidiabetic s 
Amitriptyline, c lomipramine, imipramine 
Antidepressants 
Mild/Moderate Inhibitor of CYP3A, CYP2C8, PGP and BCRP1; These drugs may 
increase concentrations of DABRAFENIB 
Therapeutic Area 
Erythromyc in 
Antibiotic 
Fluconazole 
Antifungal 


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IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 36 of 38 
 
 
 
 
 
Diltiazem, verapamil 
Antiarrhythmic s 
Aprepitant, c imetidine, montelukast 
M iscellaneous 
Substrates of CYP3A4/CYP2B6/CYP2C8/CYP2C9/CYP2C19 that may be affected by 
induction by DABRAFENIB; These drugs may lose efficacy when co-admistered with 
by DABRAFENIB 
Therapeutic Area 
Chloramphenic ol, doxyc yc line, erythromyc in, moxifloxac in 
Antibiotic s 
Caspofungin, fluc onazole, terbinafine 
Antifungals 
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, verapamil 
Antihypertensives 
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, pimozide, 
quetiapine, trazodone 
Antidepressants and 
Antipsyc hotic s Agents 
Glyburide, saxagliptin, tolbutamide 
Antidiabetic s 
Lamotrigine, valproate, divalproex, zonisamide, 
Antic onvulsants 
Alfentanil, buprenorphine, celecoxib, c odeine, fentanyl, methadone, oxyc odone 
Analgesic s 
Aprepitant, c isapride, darifenac in, disopyramide, leflunomide, methohexital, oral 
c ontrac eptives, quinine, ranitidine, solifenacin, sulfasalazine, tramadol, tolvaptan 
M iscellaneous 
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, zolpidem, zopiclone 
Hypnotic s and Sedatives 
Diergotamine, ergotamine, eletriptan 
Antimigraine agents 
Everolimus, sirolimus, tac rolimus 
Immunosuppressive 
agents 
Astemizole, c hlorpheniramine, ebastine 
Antihistamine 
Oral budesonide, methylprednisolone 
Cortic osteroids 
Sildenafil, tadalafil, vardenafil 
Erec tile Dysfunc tion 
agents 
Eplerenone 
Selec tive Aldosterone 
Bloc kers 
Disopyramide, dronedarone, mexiletine, propafenone, quinidine 
Antiarrhythmic s 
Lovastatin, atorvastatin, simvastatin 
HMG-CoA Reduc tase 
Inhibitors 
Cilostazole, warfarin 
Antic oagulants and 
Antiplatelets 
Ritonavir, nevirapine, efavirenz, zidovudine 
Antiretrovirals 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 37 of 38 
 
 
 
 
 
 
 
 
 
 
APPENDIX C 
 
Pill Diary for IRB #12-124 A(5): A Phase 2 Trial of Adjuvan t Dabrafenib (GSK2118436) in Patients 
with Surgically Resected AJCC Stage IIIC Melanoma Characterized by a BRAFV600E/K Mutation 
 
Number 
of 
Pills 
Given:                          
Total 
Daily 
Dose:                                 
(To be completed by RN) 
Pill Bottle(s) returned: Circle Yes or No 
Number of Pills returned:   
 
 
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT. 
 
SPECIAL INSTRUCTION:  DABRAFENIB is made as a 50 and 75 mg capsules.  Your study doctor will give you 
instruction on the number of pills you will take twice a day.  The doses should be taken about 12 hours apart. 
Taking the medication twice a day for four weeks is one complete cycle.  If you forget to take a dose, you should 
take the dose as soon as possible. The next dose can then be taken at its regularly scheduled time as long as it 
is at least 6 hours from the last dose. You must not eat anything for 1 hour before you take the medicine or for 2 
hours after you take the medicine.   If you vomit after you have taken the study medication,  do not take an 
additional dose before your next scheduled dose.  Please bring this completed log and any unused pill to each 
appointment. 
CYCLE #: _______  # of WEEK___________ 
 
 
 
DAY 
MEDICATION 
DATE 
TIME 
NUMBER 
of 50 mg tablets 
taken 
NUMBER 
of 75 mg tablets 
taken 
Example 
DABR AFEN IB 
01/01/2010 
9:00 
AM 
3 
DABR AFEN IB 
9:00 
PM 
3 
Day 1 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 2 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 3 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 4 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 5 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 6 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 7 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 8 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 


Memorial Sloan Kettering Cancer Center
IRB Number: 12-124 A(14) 
Approval date: 20-Jun-2018 
Page 38 of 38 
 
 
 
 
 
Day 9 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 10 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 11 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 12 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 13 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 14 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 15 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 16 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 17 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 18 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 19 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 20 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 21 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 22 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 23 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 24 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 25 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 26 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 27 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
Day 28 
DABR AFEN IB 
AM 
DABR AFEN IB 
PM 
 
 
Pa tient Signature: ___________________________________ ___ 
 Date: _____________ 
Consenting Professional Signature: __    _    __    _    _    _    _____  
Date: ___    _    __    __ 
Consenting Professional Comments: ______________________________________________ _______