INTERIM: a Randomised Phase II Feasibility Study of INTERmittent Versus Continuous Dosing or Oral Targeted Combination Therapy in Patients With BRAFV600 Mutant Stage 3 Unresectable or Metastatic Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: Cambridge University Hospitals NHS Foundation Trust

EudraCT number: 2016-005228-27         IRAS ID Number: 213113  
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INTERIM     
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Clinical Trial Protocol 
 
 
 
Trial Title: 
INTERIM: 
a 
randomised 
phase 
II 
feasibility 
study 
of 
INTERmittent versus continuous dosing of oral targeted 
combination therapy In patients with BRAFV600 mutant stage 3 
unresectable or metastatic Melanoma 
Protocol Number: 
INTERIM17  
 
EudraCT Number: 
2016-005228-27 
 
ISRCTN Number: 
18183156  
 
NIHR Portfolio CPMS: 
33584 
 
Investigational Product: Dabrafenib & Trametinib 
 
Protocol Version:  
V1.1 
 
Chief Investigator: 
Pippa Corrie 
 
CI Address: 
Oncology Centre, Box 193, 
Addenbrooke’s Hospital 
 
Hills Road 
 
Cambridge 
 
CB2 0QQ 
Telephone: 
01223 274401 
Trial Sponsor: 
Cambridge University Hospital NHS Foundation Trust 
 
R&D Department, Box 277 
Addenbrooke’s Hospital 
Hills Road 
Cambridge 
CB2 0QQ 
 
 
SAE Reporting: 
INTERIM Clinical Trial Coordinator 
 
Direct Line: 01223 216674 
 
Fax: 01223 586839 
 
Email: cctu.cancer@addenbrookes.nhs.uk 
 
An NCRI Skin Cancer Clinical Studies Group Trial 
 
 
 
 
                      
 
 

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1 
Protocol Signatures: 
I give my approval for the attached protocol entitled INTERIM: a randomised phase II 
feasibility study of INTERmittent versus continuous dosing of oral targeted in patients 
with BRAF mutant unresectable or metastatic Melanoma dated 21st September 2017 
 
Chief Investigator 
 
Name:  
 
 
Signature: 
________________________________________ 
 
Date: 
____________________________ 
 
 
 
Site Signatures 
 
I have read the attached protocol entitled INTERIM: a randomised phase II feasibility 
study of INTERmittent versus continuous dosing of oral targeted in patients with BRAF 
mutant unresectable or metastatic Melanoma dated 21st September 2017 and agree to 
abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined 
in the European Clinical Trials Directives 2001/20/EC and the GCP Directive 
2005/28/EC, the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 
2004/1031) and any subsequent amendments of the clinical trial regulations, the 
Sponsor’s SOPs, and other regulatory requirements as amended.  
 
I agree to ensure that the confidential information contained in this document will not 
be used for any other purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor 
 
Principal Investigator 
 
Name:  
 
 
 
 
Signature: 
________________________________________ 
 
Date: 
____________________________ 
 
 
 
 
 
 
 
 
 
 

EudraCT number: 2016-005228-27         IRAS ID Number: 213113  
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2 
Trial Contacts 
Dr Pippa Corrie  
(Chief Investigator) 
Cambridge University Hospital NHS Foundation Trust, 
Oncology Centre, Box 193, 
Addenbrooke’s Hospital, 
Cambridge, 
CB2 0QQ, 
Telephone: 01223 2744013 
Email: pippa.corrie@addenbrookes.nhs.uk 
Dr Rubeta Matin  
(Qualitative Research lead) 
Churchill Hospital 
Old Road, 
Oxfordshire, 
OX3 7LE 
Telephone: 01865 228264 
Email: rubeta.matin@ouh.nhs.uk 
Ms Elizabeth Gibbons 
(Qualitative Research deputy) 
Nuffield Department of Population Health 
University of Oxford 
Richard Doll Building 
Old Road Campus 
Oxford OX3 7LF 
Telephone: +44 (0)1865 289402 
Email: elizabeth.gibbons@dph.ox.ac.uk 
Dr Sarah Wordsworth 
(Health Economist) 
Health Economics Research Centre, Nuffield 
Department of Population Health, University of 
Oxford  
Old Road Campus, 
Headington 
Oxfordshire, 
OX3 7LF, 
Telephone: 01865 289268 
Email: sarah.wordsworth@dph.ox.ac.uk 
Professor Mark Middleton  
(Translational Research Lead) 
Churchill Hospital 
Old Road, 
Oxfordshire, 
OX3 7LE, 
Telephone: 01865 235315  
Email: mark.middleton@oncology.ox.ac.uk 
Anita Chhabra  
(Trial Pharmacist) 
Cambridge Clinical Trials Unit – Cancer Theme 
(CCTU-CT) 
S4, Box 279, 
Addenbrooke’s Hospital, 
Cambridge, 
CB2 0QQ, 
Telephone: 01223 596233 
Email: anita.chhabra@addenbrookes.nhs.uk 
Dr Wendi Qian 
(Trial Statistician) 
Cambridge Clinical Trials Unit – Cancer Theme 
(CCTU-CT) 
S4, Box 279, 
Addenbrooke’s Hospital, 
Cambridge, 
CB2 0QQ, 
Telephone: 01223 346363 
Email: wendi.qian@addenbrookes.nhs.uk 

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Gail Doughton  
(Senior Trial Coordinator) 
Cambridge Clinical Trials Unit – Cancer Theme 
(CCTU-CT) 
S4, Box 279, 
Addenbrooke’s Hospital, 
Cambridge, 
CB2 0QQ 
Telephone: 01223 216674 
Email: gail.doughton@addenbrookes.nhs.uk 
Claire Mather  
(Trial Coordinator) 
Cambridge Clinical Trials Unit – Cancer Theme 
(CCTU-CT) 
S4, Box 279, 
Addenbrooke’s Hospital, 
Cambridge, 
CB2 0QQ 
Telephone: 01223 348090 
Email: claire.mather@addenbrookes.nhs.uk 

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Table of Contents 
 
1 
Protocol Signatures: ................................................................................. 2 
2 
Trial Contacts ........................................................................................... 3 
3 
Abbreviations ........................................................................................... 7 
4 
Trial Synopsis ........................................................................................... 9 
4.1 
 Trial Flow Chart .................................................................................. 13 
5 
Introduction ............................................................................................14 
5.1 
Background ......................................................................................... 14 
5.2 
Choice of regimen and intermittent dosing schedule .................................. 15 
6 
Rationale for the INTERIM Trial ...............................................................16 
7 
Trial Design .............................................................................................17 
7.1 
Statement of design ............................................................................. 17 
7.2 
Number of Centres ............................................................................... 17 
7.3 
Number of Patients .............................................................................. 17 
7.4 
Patients Trial duration .......................................................................... 17 
7.5 
Trial objectives .................................................................................... 17 
7.6 
Trial Endpoints .................................................................................... 18 
8 
Selection and withdrawal of patients .......................................................19 
8.1 
Inclusion Criteria ................................................................................. 19 
8.2 
Exclusion Criteria ................................................................................. 20 
8.3 
Patient consent .................................................................................... 20 
8.4 
Screening Procedures and Pre-randomisation investigations ....................... 20 
8.5 
Treatment Assignment and Randomisation Number .................................. 22 
8.6 
Patient withdrawal criteria ..................................................................... 22 
9 
Trial Treatments ......................................................................................23 
9.1 
General Principles ................................................................................ 23 
9.2 
Investigational Medicinal products .......................................................... 23 
9.3 
Treatment  Summary ........................................................................... 24 
9.4 
Drug storage, supply and accountability .................................................. 25 
9.5 
Known drug reactions & interaction with other therapies ............................ 26 
9.6 
Dosage modifications............................................................................ 26 
9.7 
Additional treatment ............................................................................. 28 
9.8 
Treatment for Disease Progression ......................................................... 29 
9.9 
Co-enrolment guidelines ....................................................................... 29 
10 
Procedures and assessments ...............................................................29 
10.1 
Screening evaluation, pre-randomisation and randomisation procedures ...... 30 
10.2 
Trial assessments ................................................................................ 30 
10.3 
Disease Progression ............................................................................. 32 
10.4 
Follow-up if stopping treatment prior to disease progression ...................... 32 
10.5 
Follow-up if stopping treatment at or beyond disease progression ............... 33 
10.6 
End of Trial Participation ....................................................................... 33 
10.7 
Schedule of Assessments ...................................................................... 34 
10.8 
Trial restrictions ................................................................................... 36 
11 
Assessment of Safety ...........................................................................36 
11.1 
Definitions .......................................................................................... 36 
11.2 
Expected Adverse Reactions/Serious Adverse Reactions (AR /SARs) ............ 37 
11.3 
Expected Adverse Events/Serious Adverse Events (AE/SAE) ....................... 38 
11.4 
Evaluation of adverse events ................................................................. 38 
11.5 
Reporting serious adverse events ........................................................... 39 
11.6 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) .... 40 
11.7 
Pregnancy Reporting ............................................................................ 41 
12 
Evaluation of Patient Reported Outcome, Health Economics & Patient 
Experience Assessments ................................................................................41 

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12.1 
Patient Reported Outcome (PRO) ........................................................... 42 
12.2 
Health Economics assessments .............................................................. 43 
12.3 
Patient Experience evaluation ................................................................ 43 
13 
Research Blood and Tissue Samples .....................................................44 
13.1 
Translational Research .......................................................................... 44 
13.2 
Pharmacokinetics ................................................................................. 45 
14 
Statistics ..............................................................................................45 
14.1 
Number of Patients to be enrolled .......................................................... 45 
14.2 
Statistical analysis methods ................................................................... 46 
14.3 
Interim analyses .................................................................................. 48 
14.4 
Definition of the end of the trial ............................................................. 48 
15 
Data handling and record keeping ........................................................48 
15.1 
Case Report Form (CRF) ....................................................................... 48 
15.2 
Source Data ........................................................................................ 49 
15.3 
Data Protection & Patient Confidentiality ................................................. 49 
16 
Trial Committees ..................................................................................49 
16.1 
Trial management Group (TMG) ............................................................. 49 
16.2 
Independent Safety Data Monitoring Committee (ISDMC) .......................... 49 
16.3 
Trial Steering Committee (TSC) ............................................................. 50 
17 
Ethical & Regulatory considerations .....................................................50 
17.1 
Consent .............................................................................................. 50 
17.2 
Ethical committee review ...................................................................... 50 
17.3 
Regulatory Compliance ......................................................................... 50 
17.4 
Protocol Amendments ........................................................................... 51 
17.5 
Peer Review ........................................................................................ 51 
17.6 
Declaration of Helsinki and Good Clinical Practice ..................................... 51 
17.7 
GCP Training ....................................................................................... 51 
18 
Sponsorship, Financial and Insurance ..................................................51 
19 
Monitoring, Audit & Inspection .............................................................51 
20 
Protocol Compliance and Breaches of GCP ............................................52 
21 
Publications policy ...............................................................................52 
22 
References ...........................................................................................53 
23 
Appendices ..........................................................................................56 
23.1 
Appendix 1 – RECIST Version 1.1 ........................................................... 56 
23.2 
Appendix 2 – Karnofsky and ECOG Performance Status Scale ..................... 60 
23.3 
Appendix 3 – NYHA Functional Classification ............................................ 61 
23.4 
Appendix 4 - Trial Management / Responsibilities ..................................... 62 
23.5 
Appendix 5 – Authorisation of Participating Sites ...................................... 63 
23.6 
Appendix 6 Sample size ouput and predictive power ................................. 64 
23.7 
Appendix 7 - Safety reporting flowchart .................................................. 66 
23.8 
Appendix 8 – Reference Safety Information (RSI) ..................................... 67 
 

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3 
 Abbreviations 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Adverse reaction to an investigational medicinal product 
AST 
Aspartate aminotransferase 
CA 
Competent authority 
CCF 
Congestive cardiac failure 
CCTU-CT 
Cambridge Clinical Trials Unit – Cancer Theme 
CI 
Chief Investigator 
CR 
Complete response 
CRF 
Case report form 
CT 
Computerised tomography 
CTA 
Clinical Trial Authorisation 
CTCAE 
Common terminology criteria for adverse events 
ctDNA 
Circulating tumor deoxyribonucleic acids 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DSUR 
Development Safety Update Report 
EAS 
Expanded Access Study 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EORTC 
European Organisation for Research and Treatment of Cancer 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FBC 
Full blood count 
FDA 
Food and drug administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner 
Hb 
Haemoglobin 
HR 
Hazard ratio 
HRA 
Health Research Authority 
ICF 
Informed consent form 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
IQR 
Interquartile range 
ISDMC 
Independent Safety Data Monitoring Committe 
ITT 
Intention-to-treat Population 
IUD 
Intrauterine device 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LLN 
Lower Limit of Normal 
LVEF 
Left ventricular ejection fraction 
MAP 
Mitogen activated protein 
MHRA 
Medicines and healthcare products regulatory agency  

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MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 
Na 
Sodium 
NCI 
National Cancer institute 
NCI CTCAE 
National Cancer institute Common terminology Criteria for 
Adverse Events 
NHS 
National Health Service 
NICE 
National institute for Health and Care Excellence 
NIMP 
Non Investigational Medicinal Product 
NYHA 
New York Heart Association  
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PR 
Partial response 
PRO 
Patient reported outcome 
PRO-CTCAE 
Patient reported outcomes version of the Common Terminology 
Criteria for Adverse Events 
PROMS 
Patient reported outcome measures 
PSA 
Participating site agreement 
QALY 
Quality-adjusted life years 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
R&D 
Research and Development 
RA 
Regulatory Agency 
REC 
Research Ethics Committee 
RfPB 
Research for Patient Benefit 
RPED 
Retinal pigment epithelial detachment 
RSI 
Reference safety information 
RVO 
Retinal vein occlusion 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TIA 
Transient ischaemic attack 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UK 
United Kingdom                          
ULN 
Upper limit of normal range 
WBC 
White blood cell 
WCBP 
Women of child-bearing potential 
 

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4 
Trial Synopsis 
 
   
Title of clinical trial 
INTERIM: a randomised phase II feasibility 
study of INTERmittent versus continuous 
dosing of oral targeted combination therapy 
In patients with BRAFV600 mutant stage 3 
unresectable or Metastatic melanoma 
Sponsor name 
Cambridge University Hospitals NHS 
Foundation Trust  
EudraCT number  
2016-005228-27 
Medical condition or disease 
under investigation 
BRAFV600 mutant stage 3 unresectable or 
metastatic melanoma 
Purpose of clinical trial 
To investigate continuous versus intermittent 
dosing of dabrafenib plus trametinib in 
patients with BRAFV600 mutant stage 3 
unresectable or metastatic melanoma 
Primary objectives 
• To assess recruitment rate and treatment 
compliance of the intermittent dosing 
schedule as a measure of acceptance of 
intermittent dosing to patients and 
physicians; 
• To evaluate the impact on Overall quality 
of life (QoL) with intermittent dosing using 
European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30; 
• To estimate the size of clinical efficacy of 
intermittent dosing compared to  
continuous dosing, measured by 
progression-free survival (PFS). 
Secondary objectives 
• To evaluate safety, objective response 
rate, time to treatment failure and overall 
survival 
• To evaluate skin toxicity as assessed by 
clinicans and patients using patient 
reported outcome measures (PROMS) 
(Skindex-16 and patient-reported 
outcomes version of the CTCAE (PRO-
CTCAE)) 
• To assess factors which influence patients’ 
decision to enter/decline entering the trial 
• To evaluate patient experience of 
participation in this trial (using mixed 
methods) 
• To determine the QoL and cost-
effectiveness of intermittent dosing 
compared with standard continuous dosing 
Exploratory objectives 
• To explore emergence of resistance by 
means of circulating tumour DNA (ctDNA) 
collected from patients during the course 
of their treatment 

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• To determine the role of ctDNA as a useful 
biomarker for therapeutic monitoring 
• In a subset of patients (up to 20), explore 
pharmacokinetics of standard versus 
intermittent dosing schedules 
Trial Design  
INTERIM is a multi-centre, open label, two-
arm, randomised phase II feasibility trial.  
Trial Outcome Endpoints 
Primary endpoints: 
• 
Recruitment rate  
• 
Treatment compliance  
• 
Overall QoL (global health status) 
• 
PFS 
 
Secondary endpoints: 
• 
Safety  
• 
Objective response rate 
• 
Time to treatment failure 
• 
Overall survival (OS) 
• 
Patient reported outcomes 
focussing on skin toxicity 
• 
Patient experience consent and 
treatment 
• 
QoL and Health Economic 
Evaluation 
 
Exploratory endpoints: 
• 
Predictive biomarkers 
• 
Pharmacokinetics 
Sample Size 
150 patients 
Summary of inclusion criteria 
 
Main inclusion criteria: 
• 
Signed informed consent 
• 
Age ≥18 years old 
• 
Histologically or cytologically 
confirmed BRAFV600 mutant stage 3 
unresectable or metastatic melanoma 
• 
Measurable disease by Response 
Evaluation Criteria In Solid Tumors 
(RECIST V1.1)  
• 
Eastern Cooperative Oncology Group 
(ECOG) performance status 0-2 
• 
Minimum life expectancy 12 weeks 
• 
Adequate bone marrow, renal and liver 
function 
• 
Received no prior BRAF or MEK 
inhibitor therapy for metastatic disease 
• 
Willing and able to comply with the 
scheduled visits, treatment plans, 
laboratory tests, completion of QoL 
questionnaires and other trial 
procedures 
• 
Archival tumour tissue sample 
available  
Summary of exclusion criteria 
Main exclusion criteria: 
• 
Concomitant immunotherapy 

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• 
Other invasive malignancies diagnosed 
within last year 
• 
Significant acute or chronic medical or 
psychiatric condition, disease or 
laboratory abnormality 
• 
Women who are pregnant, plan to 
become pregnant or are lactating 
• 
Other investigational anti-cancer drugs 
• 
Use of strong inducers and inhibitors 
of CYP3A or CYP2C8 
Investigational medicinal product 
and dosage (Standard, 
Continuous arm) 
Dabrafenib 150mg twice daily 12 hours 
apart, on days 1 – 28 of a 28 day cycle. 
Trametinib 2mg once daily, on days 1 – 28 of 
a 28 day cycle 
Investigational medicinal product 
and dosage (Experimental, 
Intermittent arm) 
Dabrafenib 150mg twice daily 12 hours 
apart, on days 1 – 21 of a 28 day cycle. 
Trametinib 2mg once daily, on days 1 – 14 of 
a 28 day cycle 
Route(s) of administration  
Both drugs are administered orally 
Maximum duration of treatment 
of a patient 
Treatment will continue until disease 
progression or beyond, at the investigator’s 
discretion 
Procedures: Screening & 
enrolment 
Assessments for all inclusion and exclusion 
criteria will be performed within 28 days prior 
to randomisation. The key assessments are:   
• 
Written informed consent 
• 
Computerised tomography (CT) scan 
head/chest/abdomen/pelvis  
• 
Medical review 
• 
ECOG & Karnofsky performance status 
• 
Physical Examination & Blood Pressure 
• 
Haematology/biochemistry  
• 
Electrocardiogram (ECG) 
• 
Echocardiogram (ECHO) 
• 
Baseline skin record 
• 
QoL Questionnaires 
• 
Women of Child Bearing Potential 
(WCBP): Pregnancy Test as per local 
practise 
• 
Confirmation of archival tumour 
sample availability 
Procedures prior to 
randomisation 
• Confirmation that the patient satisfies all 
the eligibility criteria 
Treatment period procedures 
 
The key assessments are:   
• 
Clinical assessment and physical 
examination at 2,4,6 and 8 weeks, 
then every cycle until disease 
progression 
• 
CT scan chest/abdomen/pelvis +/- 
head at 6 weeks, then every 8 
calendar weeks until disease 
progression 
• 
ECOG & Karnofsky performance status 

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• 
Haematology/biochemistry  
• 
Adverse event documentation 
• 
QoL questionnaires at 4 weeks, then 
every calendar 12 weeks until end of 
the trial 
End of Trial 
End of trial for regulatory purposes is defined 
as 9 months from the date of randomisation 
of the last patient. Follow-up for survival will 
be a minimum of 9 months, maximum of 5 
years from date of randomisation of last 
patient, as survival beyond this point is 
unlikely. 
Procedures for safety monitoring 
during trial 
The Trial Management Group (TMG) and 
Independent Safety Data Monitoring 
Committee (ISDMC) will regularly review the 
patient safety data. Pharmacovigilance will be 
performed by the co-ordinating centre. 
Criteria for withdrawal of protocol 
treatment  
A patient may withdraw, or be withdrawn, 
from trial treatment for the following 
reasons: 
• 
Progression whilst on therapy 
• 
Unacceptable toxicity 
• 
Intercurrent illness which prevents 
further treatment 
• 
Patient choice 
• 
Any alterations in the patient’s 
condition which justifies the 
discontinuation of treatment in the 
investigator’s opinion. 
• 
No further clinical benefit expected 
• 
Patient misses more than 28 
consecutive days of planned treatment 
 
Following withdrawal of protocol treatment, 
patients will be followed up according to the 
protocol visit schedules. 

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4.1 
 Trial Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessments during treatment 
Clinical : every 2 weeks for  the first 2 cycles, and then prior to every cycle 
QoL:  Cycle 2 day 1 and every 12 calendar weeks thereafter 
Imaging assessment:  Cycle 2 Day 15 (week 6), and then every 8 calendar weeks   
Sample collection:  - blood for ctDNA Cycle 1 and 2 days 1 and 15, Cycle 3 day 1 and every other cycle thereafter  
 
       - tumour sample from any resected/biopsied progression lesion 
Eligible, consenting patients with stage 3 unresectable 
or metatastatic BRAF
V600
 mutant melanoma  
and  
Pre-randomisation QoL questionnaires completed, 
blood and tumour tissue to be collected prior to starting 
treatment 
Plan to start 
dabrafenib+trametinib  
  
Randomise  
Intermittent 
Dabrafenib 150mg bid d1-21 
   Trametinib 2mg od d1-14  
   (4 weekly cycle) 
Continuous 
Dabrafenib 150mg bid d1-28 
 Trametinib 2mg od d1-28 
 (4 weekly cycle) 
Assessments during follow-up  
  
Prior to progression: 
Clinical : every 4 weeks  
QoL: every 12 calendar weeks  
Imaging: every 8 calendar weeks 
After progression:  
Clinical and QoL: every 3 months with a minimum of 9 months follow-up from date of randomisation 

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5 
Introduction 
5.1 
Background 
 
Melanoma is the most lethal form of skin cancer: over 13,000 patients are diagnosed in 
the United Kingdom (UK) annually. Although the majority of patients are diagnosed 
with primary tumours that can be removed by surgery, around 20% will relapse. Recent 
developments in non-surgical treatments for metastatic melanoma have extended 
median survival from around 8 months to 2 years. Even so, for the majority of patients 
with advanced melanoma, this remains a terminal diagnosis: 5 year survival in 2011 
was 16%. (http://www.cancerresearchuk.org/aboutcancer/type/melanoma/treatment/ 
melanoma-statistics-and-outlook). 
 
There are two classes of drugs now established to treat metastatic melanoma: immune 
checkpoint inhibitors and, for the 45% of patients whose tumours harbour a BRAFV600 
gene mutation, mitogen activated protein (MAP) kinase pathway targeted small 
molecule inhibitors. In 2011, vemurafenib became the first BRAF kinase inhibitor 
approved for treatment of BRAF mutant metastatic melanoma, offering significant 
improvement in progression-free survival (PFS) and overall survival (OS) compared 
with standard chemotherapy (BRIM-3 trial1: median PFS 5.8 months, median OS 13.2 
months). Although remarkably high response rates are achieved with vemurafenib and 
another BRAF inhibitor, dabrafenib2, longer term experience suggested that most 
patients will suffer disease progression within 6-8 months of treatment due to emerging 
secondary resistance. 
 
Several resistance mechanisms have now been described, most of which result in re-
activation of intracellular signalling activity through MEK, downstream of BRAF3.  
Combined BRAF and MEK inhibition has been shown to be an effective strategy in the 
clinic, extending PFS and OS of treated metastatic melanoma patients compared with 
BRAF inhibitor alone4–6. Two BRAF and MEK combination regimens have been licensed 
for use to date: dabrafenib plus trametinib (dab+tram) and vemurafenib plus 
cobimetinib. Dab+tram received positive National Institute for Health and Care 
Excellence (NICE) guidance in June 2016 and is routinely available to treat patients 
with BRAF mutant advanced melanoma across the UK. Preliminary results of a trial 
comparing a third combination regimen, encorafenib plus binimetinib, with vemurafenib 
monotherapy reported improved OS in September 2016. Licensing of this regimen is 
predicted for 2018. BRAF+MEK inhibitor combination therapy has now largely replaced 
BRAF inhibitor monotherapy as standard of care worldwide. 
 
Despite these combination regimens improving patient outcomes, key challenges 
remain. Firstly, secondary resistance to therapy limits duration of benefit in most 
patients: median PFS with BRAF+MEK inhibitor combinations is around 12 months4–6. 
The need for effective strategies to overcome or delay the emergence of resistance has 
been highlighted in several international fora as a major research priority.  
 
Secondly, chronic toxicity associated with continuous daily dosing of oral molecular 
targeted agents is a recognised problem affecting patient compliance with treatment 
and requires active management7. The main toxicities of concern affect the skin, with 
rash and/or hyperkeratosis occurring in up to 40% of treated patients. Photosensitivity 
appears to be drug-specific and while almost universal in patients receiving 
vemurafenib, occurs in around 10% of patients receiving dab+tram. Interestingly, 
premalignant lesions and squamous cell skin cancers can occur in around 30% patients 
receiving BRAF inhibitor monotherapy, but the incidence reported with dab+tram is less 
than 5%, suggesting that addition of the MEK inhibitor attenuates BRAF-driven 

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hyperproliferation of normal skin. Although not usually life-threatening, these chronic 
skin adverse events mean that close patient monitoring is required and suspicious 
lesions need to be removed promptly.  
 
Other common side effects affecting patient quality of life (QoL) include fatigue and 
diarrhoea. Less common events include choreoretinopathy, hypertension and left 
ventricular failure. Unique to dab+tram is a syndrome of intermittent fevers and chills 
affecting over half of treated patients, often most prevalent at the onset on treatment. 
These 
symptoms 
occur 
most 
often 
in 
the 
absence 
of 
infection, 
although 
myelosuppression has been reported rarely. Even so, in a cancer population, 
hospitalisation and treatment for non-neutropenic sepsis is not uncommon. Toxicity is 
particularly concerning in older patients, who make up an increasing proportion of 
cancer sufferers in keeping with an ageing population. A large scale, multi-centre 
Expanded Access Study (EAS) of vemurafenib demonstrated a higher frequency of 
grade 3 and 4 adverse events in patients aged 75 years and over (59% had grade 3 
events vs 43% of under 75 years)8. 
 
The final key challenge is that BRAF+MEK inhibitors are high cost drugs and their 
prescription and toxicity management contribute to the rising overall health service 
expenditure. 
 
Clinical experience shows that intermittent dosing can successfully manage drug-
induced toxicity and sustain patients on BRAF targeted treatment. In the BRIM-3 trial1, 
38% of patients required modification and/or interruption of vemurafenib treatment. In 
the EAS, the proportion was even higher at 58%, but even so, outcomes in terms of 
PFS and OS were consistent with BRIM-3, suggesting that these changes in dosing do 
not compromise efficacy1,9. Therefore, pre-planned intermittent dosing of oral BRAF 
targeted agents may be an important way of sustaining patients on treatment for 
longer. Furthermore, intermittent drug dosing may delay the onset of disease 
progression, since continuous dosing promotes clonal expansion of drug resistant cells3. 
In a mouse model, vemurafenib resistant tumour cells were shown to become drug-
dependent10. Resistant cells suffered a fitness deficit in the absence of drug suggesting 
that intermittent dosing can delay or prevent the emergence of resistant tumour clones. 
Mice survived twice as long (200 days compared with 100 days) on an intermittent 
dosing schedule of vemurafenib (4 weeks on 2 weeks off) compared with continuous 
daily dosing. Clinical case reports also suggest that interrupted dosing of BRAF 
inhibitors can reverse resistance to the drugs11 and improve tolerability9. Intermittent 
dosing can attenuate relief of upstream feedback within the MAPkinase pathway, a 
mechanism known to contribute to drug resistance12. 
 
In summary, both preclinical and clinical data suggest that intermittent dosing could 
serve to eliminate the fitness advantage of resistant cells exposed to MAPkinase 
inhibitors, delay onset of disease progression and improve tolerability. These outcome 
benefits might be achieved with a reduction in health care costs. The intermittent 
dosing concept has never been formally tested in humans, but is the rationale for the 
INTERIM randomised trial. 
 
 
5.2 
Choice of regimen and intermittent dosing schedule 
 
The INTERIM trial is designed to test intermittent scheduling of optimal MAPkinase 
therapy in a BRAF mutant advanced melanoma population. Dab+tram is a routinely 
available BRAF+MEK inhibitor combination therapy accepted as the international 

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standard of care for these patients. Therefore, standard continuous administration of 
dab+tram will be compared with an intermittent dosing schedule of these two drugs. 
The choice of the intermittent dosing schedule has taken into account both 
pharmacokinetic and pharmacodynamic considerations as well as acceptability to 
patients and physicians. Dabrafenib has a 5.2 hour half life, but generates several 
active metabolites which persist, while trametinib has a mean terminal half life of 5.3 
days (Trametinib Summary of Product Characteristics [SmPC]). Taken together, the 
preclinical data suggest that a minimum of 1 week break from BRAF inhibitor and 2 
weeks break from MEK inhibitor is required to relieve inhibition of the MAPkinase 
pathway. The only published preclinical model of intermittent dosing is with 
vemurafenib: 4 weeks on 2 weeks off. Based on extensive experience using these 
targeted agents in the clinic as well as direct patient feedback, a 4 weekly intermittent 
dosing cycle has been designed for testing against standard of care: 
Continuous vs Intermittend Dosing cycles of Dabrafenib and Trametinib  
 
Standard Arm (continuous) 
Experimental Arm (intermittent) 
Dabrafenib 
150mg bid, d1-28 
150mg bid, d1-21 
Trametinib 
2mg od, d1-28 
2mg od, d1-14 
The intermittent dosing regimen aims to (1) be acceptable to patients and clinicians, 
(2) improve treatment tolerance, and (3) potentially overcome drug resistance thereby 
enhancing efficacy. 
 
6 
Rationale for the INTERIM Trial 
 
A strong scientific rationale argues for intermittent dosing of MAPkinase inhibitors. 
However, the concept of administering less rather than more treatment may be 
challenging in practice. A survey of metastatic melanoma patients receiving BRAF 
targeted agents identified that despite experiencing toxicity, most patients were either 
undecided or reluctant to consider interrupting their treatment either for 1 or 2 weeks 
(P Corrie, unpublished data). This feasibility trial aims to determine if intermittent 
dosing is deliverable, based on patient and professional willingness to take part in a 
randomised trial evaluating less than standard durations of treatment.  
 
The trial will evaluate treatment compliance, PFS and QoL, to inform whether a 
subsequent definitive trial is justified and how it should be designed. The trial will 
incorporate detailed clinician and patient (using patient reported outcome measures) 
evaluation of frequently occurring and problematic skin toxicities and will address the 
cost-effectiveness of an intermittent dosing regimen. In addition, tissue and blood 
samples will be collected to demonstrate proof of principle as well as to explore the role 
of circulating tumour DNA (ctDNA) as a non-invasive predictive biomarker in BRAF 
mutant melanoma. 
 
 
 
 

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7 
Trial Design 
7.1 
Statement of design 
 
INTERIM is a multi-centre, open label, two-arm, randomised phase II feasibility trial 
aimed at investigating the role of intermittent dosing of the combination BRAF and MEK 
inhibitor regimen, dab+tram. 
 
7.2 
Number of Centres 
 
Approximately 20 UK sites will participate. INTERIM is centrally co-ordinated at the 
Cambridge Clinical Trials Unit – Cancer Theme (CCTU-CT). 
 
7.3 
Number of Patients 
 
150 patients will be randomised 1:1. 
 
7.4 
Patients Trial duration 
 
The time from consent to randomisation is up to 28 days. The duration of treatment is 
until disease progression or beyond, at the investigator’s discretion. A minimum of 9 
months follow-up from the date of randomisation is required for all surviving patients.  
 
7.5 
Trial objectives 
7.5.1 
Primary Objectives 
• 
To assess recruitment rate and treatment compliance of the intermittent dosing 
schedule as a measure of acceptance of intermittent dosing to patients and 
physicians 
• 
To evaluate the impact on overall QoL with intermittent dosing using European 
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 
• 
To estimate the size of clinical efficacy of intermittent dosing compared to 
continuous dosing, measured by PFS 
7.5.2 
Secondary Objectives 
• 
To evaluate safety, objective response rate, time to treatment failure and overall 
survival 
• 
To evaluate skin toxicity as assessed by clinicians and patients using patient 
reported outcome measures (PROMS)  (Skindex-16 and patient-reported 
outcomes version of the Common Terminology Criteria for Adverse Events (PRO-
CTCAE)) 
• 
To assess factors which influence patients’ decision to enter/decline entering the 
trial 
• 
To evaluate patient experience of participation in this trial (using mixed 
methods) 
• 
To determine the QoL and cost-effectiveness of intermittent dosing compared 
with standard continuous dosing 
7.5.3 
Exploratory Objectives  
• 
To explore emergence of resistance by means of ctDNA collected from patients 
during the course of their treatment 
• 
To determine the role of ctDNA as a useful biomarker for therapeutic monitoring 
• 
In a subset of patients (up to 20), explore pharmacokinetics of standard versus 
intermittent dosing schedules 

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7.6 
Trial Endpoints 
7.6.1 
Primary Endpoints 
• 
Recruitment rate for endpoint analysis will be assessed once the trial has been 
recruiting for 15 months, or when 15 sites have been open for 6 months, 
whichever is sooner.  It will be measured as the average number of patients 
recruited per site per 2 months 
 
• 
Treatment compliance is defined as the percentage of patients completing the 
allocated treatment at 6 months from the date of randomisation. Although the 
primary aim is to assess the compliance of the intermittent dosing schedule, 
compliance of the standard continuous dosing schedule will also be assessed and 
compared with the experimental arm in an exploratory manner 
 
• 
Overall QoL is defined as the global health status score derived from the 
standard EORTC QLQ-C30 questionnaire at 6 months from date of randomisation 
 
• 
PFS is calculated as the duration from date of randomisation to the date of first 
progression or death from any cause, whichever occurs first. Progression is 
assessed according to standard Response Evaluation Criteria In Solid Tumours 
(RECIST v1.1 – appendix 1) 
 
7.6.2 
Secondary Endpoints 
 
• 
Safety is assessed using the standard cancer National Cancer institute (NCI) 
CTCAE v4.03 criteria  
 
• 
Objective Response Rate is assessed according to RECIST v1.1 (Appendix 1) 
 
Time to treatment failure  is  the time from starting drug treatment with 
dabrafenib+trametinib on day 1 of cycle 1 until the date of day 1 of the last cycle +28 
days;  
• 
Overall survival is calculated as the duration from the date of randomisation to 
the date of death from any cause 
 
• 
Patient reported outcomes focussing on skin toxicity evaluation is assessed 
using skin-specific patient reported outcome measures (PROM) – the Skindex-16 
and NCI PRO-CTCAE  
 
• 
Patient experience is assessed by a) patient experience survey of patients in 
each arm of the trial and b) semi-structured interviews in a subset of patients 
who have volunteered  
 
• 
QoL & Health Economic Evaluation: the EORTC QLQ-C30 and EQ5D generic 
measure of health status will be used for the cost-effectiveness analysis. 
 
7.6.3 
Exploratory Endoints 
Using blood and tumour tissue collected from recruited patients, we will explore:  
• 
the kinetics of BRAF mutation load in each arm of the trial  

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• 
emerging genetic changes associated with acquired resistance and whether 
these differ with intermittent therapy 
• 
the pharmacokinetics of intermittent drug scheduling 
8 
Selection and withdrawal of patients 
8.1 
Inclusion Criteria 
• 
Signed informed consent for the INTERIM trial  
 
• 
Aged ≥ 18 years old 
 
• 
Histologically or cytologically confirmed BRAFV600 mutant stage 3 unresectable 
or metastatic melanoma 
 
• 
Radiologically and/or clinically measurable disease, by RECIST version 1.1; 
baseline tumour assessments and measurements must be done within 28 days 
prior to randomisation 
 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 
 
• 
Predicted life expectancy >12 weeks  
 
• 
Adequate bone marrow function  
o 
Absolute neutrophil count (ANC) ≥1.2 x 109 /L 
o 
Haemoglobin (Hb) ≥ 90 g/L 
o 
Platelets ≥75 x 109 /L 
o 
   White blood cell count (WBC) ≥ 2 x 109 /L 
 
• 
Adequate liver function  
o 
Aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) ≤3 x upper limit of normal range (ULN) 
o 
Total bilirubin <1.5 x ULN (except if the patient has Gilbert Syndrome 
or liver metastases, in which case the bilirubin must be <3 x ULN) 
 
• 
Adequate renal function defined as a serum creatinine ≤1.5 x ULN or calculated 
creatinine clearance by Cockcroft-Gault of ≥40 mL/min 
 
• 
Received no prior BRAF or MEK inhibitors for metastatic disease (Prior adjuvant 
therapy is allowed) 
 
• 
Plan to start dabrafenib + trametinib treatment 
 
• 
If radiotherapy has previously been given;  there is measurable disease which 
has not been irradiated 
 
• 
Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, completion of QoL questionnaires and other procedures 
described in the protocol 
 
• 
Confirmation of archival tumour tissue sample available 
 
• 
Women of child-bearing potential (WCBP) and all sexually active male patients 
must agree to use effective contraception methods throughout treatment as per 
section 10.8 of this protocol 

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8.2 
Exclusion Criteria 
The presence of any of the following will exclude patients: 
 
• 
Concomitant immunotherapy being administered to treat advanced melanoma  
 
• 
Other invasive malignancies diagnosed within the last year which are not in 
complete remission, or for which additional therapy is required  
 
• 
Significant acute or chronic medical or psychiatric condition, disease or 
laboratory abnormality which in the judgment of the investigator would place the 
patient at undue risk or interfere with the trial. Examples include, but are not 
limited to: 
o 
Patients with uncontrolled ischaemic heart or other cardiovascular event 
(myocardial infarction (MI), new angina, stroke transient ischaemic attack 
(TIA), or new congestive cardiac failure (CCF)) within the last 6 months 
o 
Patients with stable but significant cardiovascular disease defined by heart 
failure (New York Heart Association Functional Classification (NYHF) III or 
IV, see Appendix 3) or frequent angina. Patients with baseline  QTC 
interval > 480 msec. 
o 
Presence of active infection  
o 
Cirrhotic liver disease, known chronic active or acute hepatitis B, or 
hepatitis C 
o 
Known allergy or hypersensitivity to dabrafenib or trametinib, or their 
excipients 
 
• 
Women who are pregnant, plan to become pregnant or are lactating during the 
trial period 
 
• 
Other investigational anti-cancer drugs  
 
• 
Use of strong inducers and inhibitors of CYP3A or CYP2C8 
 
 
8.3 
Patient consent 
Patients will be approached to consent to participate in this trial. Individuals who 
consent to the trial will be requested to complete a Consent Process Patient Experience 
Survey. Individuals who decline to participate will be invited to complete a separate 
Patient Experience Survey for individuals who declined, to explore their reasons for 
declining. 
 
Trial-specific screening activities will only be performed after patients have consented 
to trial participation and signed the informed consent form. 
 
8.4 
Screening Procedures and Pre-randomisation investigations 
The assessments below must be performed within 28 days prior to randomisation. 
 
• 
Patient must give written informed consent prior to any other trial-specific 
screening activities 
 
• 
QoL questionnaires 
 
• 
Medical history (including previous and current clinically important diseases and 
medications) and demographic data 

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• 
Physical examination, including assessment of weight and blood pressure  
 
• 
Concomitant medication assessment 
 
• 
Assessment of ECOG and Karnofsky performance status  
 
• 
Confirmation of disease diagnosis, stage and BRAF mutation status 
 
• 
Assessment 
of 
disease 
by 
Computerised 
tomography 
(CT) 
scan 
of 
head/chest/abdomen/pelvis, or Magnetic resonance imaging(MRI) if allergic to 
intravenous contrast and/or clinical measurements of visible/palpable disease; 
confirmation of measurable disease by RECIST version 1.1,  
 
• 
Biochemistry: urea, sodium (Na) , potassium (K), gamma glutamyl transferase 
(GGT), serum ALT or serum AST, total bilirubin, albumin, total protein, serum 
creatinine and creatinine clearance, serum calcium, alkaline phosphatase (ALP), 
lactate dehydrogenase (LDH)  
 
• 
Haematology: haemoglobin (Hb), WBC, differential ANC, platelets  
 
• 
Electrocardigoram (ECG)  
 
• 
Echocardiogram (ECHO) are standard safety monitoring of patients receiving 
dab+tram, not a research requirement – please refer to SmPC.  
o 
ECHO must be done as part of screening and left ventricular function 
confirmed to be >LLN prior to randomisation in patients with any 
significant cardiac history including: 
 
current hypertension defined as systolic BP > 140mm Hg or 
diastolic BP > 90mm Hg, or 
 
requirement for regular cardiac medication (other than aspirin or 
statin), or  
 
abnormal ECG 
o 
ECHO is not required at screening prior to randomisation, but must be 
performed before the Cycle 1 day 15 clinic visit in patients who fulfil all of 
the criteria below: 
 
no cardiac history 
 
normotensive 
 
normal ECG at screening 
 
• 
Women of child bearing potential: Pregnancy test (as per local hospital 
procedures) 
 
• 
Confirmation of the availability of archival tumour tissue  
 
• 
Verify that patient satisfies all protocol eligibility criteria 
 
• 
Baseline skin record completed (includes clinician record of skin assessment and 
baseline patient-reported PRO-CTCAE record) 
 
• 
Adverse Event (AE) assessment (recorded from the point of consent 
 
• 
Consent process Patient Experience Survey 
 

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The above screening procedures are summarised, together with the other procedures 
and assessments required throughout the trial, in Section 10.2 and the Schedule of 
Assessments in Section 10.7. 
 
8.5 
Treatment Assignment and Randomisation Number 
8.5.1 
Method of randomisation  
 
Eligible patients will be randomly assigned to either the standard continuous arm 
(dabrafenib 150mg bid d1-28, trametinib 2mg od d1-28) or the experimental 
intermittent arm (dabrafenib 150mg bid d1-21, trametinib 2mg od d1-14) in a 1:1 ratio 
using the minimisation with random element method.  Stratification factors are: 
• 
ECOG performance status  
• 
Disease stage (IIIc/IVM1a/IVM1b/IVM1c)  
• 
Presence or absence of brain metastases 
• 
LDH (<ULN; >ULN and <2 X ULN; >2 X ULN) 
 
8.5.2 
Procedure of randomisation 
A web-based central randomisation system supplied by Sealed Envelope will allocate 
patient randomisation numbers sequentially in the order in which the patients are 
enrolled. At the site initiation, the trial coordinator will arrange for the members of the 
trial team to be provided with a unique system username and password, which will 
allow them to access the central randomisation system.  
 
Following confirmation of eligibility and completion of pre-randomisation QoL 
questioinnaires, patient eligibility details will be sent to the INTERIM trial office. Patient 
data will be entered on the central randomisation system by the INTERIM trial office. 
The following data will be required in order to randomise a patient: 
• 
Confirmation that the patient satisfies all the eligibility criteria 
• 
Patient’s date of birth 
• 
Patient’s initials 
• 
Disease stage 
• 
ECOG PS 
• 
Baseline LDH 
• 
Presence of brain metastases (yes, no) 
• 
Date of archival tumour sample 
 
 
 
 
 
 
 
 
The treatment arm will be allocated and a unique trial number will be assigned by the 
randomisation system. Sites will receive email notification of randomisation details. 
 
8.6 
Patient withdrawal criteria 
8.6.1 
Withdrawal from Protocol Treatment 
A patient may withdraw from trial treatment for the following reasons: 
• 
Progression whilst on therapy  
• 
Unacceptable toxicity  
• 
Intercurrent illness which prevents further treatment  
• 
Patient choice  

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• 
Any alterations in the patient’s condition which justifies the discontinuation of 
treatment in the investigator’s opinion 
• 
No further clinical benefit expected 
• 
Patient misses more than 28 consecutive days of planned treatment (see section 
9.6.3) 
 
With ongoing consent, patients should remain in the trial and be followed up according 
to the protocol visit schedules.   
 
8.6.2 
Withdrawal of consent 
Patients may withdraw their consent to participate in the trial at any time. If the patient 
explicitly states their wish not to contribute further data to the trial, the investigator 
should inform the co-ordinating centre in writing and the withdrawal of consent should 
be documented by the investigator in the patient’s case report form (CRF). However, 
data and samples collected up to the time of consent withdrawal will be included in the 
data reported for the trial. 
 
9 
Trial Treatments 
 
9.1 
General Principles 
 
• 
Patients in both arms of the trial should begin their allocated treatments within 7 
days from the date of randomisation.  
 
• 
Safety assessments including haematology and biochemistry assessments are 
required prior to Day 1 treatment of each cycle for the first year and every other 
cycle thereafter. Safety assessments should also be performed, at the end of 
protocol treatment (30 days from the date of last protocol treatment dose 
administered); Details are provided in Section 10.2 and summarised in the 
Schedule of Assessments in Section 10.7. 
 
• 
Dosage modifications are summarised in Section 9.6. 
 
Specific details for the dabrafenib + trametinib regimen are given below. It is the 
responsibility of the investigator to ensure that recommendations in the UK SmPCs for 
administration of the dabrafenib and trametinib are followed. The SmPC is updated 
from time to time, up-to-date UK SmPCs are posted on the Medicine Guides Website 
http://www.medicines.org.uk.                         
 
9.2 
Investigational Medicinal products 
For the purpose of this trial, dabrafenib and trametinib are both considered as 
Investigational Medicinal Products (IMPs) conducted within a Clinical Trial Authorisation 
(CTA) under the Notification Scheme for Type A trials. 
9.2.1 
Legal status of the drugs and Risk Categorisation. 
The current regulatory framework in the UK/EU allows for a range of risk-adapted 
approaches.   
 
In this instance Dabrafenib and trametinib are both licensed for use in the UK for the 
treatment of BRAFV600 mutant stage 3 unresectable and metastatic melanoma. 

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Dabrafenib and trametinib are commercially available within the UK and are fully 
commissioned standard treatments for advanced melanoma. 
 
The INTERIM trial is designed to test intermittent scheduling of optimal MAPkinase 
therapy in a BRAF mutant advanced melanoma population. 
 
Clinical experience shows that intermittent dosing can successfully manage drug-
induced toxicity and sustain patients on BRAF targeted treatment. Intermittent dosing 
can attenuate relief of upstream feedback within the MAPkinase pathway, a mechanism 
known to contribute to drug resistance.  
 
Using the risk-categorisation method, this trial has been categorised as Type A.  
 
For further details of composition of either IMP, refer to the current version of the 
manufacturer’s Summary of Product Characteristics (SmPC) for the brand used, which 
can be accessed via the Electronic Medicines Compendium (eMC) website: 
http://www.medicines.org.uk/emc. A reference copy of both SmPCs can be found in the 
Investigator Site Files; please note however that these may not necessarily be the most 
up-to-date versions. 
 
 
9.3 
Treatment  Summary 
Patients will be randomised equally between the following arms and self administer 
both dabrafenib and trametinib. 
9.3.1 
Standard Arm: dabrafenib + trametinib standard arm (continuous 
schedule) 
Dabrafenib taken orally 150mg twice daily 12 hours apart, on days 1 – 28 of a 28 day 
cycle 
Trametinib taken orally 2mg once daily, on days 1 – 28 of a 28 day cycle 
 
9.3.2 
Experimental Arm: dabrafenib + trametinib experimental arm 
(intermittent schedule) 
Dabrafenib taken orally 150mg twice daily 12 hours apart, on days 1 – 21 of a 28 day 
cycle 
Trametinib taken orally 2mg once daily, on days 1 – 14 of a 28 day cycle 
 
9.3.3 
Duration of treatment 
Patients will continue on allocated treatment as long as they benefit from the treatment 
and it is tolerable (see section 8.6.1 for full protocol treatment withdrawal criteria) 
 
9.3.4 
Drug administration 
 
Dabrafenib 
Dabrafenib capsules are to be swallowed whole with water. The capsules should not be 
chewed or opened and should not be mixed with food or liquids due to chemical 
instability of dabrafenib. Dabrafenib should be taken at least one hour before, or at 
least 2 hours after a meal. 
 
It is recommended that the doses of dabrafenib are taken at similar times every day, 

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leaving an interval of approximately 12 hours between doses. When dabrafenib and 
trametinib are taken in combination, the once-daily dose of trametinib should be taken 
at the same time each day with either the morning dose or the evening dose of 
dabrafenib. 
 
Trametinib 
Trametinib should be taken orally with a full glass of water. Trametinib tablets should 
not be chewed or crushed. Trametinib should be taken without food, at least 1 hour 
before or 2 hours after a meal. 
 
It is recommended that the dose of trametinib is taken at a similar time every day.  
When dabrafenib and trametinib are taken in combination, the once-daily dose of 
trametinib should be taken at the same time each day with either the morning dose or 
the evening dose of dabrafenib. 
 
If a patient vomits after taking dabrafenib or trametinib, the patient should not retake 
the dose. The next scheduled dose should be taken at the normal time. 
 
For further details of administration  of either IMP, refer to the current version of the 
manufacturer’s Summary of Product Characteristics (SmPC) for the brand used, which 
can be accessed via the Electronic Medicines Compendium (eMC) website: 
http://www.medicines.org.uk/emc. 
 
 
9.4 
Drug storage, supply and accountability 
9.4.1 
Supply 
Both Dabrafenib and Trametinib are used within their licensed indication and general 
‘off the shelf’ supplies will be used. There is no requirement to ring-fence ‘off the shelf’ 
supplies of dabrafenib and Trametinib for the INTERIM trial. Both IMPs will be handled 
in line with manufacturer’s recommendations. For further details, refer to the current 
version of the manufacturer’s SmPC for the brand used. 
9.4.2 
Labelling (Type A) 
Under the Article 14 of Directive 2001/20/EC allows for adaptable provisions relating to 
labelling when the product does not require particular manufacturing or packaging 
processes and has a marketing authorisation. 
 
 
Dabrafenib and Trametinib will be used in accordance with the conditions set out in 
Regulation 46 (2) of the Medicines for Human Use (Clinical Trials) Regulations 2004 
(and amended in 2006). As both IMPs will be used within their licensed indication and 
under Type A categorisation, no special trial labelling requirements apply and both 
dabrafenib and trametinib may be labelled in accordance with the requirements of 
Schedule 5 to the Medicines for Human Use (Marketing Authorisation etc.) Regulations 
1994. 
9.4.3 
Storage, Formulation and Preparation 
Dabrafenib and Trametinib formulation, storage, and preparation are in line with the 
manufacturers’ recommendations. For further details, refer to the current version of the 
relevant manufacturer’s SmPC (via http://www.medicines.org.uk/emc) for the brand 
used. 
 

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9.4.1Use of 3rd Party Supply and Delivery of IMP  
IMP supply and/or  delivery to a participant or their home by 3rd party home 
community pharmacy or healthcare companies is permitted if this is in accordance with 
routine NHS practice at the participating trial site. The trial does not require any 
additional actions beyond existing standard care practices. CCTU  should be informed 
during the site set-up process, or if this is adopted during the life of the study. 
 
9.4.2 
Accountability and Patient compliance ( patient diaries) 
 
In this trial patient diaries and case report forms (CRF) will be used to capture 
information of IMPs dispensed/used. 
 
The sites will not require to keep detailed accountability records of batch numbers and 
expiry dates  of the IMPs dispensed.IMPs dispensed will be commercially available and 
may also be dispensed by a third party other then the trial site. 
 
Participating patients will be provided with a patient diary to keep detailed record of  all 
dabrafenib capsules and trametinib tablets taken by the patient during the trial.  
Study-site personnel will review dosing information with the patient (or legally 
authorised representative) on scheduled clinic visit days, providing instructions 
regarding dose, dose frequency and the number of tablets/capsules  to be taken for 
each dose. Patients (or legally authorised representative) will be instructed to return  all 
unused tablets/capsules and containers (empty, partially used, and/or unopened) for 
compliance check at the next scheduled clinic visits.  
A compliance check and tablet/capsule  count will be performed by study personnel 
during clinic visits. Study site personnel will record compliance information on the case 
report form (CRF). 
 
 
9.5 
Known drug reactions & interaction with other therapies 
For known drug reactions please refer to the current UK SmPCs for dabrafenib and 
trametinib. The SmPC is updated from time to time. Up to date UK SmPCs are posted 
on the Medicines Guide Website: http://www.medicines.org.uk. 
 
9.6 
Dosage modifications 
9.6.1 
Dose level reduction guidelines 
 
Dose level 
Dabrafenib 
Trametinib 
Starting dose 
150mg bid 
2mg od 
1st dose reduction 
100mg bid 
1.5mg od 
2nd dose reduction 
75 mg bid 
1mg od 
3rd dose reduction 
50mg bid 
1mg od 
 
9.6.2 
Missed doses 
 
If a dose of dabrafenib is missed at the normal time, it should not be taken if it is less 
than 6 hours until the next dose. 
 
If a dose of trametinib is missed at the normal time, only take the dose of trametinib if 
it is more than 12 hours until the next scheduled dose. 

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If treatment is interrupted within a cycle for whatever reason, please keep to the 
planned 28 day cycle visit (see section 10 for further details). 
 
9.6.3 
Maximum permitted dose delay 
The maximum permitted dose delay for omitting both dabrafenib and trametinib when 
scheduled for administration in order to allow recovery from severe toxicity or 
unscheduled procedures (eg. appendectomy) is 28 days from day 29 of the cycle in 
which the dose is interrupted. If longer delays are required then the patient will be 
discontinued from the trial treatment.   
 
It is permitted for the patient to remain on trial if only one of the two drugs is either 
stopped temporarily for any amount of time or permanently due to toxicity.  
 
9.6.4 
Specific dose modifications 
Dose modifications or interruptions are not required for adverse reactions of actinic 
keratoses, keratoacanthoma, cutenous squamous cell carcinoma, or new primary 
cutaneous melanoma. 
 
In general, dose modifications (dose interruption, reduction, discontinuation) should be 
made to both drugs simultaneously, unless otherwise specified in Section 9.6.5 below. 
 
 
Grade CTCAE 
Dose Modification 
1-2 (tolerable) 
Continue treatment and monitor as clinically indicated 
2 (intolerable) or 3 
Interrupt treatment until toxicity is < grade 1, then resume 
treatment at a reduced dose level  
4 
Interrupt treatment until toxicity is < grade 1, then resume 
treatment at a reduced dose level, or discontinue permanently 
 
When an adverse event has been actively managed, dose re-escalation following the 
same dosing steps as for de-escalation is allowed. 
 
 
9.6.5 
Dose modifications specific to one of the two drugs 
9.6.5.1 Pyrexia 
Dabrafenib therapy should be interrupted if the patient’s temperature is > 38.5oC. 
Trametinib should be continued at the same dose. Patients should be evaluated for 
signs and symptoms of infection, including performing a Full blood count (FBC).  
 
Treatment for pyrexia should include use of antipyretics such as ibuprofen or 
acetaminophen/paracetamol. Use of oral corticosteroids should be considered when 
anti-pyretics are insufficient. 
 
If FBC is normal and there is no evidence of infection, restart dabrafenib treatment 
either at the same dose or reduced by one dose level if pyrexia is recurrent and/or is 
accompanied by other severe symptoms such as dehydration, hypotension or renal 
failure. 

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9.6.5.2 Uveitis 
Dose modifications are not required for uveitis as long as effective local therapies can 
control ocular inflammation. If uveitis is not controlled by local therapy, withhold 
dabrafenib until resolution, then restart dabrafenib reduced by one dose level. No dose 
modification of trametinib is required. 
9.6.5.3 Left ventricular ejection fraction (LVEF) reduction 
In the event of an absolute decrease of >10% in LVEF, withhold trametinib. No dose 
modification of dabrafenib is required. If the LVEF recovers, treatment with trametinib 
may be restarted at a dose reduced by one dose level with careful monitoring. Grade 3 
or 4 left ventricular cardiac dysfunction or if LVEF does not recover, trametinib should 
be permanently discontinued. 
9.6.5.4 Retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) 
New visual disturbance such as diminished central vision, blurred vision or loss of vision 
at any time requires interruption of trametinib and prompt ophthalmological 
assessment. No modification of dabrafenib is required. Retinal vein occlusion warrants 
permanent discontinuation of trametinib. For RPED, the following trametinib dose 
modification table must be used: 
 
 
Grade 1 RPED 
Continue treatment with retinal evaluation monthly until 
resolution. If RPED worsens follow instructions below and 
withhold trametinib for up to 3 weeks. 
Grade 2-3 RPED 
Withhold trametinib for up to 3 weeks 
Grade 2-3 RPED improving 
to grade 0-1 within 3 
weeks 
Resume trametinib at a lower dose (reduced by 0.5 mg) or 
discontinue trametinib in patients taking trametinib 1 mg 
daily 
Grade 2-3 RPED that does 
not improve to at least 
grade 1 within 3 weeks 
Permanently discontinue trametinib 
9.6.5.5 Interstitial lung disease/pneumonitis 
Patients developing new or progressive pulmonary symptoms and findings such as 
cough, dyspnoea, hypoxia, pleural effusion, pulmonary infiltrates which cannot be 
explained by malignancy should have their trametinib stopped. No dose modification of 
dabrafenib is required. Diagnosis of pneumonitis requires permanent discontinuation of 
trametinib. 
 
 
9.7 
Additional treatment 
Patients should receive full supportive care during and after the administration of 
dab+tram. Over the course of this trial, additional medications may be required to 
manage aspects of the disease state of the patients, including side effects from 
anticancer drugs or disease progression. Please refer to toxicity management guidelines 
supplied by Welsh & Corrie7. A copy of this reference publication will be supplied to all 
trial sites for ease of reference. Details of the concomitant medication given, including 
blood and blood products, must be recorded in the patient’s medical records and the 
CRF.  
 
Supportive care, including but not limited to anti-pyretics, corticosteroids, anti-emetic 
and anti-diarrhhoeal medications, may be administered at the discretion of the 
investigator, as medically indicated. Choice of agents should be according to local 

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practice. All non-cancer treatments that the responsible physician feels are appropriate 
are allowed.  
 
Palliative radiotherapy, surgery, transfusion with blood products and bisphosphonates 
are all allowed.  
 
 
9.8 
Treatment for Disease Progression 
Treatment for disease progression is based on the investigator’s discretion and local 
practice. Patients deriving clinical benefit may continue on their allocated regimen at 
the investigator’s discretion.  
 
Patients with RECIST disease progression and disease amenable to surgical resection 
can undergo surgical resection of progressing disease and may continue to receive 
dabrafenib + trametinib as per their allocated arm after surgical resection for as long as 
they continue to derive benefit, based on patient and physician assessment. The first 
RECIST progression date will be used for measuring PFS in this trial.   
 
All anti-cancer interventions will be recorded on trial CRFs during the on-treatment and 
follow-up periods. 
 
9.9 
Co-enrolment guidelines 
Patients who have not reached inoperable disease progression may not enrol in any 
other clinical protocol or investigational treatment trial while enrolled in this study 
unless observational in nature. 
 
10 Procedures and assessments 
 
Clinical Assessments 
Patients will be clinically assessed every 2 weeks during the initial 2 cycles, then prior 
to the beginning of every cycle until inoperable disease progression, then 3-monthly for 
a minimum of 9 months follow-up from their randomisation date. Patients remaining on 
treatment beyond 52 weeks may have their treatment visits and drug prescriptions 
extended to 8 weekly. 
 
Drug should be prescribed and dispensed on the day of the clinic visit, as per schedule 
of assessments (Section 10.7). A treatment cycle starts with the morning dose, 
therefore a clinic visit associated with the start of a new cycle may occur up to 2 days 
prior to day 1 of a treatment cycle. 
 
If a clinic visit is missed for medical reasons (for example, due to a hospital admission), 
drugs can be restarted between visits as appropriate according to where the patient is 
on their defined schedule and they should return to clinic at the next preplanned visit.  
 
If the beginning of a cycle is delayed the date when a patient is ready to restart 
treatment becomes the first day of the cycle and therefore clinical visits should be 
amended in line with the new cycle pattern ie up to 2 days prior to the start of the new 
cycle. Please note that imaging for disease measurement must remain on the 8-weekly 
calendar dates set on cycle 1 day 1. 
 
Scheduled safety assessments described in section 10.7 will be undertaken at 
scheduled clinic visits. 
 

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Imaging Assessments 
Tumour imaging assessments at baseline should be performed no more than 28 days 
prior to the date of randomisation.  After starting treatment the first scan will be at 6 
weeks and then every 8 calendar weeks (±7 days), until inoperable disease 
progression. Patients continuing their treatment/follow-up prior to disease progression 
beyond 52 calendar weeks can have their scanning frequency reduced to every 12 
calendar weeks. The same imaging modality as the baseline scans for a patient should 
be used throughout the trial. 
 
At baseline, imaging must include the brain by either CT or MRI modality. Cutaneous 
lesions can be included for measurable disease if photographed with a ruler depicting 
clearly the size of target lesion(s). The same method will be used to assess response of  
the cutaneous lesions identified at baseline throughout the trial, that is, two tumour 
assessments (one for each method) will be performed at each planned assessment time 
if the ruler method is used. 
 
For patients with brain metastases at baseline, reassessment of measurable disease 
must include brain imaging with the same modality as at baseline. For patients with no 
evidence of brain metastases at baseline, regular imaging of the brain is recommended, 
but investigators should follow local guidance. It is recommended that the brain be 
imaged at least every 16 calendar weeks. 
 
Summary information on timing of interventions, procedures and assessments are 
given in the Schedule of Assessment in Section 10.7. Details are listed below.  
 
 
10.1 Screening evaluation, pre-randomisation and randomisation 
procedures 
 
See section 8.4 and 8.5. 
 
10.2 Trial assessments 
10.2.1 
Timing of assessments 
For safety reasons, patients will attend clinic every 2 weeks in the first 8 weeks. A 
window of +/- 2 days is allowed for clinic visits and associated assessments to 
ensure a treatment cycle starts with the morning dose, to account for bank holidays 
and other unforeseen circumstances.  
 
For safety reasons, the first reassessment for measurable disease will be done at 
cycle 2 d8 – d15 (week 6) (the scan(s) can be planned for any time within an 8 day 
window). In order to ensure all scans are undertaken for when patients on either 
arm of the trial are taking tablets, subsequent scans will be every 8 calendar weeks 
(±7 days) thereafter ie. weeks 14, 22, 30 etc. 
 
The ‘Treatment Patient experience survey’ should be completed 9 months after 
randomisation within the trial. A subset of patients who volunteered, will be invited 
to take part in a semi structured interview at a later date. 
10.2.2 
Cycles 1 and 2, Day 1 and Day 15 
The following assessments are to be performed during cycles 1 and 2 on days 1 
(prior to drug treatment) and 15: 
 

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• 
Concomitant medication assessment 
• 
Drug compliance assessment  
• 
Adverse event (AE) assessment 
• 
For those patients experiencing skin AEs, additional skin toxicity questionnaires 
to be completed by the patient and clinician 
• 
ECOG and Karnofsky performance status 
• 
Physical examination, Weight & Blood Pressure 
• 
Haematology (WBC, differential ANC, Platelets, Hb)- Cycle 1, day 1 may be 
omitted if screening haematology is done within 2 weeks. 
• 
Biochemistry (Urea, Na, K, GGT, ALT or AST, Total Bilirubin, Albumin, Total 
Protein, Serum Creatinine, Creatinine Clearance, Serum Calcium, ALP, LDH) 
Cycle 1, day 1 may be omitted if screening biochemistry is done within 2 weeks. 
• 
CT/MRI scans for reassessment of measureable disease using RECIST version 
1.1 (Cycle 2 Between days 8-15  only) 
• 
QoL questionnaires (Cycle 2 day 1 only) 
• 
ECHO (any time during Cycle 2 only) 
• 
Prescription and dispensing of treatment (Day 1 only) 
• 
Research blood sample (baseline sample must be taken before starting drug 
treatment) 
• 
Pharmacokinetic research blood sampling (subset of patients only) on cycle 1 
day 1, cycle 2 day 15– see Section 13 for details 
 
10.2.3 
Cycles 3 and all subsequent cycles 
The following assessments are to be performed on day 1 of all cycles after cycle 2*: 
(prior to drug treatment). 
 
• 
Concomitant medication assessment 
• 
Drug compliance assessment 
• 
AE assessment 
• 
For patients experiencing skin AEs, additional skin toxicity questionnaires to be 
completed by the patient and clinician 
• 
ECOG and Karnofsky performance status 
• 
Physical Examination, Weight & Blood Pressure 
• 
Haematology (WBC, differential ANC, Platelets, Hb) 
• 
Biochemistry (Urea, Na, K, GGT, ALT or AST, Total Bilirubin, Albumin, Total 
Protein, Serum Creatinine, Creatinine Clearance, Serum Calcium, ALP, LDH) 
• 
QoL questionnaires (every 12 calendar weeks) 
• 
CT/MRI for reassessment of measureable disease using RECIST version 1.1 
(every 8 calendar weeks ie. week 14, 22, 30 etc).  Patients continuing treatment 
beyond 52 weeks can have their scanning frequency reduced to 12 weekly. 
• 
ECHO (during cycle 5 and subsequently every 3 cycles ie. cycle 5, cycle 8, cycle 
11 etc. while on treatment) 
• 
Prescription and dispensing of treatment  
• 
Research blood sample, cycle 3, cycle 4 and every other cycle ie. cycles 6, 8, 10 
etc while on treatment 
• 
Pharmacokinetic research blood sampling (subset of patients only) – see Section 
13 for timepoints. 
*If patients have been on treatment for more than 52 weeks, clinic visits can be every 
other cycle, with telephone follow-up to ensure patient review is at least every 4 weeks 
until progression. 
 

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10.2.4 
End of Treatment visit 
This visit can take place up to 30 days after treatment discontinuation. 
 
• 
Concomitant medication assessment 
• 
Compliance assessment 
• 
AE assessment 
• 
For patients experiencing skin AEs, additional skin toxicity questionnaires to be 
completed by the patient and clinician 
• 
ECOG and Karnofsky performance status 
• 
Physical Examination, Weight & Blood Pressure 
• 
Haematology (WBC, differential ANC, Platelets, Hb) 
• 
Biochemistry (Urea, Na, K, GGT, ALT or AST, Total Bilirubin, Albumin, Total 
Protein, Serum Creatinine, Creatinine Clearance, Serum Calcium, ALP, LDH) 
 
10.3 Disease Progression 
At the time of the protocol-defined disease progression (no more than 7 days after) and 
before further protocol treatment or any new treatment is initiated, the following 
assessments are required: 
 
• 
Concomitant medication assessment 
• 
Compliance assessment 
• 
AE assessment 
• 
ECOG and Karnofsky performance status 
• 
Physical Examination, weight & Blood Pressure 
• 
Haematology (WBC, differential ANC, Platelets, Hb) 
• 
Biochemistry (Urea, Na, K, GGT, ALT or AST, Total Bilirubin, Albumin, Total 
Protein, Creatinine Clearance, Serum Creatinine, Serum Calcium, ALP, LDH) 
• 
QoL questionnaires  
• 
CT/MRI for reassessment of measureable disease using RECIST version 1.1 
• 
Research blood sample 
• 
Pharmacokinetic research blood sampling (subset of patients only) – see Section 
13 
• 
In patients undergoing surgical resection or biopsy of a progressing lesion, a 
tumour sample will be requested. 
 
10.4 Follow-up if stopping treatment prior to disease progression 
Patients will be followed-up every 4 weeks (±7 days) after stopping treatment* until 
disease progression, as follows:  
 
• 
Physical examination, Weight & Blood Pressure 
• 
Concomitant medication assessment 
• 
ECOG and Karfnofsky performance status 
• 
QoL questionnaires (every 12 calendar weeks only) 
• 
CT/MRI for reassessment of measureable disease (every 8 calendar weeks) 
 
*If patients have been on treatment/follow-up for more than 52 weeks prior to disease 
progression, follow-up visits can be every 8 weeks, with telephone follow-up to ensure 
patient review is at least every 4 weeks until progression, and repeat imaging can be 
reduced to 12 weekly. 
 

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10.5 Follow-up 
if 
stopping 
treatment 
at 
or 
beyond 
disease 
progression 
Patients will be followed-up every three months  (±7 days) after disease progression 
for a minimum of 9 months from randomisation. At every three month follow-up, the 
following assessments should be completed: 
 
• 
Concomitant medication assessment 
• 
ECOG and Karnofsky performance status 
• 
Physical Examination, Weight & Blood Pressure 
• 
QoL questionnaires 
 
10.6 End of Trial Participation 
A patient’s participation in the trial will finish at the end of trial declaration (a minimum 
of 9 months from randomisation of the last patient). Following the end of the trial 
patients may remain on dabrafenib and trametinib if the treating physician believes it is 
in the patients’ best interest to do so. Once the trial has closed, the choice of schedule 
and doses will be at the discretion of the treating physician. 

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10.7 Schedule of Assessments 
 
Screening 
Pre-
randomisation 
Cycle 1 
Cycle 2 
Cycle 3 
onwards1 
End of 
Treatment 
4-weekly 
Follow-up 
(prior to 
progression)1 
Disease 
Progression 
3-Monthly 
Follow-up 
after 
progression 
Day 1 
 
Day 
15 
Day 
1 
Day 
15 
Day 1 
-28 days 
±2 days 
+ 30 days 
±7 days 
+7 days 
±7 days 
Inclusion/Exclusion Assessment 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
Physical Examination, weight & 
Blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline Skin Record 
X 
 
 
 
 
 
 
 
 
 
ECG3 
X 
 
 
 
 
 
 
 
 
 
ECHO 
X4 
 
 
X 
X5 
 
 
 
 
Concomitant medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance Assessment 
 
X 
X 
X 
X 
X 
X 
 
X 
 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Skin Toxicity Questionnaire6 
(Patient and Clinician)  
 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG and Karnofsky Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology7 &  Biochemistry8 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
RECISTv1.1 Disease measurement9 
X10 
 
 
 
X11 
Every 8 weeks (±7 days) until protocol defined disease 
progression11 
X 
 
Prescription & Dispensing12 
 
X 
 
X 
 
X 
 
 
 
 
Treatment w/ dab+tram – Std arm 
 
dab + tram D1-28 
 
 
 
 
Treatment w/ dab+tram – Exp arm 
 
dab D1-21 + tram D1-14 
 
 
 
 
QoL Questionnaires 
X 
 
 
X 
 
Every 12 weeks13 
X 
X 
Research blood sample 
 
X 
X 
X 
X 
X 
Cycle 4, day 1 
and then 
every other 
cycle 
 
 
X 
 
PK sampling14 
 
X 
 
 
X 
X 
Cycle 4, day 1 
and then 
every other 
cycle 
 
 
X 
 
Tumour tissue15 
X 
 
 
 
 
 
 
 
X 
 
Patient Experience Survey 
X16 
 
 
 
 
9 months after randomisation17  
Patient Experience Interview 
 
 
 
 
 
X 
 

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1) 
If patients have been on treatment, or progression-free follow-up, for more than 52 weeks, clinic visits can be every other 
cycle, with telephone follow-up to ensure patient review is at least every cycle until progression 
2) 
To include confirmation of disease diagnosis, stage and BRAF mutation status  
3) 
Then as clinically indicated  
4) 
Screening ECHO to be done prior to randomisation in patients with a cardiac history including current hypertension defined 
as systolic BP > 140mm Hg or diastolic BP > 90mm Hg, or requirement for regular cardiac medication (other than aspirin 
or statin), or an abnormal ECG.  In patients without a cardiac history who are normotensive with a normal ECG, the 
baseline ECHO should be done prior to Cycle 1 day 15 and is not mandated prior to randomisation. 
5) 
ECHOs are recommended to be repeated during cycle 5 and every 12 weeks thereafter whilst on treatment (ie. during 
cycles 8, 11, 14 etc.) as per SmPC guidance. The LVEF should be within normal limits to commence/continue treatment. 
6) 
If Skin AEs are reported, skin specific questionnaires to be completed 
7) 
Haematology: WBC, differential ANC, Platelets, Hb (Not required Cycle 1, day 1 if within 2 weeks of screening) 
8) 
Biochemistry: Urea, Na, K, GGT, ALT or AST,total bilirubin, albumin, total protein, Serum creatinine, Creatinine Clearance, 
serum calcium, ALP, LDH (Not required Cycle 1, day 1 if within 2 weeks of screening) 
9) 
Disease measurement will use CT/MRI scans (and ruler) and RECIST version 1.1 
10) Baseline imaging to include head aswell as chest/abdo/pelvis. If head scan is clear, imaging of head to follow local practice 
but recommended to be repeated at least every 16 calendar weeks 
11) Imaging to be performed at or during  week 6, then every 8 calendar weeks until disease progression. If follow-up 
continues prior to disease progression beyond 52 calendar weeks since start of treatment than imaging can be reduced to 
every 12 calendar weeks.  
12) Prescription & dispensing should be within 2 days prior to the first dose of each cycle, which should start with the morning 
dose 
13) Quality of Life Questionnaires to be completed every 12 calendar weeks at the closest clinical visit 
14) In a subset of consenting patients only, PK samples to be collected, see section 13 for further details 
15) Archival tumour block to be requested prior to randomisation; tumour sample to be collected from any resected/biopsied 
progression lesion 
16) Consent Process Patient Experience Survey 
17) Treatment Patient Experience Survey 
 

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10.8 Trial restrictions 
 
Women of child-bearing potential are required to use adequate contraception for the 
duration of treatment and for 4 months after the last dose. This includes: 
• 
Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap 
with spermicide) 
• 
True abstinence (where this is in accordance with the patients preferred and 
usual lifestyle) 
 
Please note: If a Hormonal based contraception (pill, contraceptive injection or 
implant etc) or Intrauterine Device (IUD) is used another method of contraception 
must also be used as dabrafenib may render hormonal contraceptives less effective 
 
Men are required to use adequate contraception for the entire duration of treatment 
and for 4 months after the last dose. This includes: 
• 
Barrier contraception (condom and spermicide) even if female partner(s) are 
using another method of contraception or are already pregnant 
• 
True abstinence (where this is in accordance with the patients preferred and 
usual lifestyle) 
 
The potential for sperm banking/egg collection should be discussed, where appropriate, 
according to local practice. 
 
11 Assessment of Safety  
11.1 Definitions 
11.1.1 
Adverse event (AE) 
 
Any untoward medical occurrence in a patient or clinical trial patient administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not considered related to the 
investigational medicinal product. 
 
Please note: Recording of all adverse events must start from the point of Informed 
Consent regardless of whether a patient has yet received a medicinal product. 
 
11.1.2 
Adverse reaction to an investigational medicinal product (AR) 
 
All untoward and unintended responses to an investigational medicinal product 
related to any dose administered. All adverse events judged by either the reporting 
investigator or the sponsor as having a reasonable causal relationship to a medicinal 
product qualify as adverse reactions. The expression reasonable causal relationship 
means to convey in general that there is evidence or argument to suggest a causal 
relationship. 
 
 

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11.1.3 
Unexpected adverse reaction  
 
An adverse reaction, the nature, or severity of which is not consistent with the 
current approved reference safety information (RSI) 
 
When the outcome of the adverse reaction is not consistent with the current 
approved RSI this adverse reaction should be considered as unexpected. 
 
The term “severe” is often used to describe the intensity (severity) of a specific 
event. This is not the same as “serious,” which is based on patient/event outcome or 
action criteria. 
11.1.4 
Serious adverse event or serious adverse reaction (SAE / SAR) 
 
Any untoward medical occurrence that at any dose: 
- 
results in death, 
- 
is life-threatening 
- 
requires hospitalisation or prolongation of existing inpatients´ hospitalisation, 
- 
results in persistent or significant disability or incapacity, 
- 
is a congenital anomaly or birth defect. 
- 
is an important medical event - Some medical events may jeopardise the patient 
or may require an intervention to prevent one of the above characteristics/ 
consequences. Such events (hereinafter referred to as ‘important medical 
events’) should also be considered as ‘serious’.  
 
Life-threatening in the definition of a serious adverse event or serious adverse 
reaction refers to an event in which the patient was at risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death if 
it were more severe. 
 
11.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent with 
the information set out in the Reference Safety Information 
 
11.1.6 
Reference Safety Information (RSI) 
The information used for assessing whether an adverse reaction is expected.   
 
 
For the INTERIM trial the Reference Safety Information is contained in the 
trial-specific RSI document approved by the MHRA for use in this trial and 
attached as appendix 8 – Reference safety information. 
  
 
11.2 Expected Adverse Reactions/Serious Adverse Reactions (AR 
/SARs) 
All expected Adverse Reactions are listed in the reference safety information contained 
in Appendix 8 as specified in section 11.1.6. This must be used when making a 
determination as to the expectedness of the adverse reaction.  
Use the following tables to determine expectedness: 

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• 
Table 1: To determine expectedness in relation to dabrafenib in patients taking 
dabrafenib monotherapy 
• 
Table 2: To determine expectedness in relation to trametinib in patients taking 
trametinib monotherapy 
• 
Table 3: To determine expectedness in relation to dabrafenib in patients taking 
dabrafenib in combination with trametinib 
• 
Table 4: To determine expectedness in relation to trametinib in patients taking 
trametinib in combination with dabrafenib 
 
If the adverse reaction meets the criteria for seriousness, this must be reported as per 
section 11.5. 
 
11.3 Expected Adverse Events/Serious Adverse Events (AE/SAE) 
For this trial the following events must not be reported as SAEs, but must be recorded 
on the patient CRF: 
• 
Disease progression or death as a result of disease progression 
• 
Elective hospitalisation and surgery for treatment of melanoma 
• 
Elective hospitalisation for pre-existing conditions that have not been 
exacerbated by trial treatment 
• 
Elective hospitalisation for trial treatment or disease related procedures unless 
associated with another serious event 
 
11.4 Evaluation of adverse events  
Adverse events will be recorded from the point of starting treatment until 30 days after 
the last dose of protocol treatment and resolution of all >grade 2 AEs . Individual 
adverse events should be evaluated by the investigator. This includes the evaluation of 
its seriousness, causality and any relationship between the investigational medicinal 
product(s) and/or concomitant therapy and the adverse event.   
11.4.1 
Assessment of seriousness  
 
Seriousness is assessed against the criteria in section 11.1.4.This defines whether the 
event is an adverse event, serious adverse event or a serious adverse reaction 
11.4.2 
Assessment of causality 
 
Definitely: A causal relationship is clinically/biologically certain. This is therefore an 
Adverse Reaction 
Probable: A causal relationship is clinically / biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product and there is a reasonable response on 
withdrawal. This is therefore an Adverse Reaction. 
Possible: A causal relationship is clinically / biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product. This is therefore an Adverse Reaction. 
Unlikely: A causal relation is improbable and another documented cause of the AE is 
most plausible. This is therefore an Adverse Event. 
Unrelated: A causal relationship can be definitely excluded and another documented 
cause of the AE is most plausible. This is therefore an Adverse Event. 
 
Unlikely and Unrelated causalities are considered NOT to be trial drug related 
Definitely, Probable and Possible causalities are considered to be trial drug related 
 
A pre-existing condition must not be recorded as an AE or reported as an SAE unless 

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the condition worsens during the trial and meets the criteria for reporting or recording 
in the appropriate section of the CRF. 
11.4.3 
Clinical assessment of severity 
All events should be graded for severity according to the NCI-CTCAE Toxicity Criteria 
(Version4. 03). CTCAE v4. 03 can be downloaded from the following URL: 
http://ctep.cancer.gov/reporting/ctc.html 
11.4.4 
Recording of adverse events 
All  Serious Adverse Events and Serious Adverse Reactions should be reported to the 
sponsor as detailed in section 11.5. 
 
Adverse events not meeting SAE criteria should be reported if they meet one of the 
following criteria: 
• 
Any grade > 2 CTCAE 
• 
Skin related AE of any grade (Adverse event of special interest) 
• 
Any other adverse event that the clinician considers to be clinically significant 
 
In the event of any skin AE being reported, the patient and clinician will complete the 
skin toxicity questionnaires. 
 
11.5 Reporting serious adverse events 
Each Principal Investigator needs to record all adverse events and report serious 
adverse events to the Chief Investigator using the trial specific SAE form within 24 
hours of their awareness of the event. The Chief Investigator is responsible for ensuring 
the assessment of all SAEs for expectedness and relatedness is completed and the 
onward notification of all SAEs to the Sponsor immediately but not more than 24 hours 
of first notification. The sponsor has to keep detailed records of all SAEs reported to 
them by the trial team.  
 
The Chief Investigator is also responsible for prompt reporting of all serious adverse 
event findings to the competent authority (e.g. MHRA) of each concerned Member State 
if they could: 
• 
adversely affect the health of patients  
• 
impact on the conduct of the trial  
• 
alter the risk to benefit ratio of the trial 
• 
alter the competent authority’s authorisation to continue the trial in accordance 
with Directive 2001/20/EC.  
 
An adverse event or reaction that meets serious criteria, irrespective of consistency 
(expected or unexpected) with the current approved Reference Safety Information 
contained in Appendix 8, must be reported to the Sponsor, with the exception of events 
listed within Section 11.3 Expected Serious Adverse Events.  
 
In the case of an SAE, the Investigator or designee must immediately:  
Complete a ‘Serious Adverse Event Form’ and Fax it to the CCTU-CT at 
Fax number: 01223 586839 
 
The SAE form should be completed and signed by an appropriate member of the site 
trial team and faxed within 24 hours of becoming aware of the event to the CCTU-CT. 
The Principal Investigator must counter sign as soon as possible.  
 
Even if only limited information is initially available, this should be provided and faxed 
on an SAE form. Further details should be submitted as soon as they become available. 

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Relevant AEs related to the SAE, in the opinion of the Principal Investigator, should be 
reported at the same time as the SAE.  
 
In the case of death or life-threatening events, in addition to faxing an SAE form to the 
CCTU-CT, please TELEPHONE the CCTU-CT (on day of awareness), on  
 
Tel number: 01223 216083 
 
Where available, autopsy data for deaths occurring from registration until 30 days after 
last drug administration should be provided to the CCTU-CT. In addition, available 
autopsy data should be provided for any death occurring after this time, if there is a 
possibility that the death could be related to protocol treatment with the trial drug. 
 
Where a reported serious adverse event is judged to be both related to the IMP and 
unexpected (i.e. is a SUSAR), the investigator must assist the CCTU-CT by supplying all 
requested information to the Sponsor to allow the appropriate regulatory timeline to be 
met. The CCTU-CT will inform the Research Ethics Committee (REC), the MHRA 
(Medicines and healthcare products regulatory agency) and the sponsor within the 
legally required time frame.  
 
11.6 Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
All suspected adverse reactions related to an investigational medicinal product (the 
tested IMP and comparators) which occur in the concerned trial, and that are both 
unexpected and serious (SUSARs) are subject to expedited reporting. Please see 
Appendix 8 – Reference Safety Information (RSI) for the Reference Safety Information 
to be used in this trial. 
 
11.6.1 
Who should report and whom to report to? 
 
The Sponsor delegates the responsibility of notification of SUSARs to the Chief 
Investigator. The Chief Investigator must report all the relevant safety information 
previously described, to the:  
• 
Sponsor,  
• 
Competent authorities in the concerned member states (eg MHRA) 
• 
Ethics Committee in the concerned member states 
 
The Chief Investigator shall inform all investigators concerned of relevant information 
about SUSARs that could adversely affect the safety of patients. 
11.6.2 
When to report? 
11.6.2.1 Fatal or life-threatening SUSARs 
All parties listed in 11.6.1 must be notified as soon as possible but no later than 7 
calendar days after the trial team and Sponsor has first knowledge of the minimum 
criteria for expedited reporting. 
In each case relevant follow-up information should be sought and a report completed as 
soon as possible. It should be communicated to all parties within an additional 8 
calendar days. 
11.6.2.2 Non fatal and non life-threatening SUSARs 
All other SUSARs and safety issues must be reported to all parties listed in section 
11.6.1 as soon as possible but no later than 15 calendar days after first knowledge of 

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the minimum criteria for expedited reporting. Further relevant follow-up information 
should be given as soon as possible. 
11.6.3 
How to report? 
11.6.3.1 Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may 
not be available within the required time frames for reporting. For regulatory purposes, 
initial expedited reports should be submitted within the time limits as soon as the 
minimum following criteria are met: 
a) a suspected investigational medicinal product, 
b) an identifiable patient (e.g. trial patient code number), 
c) an adverse event assessed as serious and unexpected, and for which there is a 
reasonable suspected causal relationship, 
d) an identifiable reporting source, 
 
and, when available and applicable: 
- an unique clinical trial identification (EudraCT number or in case of non-
 European Community trials the sponsor's trial protocol code number) 
- an unique case identification (i.e. sponsor's case identification number). 
11.6.3.2 Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate 
information for an adequate analysis of causality should be actively sought from the 
reporter or other available sources. Further available relevant information should be 
reported as follow-up reports. 
 
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome 
of a particular reaction. 
11.6.3.3 Format of the SUSARs reports 
Electronic reporting is the expected method for expedited reporting of SUSARs to the 
competent authority. The format and content as defined by the competent authority 
should be adhered to. 
 
11.7 Pregnancy Reporting 
All pregnancies occurring during the trial period (either the trial participant or the 
participant’s partner) should be reported to the Chief Investigator and the Sponsor 
using the relevant Pregnancy Reporting Form within 24 hours of notification.  
Completed Pregnancy Reporting Forms must be reported using the contacts as detailed 
in section 11.5. 
 
Pregnancy is not considered an AE unless a negative or consequential outcome is 
recorded for the mother or child/foetus. If the outcome meets the serious criteria, this 
would be considered an SAE. 
 
12 Evaluation of Patient Reported Outcome, Health Economics & 
Patient Experience Assessments 
 
In this study the generic instrument EQ-5D will be used to evaluate global health-
related quality of life and the cancer-specific instrument – EORTC-QLQ-C30 will be used 
to measure impact of the treatment arms on quality of life (41-43). 

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12.1 Patient Reported Outcome (PRO) 
 
A variety of cutaneous adverse effects have been reported with BRAFi monotherapy, 
MEK inhibitor monotherapy and combination therapy7,13–18. These range from common 
morbilliform drug eruptions to unique toxicities (such as cutaneous squamous cell 
carcinoma development and severe photosensitivity) to life-threatening drug reactions 
including Stevens Johnson syndrome and toxic epidermal necrolysis18. Adverse effects 
affecting the skin as a result of targeted therapies have significant impact on QoL, 
which includes emotional, psychological, social and physical well-being19. The severity 
of skin toxicity is often underestimated by clinicians20,21 and the visible degree of 
involvement may not correlate with impact on QoL. PRO instruments have the potential 
to better capture these data. While standardised assessment tools have been developed 
for physicians to assess severity of adverse events (e.g. NCI CTCAE), it is well 
recognised that there is discord between objective and subjective measures. A 
systematic review reported moderate agreement at best between NCI CTCAE and PRO 
reporting of adverse effects in cancer clinical trials, highlighting the importance of 
integrating PROs with clinician reporting22.  
 
Several PRO instruments have been used to evaluate skin toxicity in cancer clinical 
trials of targeted therapies20 and a systematic review recently evaluated PRO 
instruments of dermatologic adverse events associated with targeted therapies in 
particular19. The two PRO questionnaires used in the INTERIM trial (Skindex-16 and NCI 
PRO-CTCAE) were chosen based on these data.  
 
12.1.1 
Skindex-16 
The Skindex-16 is a 16-question survey developed from the longer Skindex-29 that has 
been validated to accurately and sensitively measure how much a patient is bothered 
by a skin condition. It uses questions to assess how bothered a patient is by his/her 
skin condition on a seven-point scale (0-6) from ‘never bothered’ (0) to ‘always 
bothered’ (6) and assesses health-related QoL as it pertains to three domains of life – 
symptoms, emotions and functioning. The Skindex-16 has been shown to have good 
reproducibility (r=0.88-0.90)23. The survey has also been tested with several targeted 
therapies, including epidermal growth factor receptor inhibitors and tyrosine kinase 
inhibitors and these have shown significant correlation between survey QoL scores and 
other outcome measures including severity grading and NCI CTCAE scores24–27. The 
Skindex-16 has been shown to add supplemental information regarding skin toxicity 
which are not captured by CTCAE and also allows patient rating of emotional and 
functional burden which the CTCAE does not take into account28. 
 
The single-page length of the PRO instrument reduces patient burden29. The 
disadvantage is that the Skindex-16 does not specifically address toxicities of hair, nails 
or mucous membranes.   
12.1.2 
NCI PRO-CTCAE 
A PRO version of the NCI CTCAE was developed by multidisciplinary collaborators with 
NCI and Food and Drug Administration(FDA) input in 200830 and is called the PRO-
CTCAE. It consists of a library of 78 toxicities mapped to the CTCAE with up to three 
patient questions per toxicity. Patient questions were developed with extensive 
qualitative patient input including cognitive interviewing31 and quantitative evaluation of 
measurement properties32,33. The purpose of the PRO-CTCAE is to improve the precision 
and patient-centredness of symptomatic adverse event assessment30 and for the 
purpose of the INTERIM trial will be limited to skin specific items. NCI PRO-CTCAE skin 

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specific items relating to symptoms previously identified in trials of BRAF-inhibitors, 
MEK-inhibitors and combination treatment7,13–18 were chosen for inclusion.  
 
 
To evaluate skin toxicity in the INTERIM trial, two sources of data will be concurrently 
collected using a) the Clinician Skin Toxicity Q and b) the Patient Skin Toxicity Q. The 
statistical plan for data analysis is detailed in section 14.2.2.1. 
 
 
12.2 Health Economics assessments 
The economic evaluation will be a cost-effectiveness analysis which will compare the 
costs and effects of intermittent dosing compared with standard continuous dosing of 
oral targeted combination therapy in patients with BRAFV600 mutant stage 3 
unresectable or metastatic melanoma and will follow established guidelines as set out 
by NICE34. The main outcome measure for the economic evaluation will be quality 
adjusted life years (QALYs)35, estimated using the EuroQol EQ-5D 5L,which will be 
administered pre-randomisation (screening visit) , day 1 of cycle 2, and then every 12 
weeks until the end of the trial, plus at Progression. Resource use data will be collected 
on the two alternative treatment regimens, treatment complications (including non 
serious and serious adverse events), and length of stay by adding questions to the trial 
CRFs. Unit costs will be derived from nationally published sources such as eMIT36, the 
British National Formularly37 and Department of Health reference cost database38 and 
attached to the resource use data.  
 
We will report the cost and QoL data for each trial arm and the difference between the 
trial arms. Then we will calculate the average cost and outcome on a per patient basis 
to produce incremental cost-effectiveness ratios for the two arms, producing an 
incremental cost per QALY39 This  incremental analysis will be able to provide evidence 
on which treatment option is most likely to provide value for money for the National 
Health Service (NHS) and the greatest value for patients. Finally, we will undertake a 
budget impact analysis to estimate what the likely financial impact of moving to 
intermittent dosing is likely to be for the NHS.  
  
 
12.3 Patient Experience evaluation 
12.3.1 
Patients who decline to enter the trial 
12.3.1.1  Patient experience survey 
Patients who are approached to enter the trial but decline to participate will be 
invited to complete a Patient Experience Survey to explore their reasons for not 
participating. The questionnaire will be self-completed. 
 
12.3.2 
Trial Participants 
12.3.2.1  Patient Experience Survey 
Patients who agree to participate in the trial will be requested to complete a Consent 
Process-Patient Experience survey at the first screening visit. In addition, after 9 
months participation within the trial a short Trial Treatment Patient Experience Survey 
will be administered to all participants. Questions in the latter survey will include 
exploration of: 
A) experience of participating in the trial  
B) experience of toxicity – single global scale 

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C) relevance of the PROMS tools used to measure toxicity 
The questionnaire will be self-completed. 
 
12.3.2.2  Semi-Structured interviews 
Patients will be invited to volunteer their contact details in section 3 of the Patient Trial 
Treatment Experience Survey, if they are willing to be contacted to participate in semi-
structured interviews at a later date.  
 
Patients who have volunteered their contact details in section 3 of the Patient 
Experience Survey, will be contacted by the qualitative researcher, who will confirm 
they are still willing to participate in an interview before sending them further 
information about the interviews and answering any questions  they may have. Patients 
who agree to participate in the interviews will be consented by the qualitative 
researcher and invited to attend face-to-face / skype / telephone interviews.   
 
A convenience sample of patients will be  recruited from up to four sites. Fifteen 
patients will be interviewed from each arm of the trial (total 30 interviews). Patients will 
be informed that it is possible that they will not be interviewed if too many people 
volunteer. 
Patients 
will 
be 
selected 
as 
they 
volunteer 
consecutively 
and 
opportunistically.   
 
A dedicated qualitative researcher will lead and undertake patient interviews evaluating 
three main areas detailing topics covered in the Patient Experience Survey. The 
responses from the Consent and Trial Treatment Patient Experience Surveys will inform 
the interview but the interview schedule will broadly expand on the following issues:  
 
A) Trial participation and the consent process (Consent Patient Experience Survey) 
a. How did you decide to consent to be a participant in the trial? 
b. What was your experience of being a research participant? 
c. Were you given enough information prior to entering the trial? 
d. What are your feelings about being randomized in a trial i.e. acceptability 
of the two arms of the trial in principle and in practice? 
e. Overall experience of the trial 
B) Experience of toxicity of treatment 
a. What was your experience of the treatment? 
b. What toxicity did you experience and what was the severity?  
c. What was the impact of the toxicity on your quality of life? e.g. social 
impact, psychological and emotional well-being.  
C) Experience of Patient Skin Toxicty Q and PROMS tools 
a. How easy was it to complete? 
b. What was the burden of completion? 
c. Did the tools capture the aspects of quality of life it affected which are 
relevant to the patient? 
d. How useful was the Patient Skin Toxicity Q? 
 
13 Research Blood and Tissue Samples 
13.1 Translational Research 
Tissue and blood samples will be collected from all patients for analysis of ctDNA.  
 
Research blood samples (20mls, 40mls baseline) will be taken from all 150 patients at 
the following time points: Baseline (pre-treatment), 2 weeks, 4 weeks, 6 weeks, 8 
weeks, 12 weeks and then every 8 weeks until progression, plus at progression. 

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Research blood samples will be taken at the same time, where possible, as routine 
haematology and biochemistry blood samples to minimise the impact on the patient. 
 
A block of the most recent archived melanoma tumour sample (from a metastasis or 
primary site) will be requested at screening. Additional blocks will be collected from any 
patients undergoing routine surgery to remove metastatic melanoma at progression. 
 
Blood and tissue samples will be sent to Oxford University for analysis. Please refer to 
the INTERIM Laboratory Manual for details of sample collection and processing 
procedures.  
 
13.2 Pharmacokinetics 
In a subset of patients (up to 20) the pharmacokinetics of standard versus intermittent 
dosing schedules will be explored. Patients who have consented to take part in the 
additional pharmacokinetic study will have samples collected during the following visits; 
Cycle1, day 1 and cycle 2, day 15 (6 weeks into treatment).  
Blood (2mls) will be taken at the following time points: 
 
Pre-dose 
30mins  
+/- 5mins 
1hr 
 
+/- 5mins 
1hr 30mins +/- 5mins 
2hrs 
 
+/- 5mins 
3hrs 
 
+/- 30mins 
4hrs 
 
+/- 30mins 
6hrs 
 
+/- 30mins 
8hrs 
 
+/- 60mins 
 
In addition a blood sample (2mls) will be taken pre-dose at the beginning of cycle 3, 
cycle 4 and then every other cycle  (cycle 6, cycle 8, cycle 10….).These samples will be 
taken at the same time as the translational blood samples. 
Finally at disease progression, 3 further blood samples (2mls) will be taken at the 
following time points: pre-consultation, post-consultation and 30-60 minutes later. 
 
Pharmacokinetic blood samples will be sent to Oxford University for analysis. Please 
refer to the INTERIM Laboratory Manual for details of sample collection and processing 
procedures. 
14 Statistics 
14.1 Number of Patients to be enrolled 
It is planned to recruit 150 patients (75 patients in each arm) in 18 months with a 
minimum of 9 months follow up from around 20 UK sites. This will provide reliable 
information and evidence to inform the design of a definitive trial which will be powered 
to test the hypothesis that intermittent dosing of BRAF+MEKi combination will prolong 
progression-free survival compared with standard continuous dosing, with fewer side 
effects and better quality of life for patients.   
 
Recruitment 
The planned recruitment period is 18 months. Recruitment will be assessed once the 
trial has been open for 15 months, or 15 centres have been open for 6 months, 
whichever is the sooner. Recruitment will be considered acceptable if 15 of the target 
20 sites are entering an average of 1 patient every 2 months. 
 

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The targeted recruitment rate per site is, on average, 6 patients per year. If this target 
is achieved, around 1000 patients could be recruited from 50 sites in 4 years indicating 
that a phase III trial fully powered (see appendix 6) to detect a median improvement in 
progression-free survival  from 12 to 15 months trial (a hazard ratio of 0.8, being less 
than the 50% relative reduction in death reported in the mouse model) will be feasible. 
 
Treatment compliance 
Approximately 13% of patients stop treatment early due to intolerable toxicity with 
continuous dosing schedules. An intermittent dosing schedule will not be considered 
feasible if the treatment compliance at 6 months is less than 60%; it will be considered 
feasible if it is over 75%. With a 5% significance level (one-sided), and 80% power, 65 
patients40 are required in the intermittent dosing arm to detect a difference of ≤60% 
versus ≥75%. A patient leaving the trial to move to continuous dosing will constitute a 
failure of intermittent treatment, as will stopping for intolerable toxicity or disease 
progression. 
 
Quality of life 
QoL improvement will be assessed primarily using the global health status derived from 
the EORTC QLQ-C30 questionnaire at 6 months from baseline (change from baseline in 
global health status score)  between the standard and the experimental arms. This will 
be calculated as per scoring instructions in the EORTC QLQ-C30 manual41–43. 
Considering 80% patients will complete QoL at 6 months, a total of 150*80%= 120 
patients’ data will be available. With the estimated standard deviation of 12, which is 
based on 465 patients at 24 weeks from the COMBI-V trial44, 120 patients will provide 
us a one-sided 90% confidence interval of a 5 points45 improvement (a minimum 
clinical 
meaningful 
improvement) 
under 
the 
0-100 
scale excluding 
0 
(5 
– 
1.28*12*(1/60**0.5 + 1/60**0.5)  = 1.0 >0).   
 
Estimate the hazard ratio for progression-free survival 
The estimated median PFS is 12 months for the standard continuous arm. Assuming a 
hazard ratio (HR) of 0.8  and 150 patients randomised in 18 months with a further 9 
months follow up, approximately 90 PFS events will be observed based on estimated 
median PFS of 12 months for the standard continuous dosing schedule. This will 
generate a 1-sided 90% confidence interval of the estimated HR (exp(log(0.8) + 
1.28*(4/90)**0.5 = 0.995)<1 in favour of the intermittent dosing schedule should the 
assumption be correct.  
 
Assuming the anticipated 3 months improvement in median PFS from 12 in continuous 
dosing to 15 months in intermittent dosing is true, the estimated HR will be obtained 
based on at least 90 PFS events. If the estimated HR is less than 0.8, there is over 72% 
confidence (predictive power) that the planned phase III trial will test the hypothesis 
successfully. If the estimated HR is less than 0.75, there is over 81% confidence that 
the definitive phase III trial will test the hypothesis successfully (see appendix 6). 
 
14.2 Statistical analysis methods  
14.2.1 
Analysis population  
 
The following populations will be defined for efficacy and safety analyses 
 
• 
Intention-to-treat Population (ITT) 
The ITT population is defined as all patients randomised in the trial, regardless of 
whether they actually received treatment. The treatment group will be analysed as 
randomised. 

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• 
Minimum treatment population  
Minimum treatment population is defined as all patients who received at least two 
cycles of allocated protocol treatment. The treatment group will be analysed as treated. 
 
• 
Safety Population 
The safety population comprises all patients randomised and having received at least 
one dose of trial treatment. The treatment group will be analysed as treated.  
 
14.2.2 
Statistical analysis 
Statistical analyses for this feasibility trial will be mainly descriptive. A detailed statistical 
analysis plan will be drafted before any analyses are performed. Briefly, recrutiment 
rate will be estimated based on all patients randomised and summarised as an average 
number of patients recruited per month per site. Treatment compliance will be analysed 
based on patients who have received at least one dose of protocol treatment. The 
treatment compliance will be compared between the arms in an exploratory manner. 
Initial evidence of intermittent dosing benefit in quality of life (the estimated confidence 
interval of the difference of change from baseline in global health status score at 6 
months between arms) and progression-free survival (estimated hazard ratio, together 
with the confidene interval) will be analysed based on intention-to-treat population and 
minimum treatment population. Safety analyses will be based on safety population and 
summarised using the frequency tables and listings.   
 
14.2.2.1 Statistical analysis PROMs 
Descriptive statistics will be produced, using medians and interquartile ranges (IQRs) 
instead of means and standard deviations in cases of heavily skewed data. The 
standardized Skindex-16 questionnaire and NCI-PRO-CTCAE data will be analysed and 
missing data handled in accordance with their respective guidelines29,33. Proportion of 
patients experiencing a change from baseline for each measure as well as mean group 
changes will be calculated for skin toxicity. Associations between the reporting of skin 
toxicity between clinician and patients at the same timepoints will be explored. 
Associations between Skindex-16 and PRO-CTCAE scores with reported manifestations 
of skin toxicity will be explored. In addition, sub-group analyses based on age, gender, 
treatment arm, will be undertaken. Statistical significance tests will be carried out if 
clinically significant differences are observed. Independent samples t-tests will be used 
to compare means, and the nonparametric equivalent will be used to compare medians 
in the case of skewed data. Proportions will be compared using the chi-square test. 
Associations will be explored using multivariate regression analyses if sample size 
allows. 
 
14.2.2.2 Statistical analysis Patient Experience Survey 
Quantitative:  
Data analysis of Patient Experience will be undertaken (obtained both from those 
patients who have declined to enter the trial and those who have participated). 
Descriptive results will be reported and statistics will be used where relevant, using 
medians and IQRs instead of means and standard deviations in cases of heavily skewed 
data. In addition for participants, sub-group analyses based on age, gender and 
treatment arm, will be undertaken. Statistical significance tests will be carried out if 
clinically significant differences are observed. Independent samples t-tests will be used 
to compare means, and the nonparametric equivalent will be used to compare medians 
in the case of skewed data. Proportions will be compared using the chi-square test. 

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Associations will be explored using multivariate regression analyses if sample size 
allows. 
 
 
Qualitative:  
All interviews will be recorded using Olympus DSS digital recorder and transcribed 
verbatim. A framework analysis approach will be undertaken which will be developed 
from the interview schedule and from themes that emerge during the interviews and 
will be conducted using NVivo V.10 qualitative analysis software. All coding will be 
performed by the Qualitative Researcher. Qualitative data from the interviews will be 
integrated with the responses from the questionnaires and used to evaluate patient 
experience for patients who have participated in the INTERIM trial.  
 
 
14.3 Interim analyses 
An Independent Safety Data Monitoring Committee (ISDMC) will review trial 
progression and trial data, by treatment group, on the safety of patients in the trial. 
The ISDMC will meet approximately every 6 months while patients  are receiving 
protocol treatment or until end of the trial.  Interim progress reports will be produced 
for each ISDMC meeting. 
 
14.4 Definition of the end of the trial  
The trial will be considered closed for regulatory purposes 9 months from the date of 
randomisation of the last patient. Further observational follow-up on survival of all 
patients enrolled in the trial will be performed for a minimum of 9 months to a 
maximum of 5 years from the date of randomisation of the last patient, as survival 
beyond this point is unlikely.This will initially be via hospitals and clinics, but in the 
longer term may exploit national registers.  
 
15 Data handling and record keeping 
15.1 Case Report Form (CRF) 
All anonymous data will be transferred into a CRF which will be anonymised.  All trial 
data in the CRF must be extracted from and be consistent with the relevant source 
documents. The CRFs must be completed, dated and signed by the investigator or 
designee in a timely manner. It remains the responsibility of the investigator for the 
timing, completeness, legibility and accuracy of the CRF pages. The CRF will be 
accessible to trial coordinators, data managers, the investigators, Clinical Trial 
Monitors, Auditors and Inspectors as required. 
 
Completed originals of the CRFs should be posted within two weeks of the trial visit to 
the trial coordination centre: 
INTERIM Trial Coordinator 
Cambridge Clinical Trials Unit – Cancer Theme (CCTU-CT) 
Box 279 (S4) 
Addenbrooke’s Hospital 
Hills Road 
Cambridge 
CB2 0QQ 
 

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The investigator will retain a copy of each completed CRF page at site. The investigator 
will also supply the trial coordination centre with any required, anonymised background 
information from the medical records as required. 
 
The investigators must ensure that the CRFs and other trial related documentation is 
sent to the trial coordination centre containing no patient identifiable data. 
 
All CRF pages must be clear, legible and completed in black ink. Any errors should be 
crossed with a single stroke so that the original entry can still be seen. Corrections 
should be inserted and the change dated and initialled by the investigator or designee.  
If it is not clear why the change has been made, an explanation should be written next 
to the change. Typing correction fluid must not be used.   
 
15.2 Source Data 
To enable peer review, monitoring, audit and/or inspection the investigator must agree 
to keep records of all participating patients (sufficient information to link records e.g., 
CRFs, hospital records and samples), all original signed informed consent forms and 
copies of the CRF pages. 
 
Source data include, but are not limited to: 
• 
Patient Medical Records 
• 
Online Medical Records eg. medical records, prescribing records, results/reports 
from clinical investigations such as blood tests or scans 
• 
Signed and dated informed consent forms 
• 
Baseline Skin Report 
• 
Pharmacy records 
• 
Worksheets for sample collection, processing storage and shipment  
• 
QoL questionnaires 
• 
Clinician Skin Toxicity Questionnaire 
• 
Patient Skin Toxicity Questionnaire 
• 
Patient Diary Card 
• 
Patient Experience surveys (Consent and Trial Treatment) 
• 
Qualitative research interview recordings and transcripts 
 
15.3 Data Protection & Patient Confidentiality 
All investigators and trial site staff involved in this trial must comply with the 
requirements of the Data Protection Act 1998 and Trust Policy with regards to the 
collection, storage, processing and disclosure of personal information and will uphold 
the Act’s core principles. 
16     Trial Committees 
16.1 Trial management Group (TMG) 
The TMG will meet approximately monthly by teleconference to oversee the running of 
the trial. TMG members will review SAEs which have occurred in the trial. If there are 
specific safety concerns these may be raised with the TSC and ISDMC. TMG members 
will include all INTERIM trial co-investigators, trial statistician, trial pharmacist, and the 
Trial co-ordinator. 
 
16.2 Independent Safety Data Monitoring Committee (ISDMC) 
The ISDMC is independent of investigators and the Cambridge Clinical Trials Unit-
Cancer Theme. The group will meet approximately every 6 months while patients are 
receiving trial treatment or until end of trial. The ISDMC will review reports from the 
CCTU-CT and give advice on continuing recruitment. There are no formal stopping rules 

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for efficacy. A recommendation to discontinue recruitment (in all patients or in selected 
subgroups) will be made only if the emerging safety data indicate that the safety of the 
patients is not maintained. If a decision is made to continue, the ISDMC will advise on 
the frequency of future reviews of the data on the basis of accrual and event rates. The 
ISDMC will make recommendations to the TSC as to the continuation of the trial. The 
ISDMC will also be monitoring compliance of patients randomised to the intermittent 
arm of the trial and outcomes of both arms on a 6 monthly basis throughout the trial. 
 
16.3 Trial Steering Committee (TSC) 
The TSC includes members who are independent of the trial investigators and the 
CCTU-CT. It will provide overall supervision of the trial. It will meet at approximately 6-
monthly intervals and will receive reports from the CCTU-CT, TMG and ISDMC. 
 
17 Ethical & Regulatory considerations 
17.1 Consent 
The Informed Consent form must be approved by the REC and must be in compliance 
with GCP, local regulatory requirements and legal requirements. The investigator must 
ensure that each trial participant, or his/her legally acceptable representative, is fully 
informed about the nature and objectives of the trial and possible risks associated with 
their participation. 
 
The investigator will obtain written informed consent from each patient or the patient’s 
legally acceptable representative before any trial-specific activity is performed. The 
informed consent form used for this trial and any change made during the course of 
this trial, must be prospectively approved by the REC. The investigator will retain the 
original of each patients signed informed consent form. 
 
Should a patient require a verbal translation of the trial documentation by a locally 
approved interpreter/translator, it is the responsibility of the individual investigator to 
use locally approved translators.   
 
Any new information which becomes available, which might affect the patient’s 
willingness to continue participating in the trial will be communicated to the patient as 
soon as possible. If the patient’s next trial visit is imminent the new information will be 
communicated in person at that trial visit. Otherwise, the patient will be contacted over 
the telephone by a member of the trial team, eg. Investigator or Research Nurse. 
 
17.2 Ethical committee review 
Before the start of the trial or implementation of any amendment we will obtain 
approval of the trial protocol, protocol amendments, informed consent forms and other 
relevant documents e.g., advertisements and GP information letters if applicable from 
the REC. All correspondence with the REC will be retained in the Trial Master 
File/Investigator Site File. 
 
Annual reports will be submitted to the REC in accordance with national requirements. 
It is the Chief Investigator’s responsibility to produce the annual reports as required. 
 
17.3 Regulatory Compliance  
The trial will not commence until a CTA under the Notification Scheme for Type A trials 
is obtained from the MHRA. The protocol and trial conduct will comply with the 
Medicines for Human Use (Clinical Trials) Regulations 2004 and any relevant 
amendments. 

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Development Safety Update Reports (DSURs) will be submitted to the MHRA in 
accordance with national requirements. It is the Chief Investigators responsibility to 
produce the annual reports as required. 
 
17.4 Protocol Amendments 
Protocol amendments must be reviewed and agreement received from the Sponsor for 
all proposed amendments prior to submission to the HRA, REC and/or MHRA. 
 
The only circumstance in which an amendment may be initiated prior to REC and/or 
MHRA approval is where the change is necessary to eliminate apparent, immediate 
risks to the patients (Urgent Safety Measures). In this case, accrual of new patients will 
be halted until the HRA, REC and/or MHRA approval has been obtained.   
In the event of an urgent safety measure, the chief investigator (or delegate) will 
cascade the information verbally and/or by email to each participating site within 24 
hours. 
 
17.5 Peer Review 
This clinical trial has been peer reviewed by the National Institute for Health Research 
(NIHR) Research for Patient Benefit (RfPB) funding committee. 
 
17.6 Declaration of Helsinki and Good Clinical Practice 
The trial will be performed in accordance with the spirit and the letter of the declaration 
of Helsinki, the conditions and principles of Good Clinical Practice, the protocol and 
applicable local regulatory requirements and laws. 
 
17.7 GCP Training 
All trial staff must hold evidence of appropriate GCP training or undergo GCP training 
prior to undertaking any responsibilities on this trial.  This training should be updated 
every 2 years or in accordance with your Trust’s policy.  
 
18 Sponsorship, Financial and Insurance  
The trial is sponsored by Cambridge University Hospitals NHS Foundation Trust. The 
main trial will be funded by an NIHR RfPBgrant. The translational research and 
Pharmacokinetics will be funded by a CRUK grant. 
 
Cambridge University Hospitals NHS Foundation Trust, as a member of the NHS Clinical 
Negligence Scheme for Trusts, will accept full financial liability for harm caused to 
participants in the clinical trial caused through the negligence of its employees and 
honorary contract holders. There are no specific arrangements for compensation should 
a participant be harmed through participation in the trial, but no-one has acted 
negligently.  
  
19 Monitoring, Audit & Inspection 
The investigator must make all trial documentation and related records available should 
an MHRA Inspection occur. Should a monitoring visit or audit be requested, the 
investigator must make the trial documentation and source data available to the 
Sponsor’s representative. All patient data must be handled and treated confidentially. 
 
The Sponsor’s monitoring frequency will be determined by an initial risk assessment 
performed prior to the start of the trial. A detailed monitoring plan will be generated 

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detailing the frequency and scope of the monitoring for the trial. Throughout the course 
of the trial, the risk assessment will be reviewed and the monitoring frequency adjusted 
as necessary. 
 
Remote monitoring will be conducted for all participating sites. The scope and frequency 
of the monitoring will be determined by the risk assessment and detailed in the 
Monitoring Plan for the trial. 
 
20 Protocol Compliance and Breaches of GCP 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK 
regulations on Clinical Trials and must not be used.  
 
Protocol deviations, non-compliances, or breaches are departures from the approved 
protocol. They can happen at any time, but are not planned. They must be adequately 
documented on the relevant forms and reported to the Chief Investigator and Sponsor 
immediately.   
 
Deviations from the protocol which are found to occur constantly again and again will 
not be accepted and will require immediate action and could potentially be classified as 
a serious breach.  
 
Any potential/suspected serious breaches of GCP must be reported immediately to the 
Sponsor without any delay. 
 
21 Publications policy 
 
Ownership of the data arising from this trial resides with the TMG. On completion of the 
trial the data will be analysed and tabulated and a Final Trial Report prepared. 
 
The main trial results will be presented at national and international conferences and 
published in a peer-reviewed journal, on behalf of all collaborators. All presentations 
and publications relating to the trial must be authorised by the TMG. 
 
The manuscript will be prepared by a writing group appointed from amongst the TMG 
and high-accruing investigators. The CCTU-CT, NIHR, CRUK and all participating sites 
and Investigators will be acknowledged in publications and presentations. Senior 
authorship shall be shared between members of the TMG according to their leadership 
role in the trial. Priority will be given to the lead sites (Cambridge and Oxford) co-
ordinating the trial, then to participating sites, ordered by recruitment.     
 
In addition patients who have consented to receive updates on trial progress and 
results of the trial, will be provided with trial updates and summary of the results in lay 
terms. 
 

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22 References 
 
 
1. 
Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF 
V600E mutation. N Eng J Med 364, 2507–2516 (2011). 
2. 
Hauschild, A. et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, 
open-label, phase 3 randomised controlled trial. Lancet 380, 358–365 (2012). 
3. 
Alcalá, Alexander Marzuka, Flaherty, K. T. BRAF inhibitors for the treatment of 
metastatic melanoma: clinical trials and mechanisms of resistance. Clin. Cancer Res. 
18, 33–9 (2012). 
4. 
Robert, C. et al. Improved Overall Survival in Melanoma with Combined Dabrafenib 
and Trametinib. N. Engl. J. Med. 372, 141116004513004 (2014). 
5. 
Long, G. V. et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 
BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled 
trial. Lancet 386, 444–451 (2015). 
6. 
Ascierto, P. A. et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-
mutant melanoma (coBRIM): updated efficacy results from a randomised, double-
blind, phase 3 trial. Lancet Oncol. 17, 1248–1260 (2016). 
7. 
Welsh, S. J. & Corrie, P. G. Management of BRAF and MEK inhibitor toxicities in 
patients with metastatic melanoma. Ther. Adv. Med. Oncol. 7, 122–36 (2015). 
8. 
Larkin, J. et al. Vemurafenib in patients with BRAF(V600) mutated metastatic 
melanoma: an open-label, multicentre, safety study. Lancet Oncol. Oncol. 436–444, 
(2014). 
9. 
Dooley, A. J., Gupta, A., Bhattacharyya, M. & Middleton, M. R. Intermittent dosing 
with vemurafenib in BRAF V600E-mutant melanoma: review of a case series. Ther. 
Adv. Med. Oncol. 6, 262–6 (2014). 
10. 
Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a 
strategy to forestall drug resistance. Nature 494, 251–255 (2013). 
11. 
Seghers, A., Wilgenhof, S., Lebbe, C. & Neyns, B. Successful rechallenge in two 
patients with BRAF-V600-mutant melanoma who experienced previous progression 
during treatment with a selective BRAF inhibitor. Melanoma Res. December 2, 466–
472 (2012). 
12. 
Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of 
aberrantly spliced BRAF(V600E). Nature 480, 387–90 (2011). 
13. 
Belum, V. R., Fischer, A., Choi, J. N. & Lacouture, M. E. Dermatological adverse 
events from BRAF inhibitors: A growing problem. Curr. Oncol. Rep. 15, 249–259 
(2013). 
14. 
Gencler, B. & Gonul, M. Cutaneous side effects of BRAF inhibitors in advanced 
melanoma: Review of the literature. Dermatology Research and Practice 2016, 
(2016). 
15. 
Lacroix, J. & Wang, B. Prospective Case Series of Cutaneous Adverse Effects 
Associated With Dabrafenib and Trametinib. J. Cutan. Med. Surg. 21, (2016). 
16. 
Carlos, G. et al. Cutaneous toxic effects of BRAF inhibitors alone and in combination 
with MEK inhibitors for metastatic melanoma. JAMA dermatology 151, 1103–9 
(2015). 
17. 
Sanlorenzo, M. et al. Comparative profile of cutaneous adverse events: BRAF/MEK 
inhibitor combination therapy versus BRAF monotherapy in melanoma. J. Am. Acad. 
Dermatol. 71, 1102–1109.e1 (2014). 
18. 
de Golian, E., Kwong, B. Y., Swetter, S. M. & Pugliese, S. B. Cutaneous Complications 
of Targeted Melanoma Therapy. Current Treatment Options in Oncology 17, (2016). 
19. 
Chan, A. et al. A systematic review of patient-reported outcome instruments of 

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dermatologic adverse events associated with targeted cancer therapies. Support. 
Care Cancer 23, 2231–44 (2015). 
20. 
Maio, M. Di, Basch, E., Bryce, J. & Perrone, F. Patient-reported outcomes in the 
evaluation of toxicity of anticancer treatments. Nat. Rev. Clin. Oncol. 13, 319–325 
(2016). 
21. 
Basch, E. The missing voice of patients in drug-safety reporting. N. Engl. J. Med. 363, 
1–5 (2010). 
22. 
Atkinson, T. M. et al. The association between clinician-based common terminology 
criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a 
systematic review. Supportive Care in Cancer 24, 3669–3676 (2016). 
23. 
Chren, M. M., Lasek, R. J., Sahay,  a P. & Sands, L. P. Measurement properties of 
Skindex-16: a brief quality-of-life measure for patients with skin diseases. J. Cutan. 
Med. Surg. 5, 105–10 (2001). 
24. 
Joshi, S. S. et al. Effects of epidermal growth factor receptor inhibitor-induced 
dermatologic toxicities on quality of life. Cancer 116, 3916–3923 (2010). 
25. 
Nardone, B. et al. The effect of hand-foot skin reaction associated with the 
multikinase inhibitors sorafenib and sunitinib on health-related quality of life. J. Drugs 
Dermatol. 11, e61-5 (2012). 
26. 
Rosen, A. C. et al. Impact of dermatologic adverse events on quality of life in 283 
cancer patients: A questionnaire study in a dermatology referral clinic. Am. J. Clin. 
Dermatol. 14, 327–333 (2013). 
27. 
Jatoi, A. et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-
induced skin rashes: Results of a placebo-controlled trial from the North Central 
Cancer Treatment Group (N03CB). Cancer 113, 847–853 (2008). 
28. 
Atherton, P. J. et al. Using the skindex-16 and common terminology criteria for 
adverse events to assess rash symptoms: Results of a pooled-analysis (N0993). 
Support. Care Cancer 20, 1729–1735 (2012). 
29. 
Chren, M.-M. The Skindex instruments to measure the effects of skin disease on 
quality of life. Dermatol. Clin. 30, 231–6, xiii (2012). 
30. 
Basch, E. et al. Development of the National Cancer Institute’s Patient-Reported 
Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-
CTCAE). JNCI J. Natl. Cancer Inst. 106, dju244-dju244 (2014). 
31. 
Atkinson, T. M. et al. Reliability of adverse symptom event reporting by clinicians. 
Qual. Life Res. 21, 1159–1164 (2012). 
32. 
Hay, J. L. et al. Terminology Criteria for Adverse Events ( PRO-CTCAE ). 23, 257–269 
(2014). 
33. 
Dueck, A. C. et al. Validity and Reliability of the U.S. National Cancer Institute’s 
Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE). JAMA dermatology 1, 1051–1059 (2015). 
34. 
National Institute for Health and Clinical Excellence (NICE). Guide to the methods of 
technology appraisal. 1–78 (2009). doi:10.2165/00019053-200826090-00002 
35. 
Dolan, P. Modeling valuations for EuroQol health states. Med. Care 35, 1095–108 
(1997). 
36. 
Department of Health Commercial Medidicines Unit. Electronic Marketing Information 
Tool (eMIT). Available at: http://cmu.dh.gov.uk/electronic-market-information-tool-
emit/. (Accessed: 14th November 2016) 
37. 
Joint Formulary Committee. British National Formulary (BNF) 70. 88–150 (2015). 
38. 
Department of Health. Reference Costs 2015-16. (2016). 
39. 
Gray, A. M. Applied Methods of Cost-effectiveness Analysis in Health Care (Handbooks 
in Health Economic Evaluation Series). (Oxford University Press, 2010). 
40. 
A’Hern, R. P. Sample size tables for exact single-stage phase II designs. Stat. Med. 
20, 859–866 (2001). 

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41. 
Cocks, K. et al. Evidence-based guidelines for determination of sample size and 
interpretation of the European organisation for the research and treatment of cancer 
quality of life questionnaire core 30. J. Clin. Oncol. 29, 89–96 (2011). 
42. 
Cocks, K. et al. Evidence-based guidelines for interpreting change scores for the 
European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30. Eur. J. Cancer 48, 1713–1721 (2012). 
43. 
Bottomley, A. et al. Analysing data from patient-reported outcome and quality of life 
endpoints for cancer clinical trials: a start in setting international standards. The 
Lancet Oncology 17, e510–e514 (2016). 
44. 
Grob, J. J., Amonkar, M. M., Karaszewska, B. & Schachter, J. Comparison of 
dabrafenib and trametinib combination therapy with vemurafenib monotherapy on 
health-related quality of life in patients with unresectable or …. Lancet … 16, 1389–
1398 (2015). 
45. 
Osoba, D., Rodrigues, G., Myles, J., Zee, B. & Pater, J. Interpreting the significance of 
changes in health-related quality-of- life scores. J. Clin. Oncol. 16, 139–144 (1998). 
46. 
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009). 
47. 
Schag, C. C., Heinrich, R. L. & Ganz, P. A. Karnofsky performance status revisited: 
Reliability, validity, and guidelines. J. Clin. Oncol. 2, 187–193 (1984). 
48. 
Oken, M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. American Journal of Clinical Oncology 5, 649–656 (1982). 
49. 
Buccheri, G., Ferrigno, D. & Tamburini, M. Karnofsky and ECOG performance status 
scoring in lung cancer: A prospective, longitudinal study of 536 patients from a single 
institution. Eur. J. Cancer Part A 32, 1135–1141 (1996). 
50. 
The Criteria Committee of the New York Heart & Association. Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Human Biology 83, 
(1994). 
 
 
 
 

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23 Appendices 
 
23.1 Appendix 1 – RECIST Version 1.1  
 
For the full RECIST version 1.1, please refer to Eisenhauer E.A. et al.46.  
A summary of the criteria applicable for INTERIM is given below. 
 
 
Methods of Assessment 
 
Tumour assessments for response and progression require CT scan (or MRI if allergic to 
intravenous contrast) of thorax/abdomen/pelvis/head or measured by photography 
including a ruler. The same assessment technique should be used to characterise each 
identified and reported lesion at baseline and throughout the trial.  
 
 
Measurable Disease  
 
Patients will be classified as having measurable or non-measurable disease at baseline 
and at each imagining assessment.  
 
Definition of Measurable Disease lesions  
Must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of 10 mm by CT scan (CT scan 
slice thickness no greater than 5 mm; when CT scans have slice thickness >5 mm, the 
minimum size should be twice the slice thickness).  
 
Cutaneous lesions measured by photography including a ruler to indicate size, must be 
a minimum of 10mm in diameter. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measured, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan. At baseline and 
in follow-up, only the short axis will be measured and followed. 
 
Definition of Non-measurable lesions 
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with 10 to <15 mm short axis), as well as truly 
non-measurable 
lesions. 
Lesions 
considered 
truly 
non-measurable 
include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
 
 
Baseline Tumour Assessment 
 
The baseline tumour assessment evaluation should be performed within 4 weeks of 
date of randomisation. 
 
 
 

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Baseline Documentation of “Target” and “Non-Target” Lesions 
 
Target Lesions 
• 
All measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  
 
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, as well as their suitability for 
reproducible, repeated measurements. 
 
• 
Pathological nodes which are defined as measureable and may be identified as 
target lesions must meet the criterion of a short axis of ≥15 mm by CT scan. 
 
Sum of the Diameters 
Sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  
 
Non-target Lesions 
All lesions (or sites of disease) not identified as target lesions, including pathological 
lymph nodes and all non-measurable lesions, should be identified as non-target lesions 
and be recorded at baseline. Measurements of these lesions are not required 
 and they should be followed as ‘present’, ‘absent’ or in rare cases, ‘unequivocal 
progression’. 
 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum of diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on trial (this may include the baseline sum). The sum must also 
demonstrate an absolute increase of at least 5 mm. 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. 
 
 
Evaluation of Non-target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalisation of tumour marker levels. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
 
 

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Non-CR / Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker 
levels above normal limits. 
 
Progressive Disease (PD): 
 
Unequivocal progression of existing non-target lesions. 
• 
When patient has measurable disease. To achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target 
disease, 
the 
overall 
tumour 
burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target 
lesions is not usually sufficient to qualify for unequivocal progression status. 
 
• 
When patient has only non-measurable disease. There is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily 
quantified, a useful test that can be applied is to consider if the increase in overall 
disease burden based on change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable 
disease. Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or 
an increase in lymphangitic disease from localized to widespread. 
 
 
New lesions 
 
The appearance of new malignant lesions denotes disease progression: 
 
• 
The finding of a new lesion should be unequivocal (i.e., not attributable to 
differences in scanning technique, change in imaging modality or findings 
thought to represent something other than tumour, especially when the patient’s 
baseline lesions show partial or complete response). 
 
• 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease. If 
repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
 
• 
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and disease progression. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Time Point Response 
 
The table below provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. 
 
Time point response: patients with target (=/- non-target) disease  
Target lesions 
Non-target lesions 
New  lesions 
Overall  
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any  
Yes 
PD 
 
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable. 

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23.2 Appendix 2 – Karnofsky and ECOG Performance Status Scale  
 
Karnofsky Performance Status Scale47 
Condition  
PS % 
Comments 
Able to carry on normal 
activity and to work. No 
special care needed. 
100 
Normal. No complaints. No evidence of 
disease. 
90 
Able to carry on normal activity. Minor 
signs or symptoms of disease. 
80 
Normal activity with effort; Some signs 
or symptoms of disease.  
Unable to work. Able to live 
at home, care for most 
personal needs. A varying 
amount 
of 
assistance 
needed. 
70 
Cares for self. Unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self. 
Requires 
equivalent 
of 
institutional 
or 
hospital 
care.  Disease may be 
progressing rapidly. 
40 
Disabled. Requires special care and 
assistance. 
30 
Severely 
disabled. 
Hospitalisation 
is 
indicated although death not imminent. 
20 
Hospitalisation necessary, very sick; 
active supportive treatment necessary. 
10 
Moribund. Fatal processes progressing 
rapidly. 
0 
Dead 
 
 
 
ECOG Performance Status Scale48 
Scale 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or
chair 
5 
Dead 
 
 
 
Comparisons49 
 
ECOG 0-1 equals Karnofsky 80-100 
ECOG 2 equals Karnofsky 60-70 
ECOG 3-4 equals Karnofsky 10-50 
 

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23.3 Appendix 3 – NYHA Functional Classification 
The New York Heart Association (NYHA) Functional Classification50 provides a 
simple way of classifying the extent of heart failure. It places patients in one of four 
categories based on how much they are limited during physical activity; the 
limitations/symptoms are in regards to normal breathing and varying degrees in 
shortness of breath and or angina pain: 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary 
physical activity, e.g. shortness of breath when walking, climbing 
stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-
than-ordinary activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 

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23.4 Appendix 4 - Trial Management / Responsibilities 
23.4.1 
Patient registration/ Randomisation procedure 
A web-based central randomisation system, supplied by Sealed Envelope, will allocate 
patient randomisation numbers sequentially in the order in which the patients are 
enrolled. At the site initiation, the trial coordinator will arrange for the member of trial 
team who is authorised to randomise patients to be provided with a unique system 
username and password, which will allow them to access the central randomisation 
system. The trial coordinator will also train site staff in how to access and use the 
randomisation system. 
 
Using the web-base central randomisation system authorised site staff should 
randomise patients using their unique system username and password. Data required 
in order to randomise a patient is outlined in section 8.5. The treatment arm will be 
allocated and a unique trial number will be assigned by the randomisation system. 
 
23.4.2 
CRF Completion & Data management 
CRFs should be completed by the site and sent to the coordinating centre in a timely 
manner, please refer to the CRF completion guidelines for more information. Data 
management at the coordinating centre will include CRF checking and raising data 
queries as required, for further information please refer to the Data Management Plan. 
23.4.3 
Data protection/ confidentiality 
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted 
below. 
 
Case report forms will contain the patient’s initials, Date of Birth and unique  trial 
number. Medical information may be given to the ’s medical team and all appropriate 
medical personnel responsible for the patient’s welfare.  
 
This transfer of identifiable data is disclosed in the Patient Information Sheet. The trial 
team will preserve the confidentiality of patients taking part in the trial. 
 
23.4.4 
Trial documentation & archiving 
Each participating site is responsible for archiving their own trial data including source 
data, the Investigator Site File (ISF) for the appropriate time period as determined by 
the regulations governing clinical trials in place at the time of archival. The archiving 
facility may be at the participating site or at another appropriate location off-site as per 
local policy. The trial team will advise when the site may commence archiving. The site 
will need to provide the name and address of the archival facility to the Trial team. In 
case of audit or inspection following archival, the participating site will be expected to 
retrieve the relevant documentation within a reasonable timeframe. 

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23.5 Appendix 5 – Authorisation of Participating Sites 
23.5.1 
Required Documentation 
The following documentation must be in place prior to a site being opened to 
recruitment by the CCTU-CT trial team: 
 
• Trial specific registration of interest form (identifying relevant local trial team) 
• All relevant institutional approvals (e.g. local NHS confirmation) 
• A signed participating site agreement (PSA) or Statement of Activities between 
the Sponsor and the relevant institution (typically the sites local NHS Trust) 
• CV signed and dated and GCP certificates for the site trial team 
• An example of patient documentation (PIS/ICF etc) and GP Letter on local 
Trust-headed paper and with local contact details added. 
• Example of IMP prescription 
• Local Laboratory accreditation (or equivalent) and reference ranges for the 
protocol-specified paramaters 
• Completed and signed Trial Initiation Form 
 
The Principal Investigator (PI), other delegated site investigators and all staff involved 
in the conduct of the trial at site must be identified on the site delegation log held at 
site and copied to CCTU-CT prior to site activation 
23.5.2 
Procedure for initiating/opening a new site 
Once the trial team at CCTU-CT have confirmed that all documentation is in place, a 
site activation letter will be issued to the PI, at which point the site may start to 
approach patients. 
23.5.3 
Principal Investigator Responsibilities 
Once the site has been activated by CCTU-CT, the PI at each site is responsible for 
ensuring the following: 
 
• Attendance at the site initiation meeting 
• Adherence to the most recent version of the protocol 
• All relevant staff are trained in protocol requirements 
• Delegation of activities to appropriately trained staff (this must be documented 
on the delegation of responsibility and signature log) 
• Appropriate recruitment and medical care of patients in the trial 
• Timely completion and return of CRFs 
• Accurate maintenance of the ISF 
• Dissemination of all trial related information 
• Ensuring appropriate attendance at the TMG teleconferences if required and 
ensure appropriate safety information is made available to the CCTU-CT in 
advance of the meeting.  
• Dissemination of important safety or trial related information to all stakeholders 
at the participating site  
• Safety reporting within the timelines and assessment of causality and 
expectedness of all SAEs 

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23.6 Appendix 6 Sample size ouput and predictive power 
 
Sample size for a planned phase III trial: sample size N=~1000, number of PFS events 
m=846 
 
Sample size with a 5% significance level and 90% power for a hazard ratio = 0.80, a median PFS of 
12 months, a 4-year recruitment, a 2-year follow up. 
 
 
. artsurv, method(l) nperiod(6) ngroups(2) fp(0) median(1) hratio(1, 0.8, 0.8) alpha(0.05) 
power(0.9) aratios(1 1 ) recrt(4 0, 1, 0 ) distant(0) detail(0) onesid  ed(0) ni(0) tunit(1) 
trend(0) 
 
ART - ANALYSIS OF RESOURCES FOR TRIALS        (version 1.0.7, 19 October 2009) 
------------------------------------------------------------------------------ 
A sample size program by Abdel Babiker, Patrick Royston & Friederike Barthel, 
MRC Clinical Trials Unit, London NW1 2DA, UK. 
------------------------------------------------------------------------------ 
Type of trial                            Superiority - time-to-event outcome 
Statistical test assumed                 Unweighted logrank test (local) 
Number of groups                         2 
Allocation ratio                         Equal group sizes 
 
Total number of periods                  6 
Length of each period                    One year 
 
Baseline median survival time            1 year 
Survival probs per period (group 1)      0.500 0.250 0.125 0.063 0.031 0.016 
Survival probs per period (group 2)      0.574 0.330 0.189 0.109 0.063 0.036 
Number of recruitment periods            4 
Number of follow-up periods                 2 
Method of accrual                        Uniform 
Recruitment period-weights               1 1 1 1 0 0 
 
Hazard ratios as entered (groups 1,2)    1, 0.8 
Alpha                                              0.050 (two-sided) 
Power (designed)                         0.900 
 
Total sample size (calculated)                949 
Expected total number of events          846 
------------------------------------------------------------------------------ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Predictive power for a successful phase III trial 
 
 
 ~ 
,   
 
 
 
,  
 ,    
 
 
 
 
The preditive power 
to reject H0 ( hazard ratio (HR) ≥1, or log (HR)  ≥0 (δ=0)) of no PFS benefit 
of intermittent dosing schedul is 
 
   
 
 
With a prior of no difference and 1 PFS event, that is 
 ~ 
, significance level 
  n=90 
PFS events observed in the feasiblity study, 
• 
if the observed HR=0.80 (an improvement in median PFS from 12 to 15 months) in the phase II 
trial, the predictive power to reject the null hypothesis of no PFS benefit of intermittent dosing 
schedule under the planned phase III trial (m=846) is 72%. 
 
• 
If the observed HR=0.75 (an improvement in median PFS from 12 to 16 months) in the phase II 
trial, the predictive power to reject the null hypothesis of no PFS benefit of intermittent dosing 
schedule   under the planned phase III trial (m=846) is 81%. 

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23.7 Appendix 7 - Safety reporting flowchart 
 
 
 
 

EudraCT number: 2016-005228-27         IRAS ID Number: 213113  
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23.8 Appendix 8 – Reference Safety Information (RSI) 
 
Data taken from: 
Debrafenib -  Summary of Product Characteristics - updated 19 April 2017. 
Trametinib - Summary of Product Characteristics - updated 19April 2017. 
Tabulated summary of adverse reactions 
ADRs which were reported are listed below by MedDRA body system organ class and by 
frequency. The following convention has been utilised for the classification of 
frequency: 
Very common ≥1/10 
Common ≥1/100 to <1/10 
Uncommon ≥1/1,000 to <1/100 
Rare ≥1/10,000 to <1/1,000 
Not known (cannot be estimated from the available data) 
For SUSAR reporting use the following tables to determine expectedness: 
• 
Table 1: To determine expectedness in relation to dabrafenib in patients taking 
dabrafenib monotherapy 
• 
Table 2: To determine expectedness in relation to trametinib in patients taking 
trametinib monotherapy 
• 
Table 3: To determine expectedness in relation to dabrafenib in patients taking 
dabrafenib in combination with trametinib 
• 
Table 4: To determine expectedness in relation to trametinib in patients taking 
trametinib in combination with dabrafenib 
 
 

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Table 1:Adverse reactions reported in the integrated safety population of 
dabrafenib monotherapy (n=578)  
System Organ Class 
Frequency (all grades) 
Adverse Reactions 
Neoplasms benign, 
malignant and unspecified 
(including cysts and 
polyps) 
Very common 
Papilloma 
Common 
Cutaneous squamous cell 
carcinoma 
Seborrhoeic keratosis 
Acrochordon (skin tags) 
Basal cell carcinoma 
Uncommon 
New primary lesions 
Immune system disorders 
Uncommon 
Hypersensitivity 
Metabolism and nutrition 
disorders 
Very common 
Decreased appetite 
Common 
Hypophosphataemia 
Hyperglycaemia 
Nervous system disorders 
Very common 
Headache 
Eye disorders 
Uncommon 
Uveitis 
Respiratory, thoracic and 
mediastinal disorders 
Very common 
Cough 
Gastrointestinal disorders 
Very common 
Nausea 
Vomiting 
Diarrhoea 
Common 
Constipation 
Uncommon 
Pancreatitis 
Skin and subcutaneous 
tissue 
disorders 
Very common 
Hyperkeratosis 
Alopecia 
Rash 
Palmar-plantar 
erythrodysaesthesia 
Common 
Dry skin 
Pruritus 
Actinic keratosis 
Skin lesion 
Erythema 
Photosensitivity Reaction 
Uncommon 
Panniculitis 
Musculoskeletal and 
connective 
tissue disorders 
Very common 
Arthralgia 
Myalgia 
Pain in extremity 
Renal and urinary 
disorders 
Uncommon 
Renal failure, acute renal 
failure 
Nephritis 
General disorders and 
administration site 
conditions 
Very common 
Pyrexia 
Fatigue 
Chills 
Asthenia 
Common 
 Influenza-like illness 
 
 

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Table 2 Adverse reactions reported in the integrated safety population of 
trametinib monotherapy (n=329) 
System Organ Class 
Frequency (all grades) 
Adverse Reactions 
Infections and infestation 
Common 
Folliculitis 
Paronychia 
Cellulitis 
Rash pustular 
Blood and lymphatic 
system 
disorders 
Common 
Anaemia 
Immune system disorders 
Common 
Hypersensitivitya 
Metabolism and nutrition 
disorders 
Common 
Dehydration 
Eye disorders 
Common 
Vision blurred 
Periorbital oedema 
Visual impairment 
Uncommon 
Chorioretinopathy 
Papilloedema 
Retinal detachment 
Retinal vein occlusion 
Cardiac disorders 
Common 
Left ventricular 
dysfunction 
Ejection fraction decreased 
Bradycardia 
Uncommon 
Cardiac failure 
Vascular disorders 
Very common 
Hypertension 
Haemorrhageb 
Common 
Lymphoedema 
Respiratory, thoracic and 
mediastinal disorders 
Very common 
Cough 
Dyspnoea 
Common 
Pneumoniti 
Uncommon 
Interstitial lung disease 
Gastrointestinal disorders 
Very common 
Diarrhoea 
Nausea 
Vomiting 
Constipation 
Abdominal pain 
Dry mouth 
Common 
Stomatitis 
Uncommon 
Gastrointestinal 
perforation 
Colitis 
Skin and subcutaneous 
disorders 
Very common 
Rash 
Dermatitis acneiform 
Dry skin 
Pruritus 
Alopecia 
Common 
Erythema 
Palmar-plantar 
erythrodysaesthesia 
syndrome 
Skin fissures 
Skin chapped 

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Musculoskeletal and 
connective 
tissue disorders 
Uncommon 
Rhabdomyolysis 
General disorders and 
administration site 
conditions 
Very Common 
Fatigue 
Oedema peripheral 
Pyrexia 
Common 
Face oedema 
Mucosal inflammation 
Asthenia 
Investigations 
Very common 
Aspartate 
aminotransferase 
increased 
Common 
Alanine aminotransferase 
increased 
Blood alkaline 
phosphatase increased 
Blood creatine 
phosphokinase increased 
a May present with symptoms such as fever, rash, increased liver transaminases, 
and visual disturbances 
b Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, 
haematuria, and rectal,haemorrhoidal, gastric, vaginal, conjunctival, intracranial and 
post procedural haemorrhage. 
 
 
Table 3 Adverse reactions reported in the integrated safety population of 
dabrafenib in combination with trametinib (n=641) 
System Organ Class 
Frequency (all grades) 
Adverse Reactions 
Infections and infestations 
Very common 
Urinary tract infection 
Nasopharyngitis 
Common 
Cellulitis 
Folliculitis 
Paronychia 
Rash pustular 
Neoplasms benign, 
malignant 
and unspecified (incl cysts 
and 
polyps) 
Common 
Cutaneous squamous cell 
carcinomaa 
Papillomab 
Seborrhoeic keratosis 
Uncommon 
New primary melanoma 
Acrochordon (skin tags) 
Blood and lymphatic 
system 
disorders 
Very common 
Neutropenia 
Common 
Anaemia 
Thrombocytopenia 
Leukopenia 
Immune system disorders 
Uncommon 
Hypersensitivityc 
Metabolism and nutrition 
disorders 
Very common 
Decreased appetite 
Common 
Dehydration 
Hyponatraemia 
Hypophosphataemia 
Hyperglycaemia 

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Nervous system disorders 
Very common 
Headache 
Dizziness 
Eye disorders 
Common 
Vision blurred 
Visual impairment 
 
Chorioretinopathy 
Uveitis 
Retinal detachment 
Periorbital oedema 
Cardiac disorders 
Common  
Ejection fraction decreased 
Uncommon  
Bradycardia 
Not Know 
Myocarditis 
Vascular disorders 
Very common 
Hypertension 
Haemorrhaged 
Common 
Hypotension 
Lymphoedema 
Respiratory, thoracic and 
mediastinal disorders 
Very common 
Cough 
Common 
Dyspnoea 
Pneumonitis 
Gastrointestinal disorders 
Very common 
Abdominal pain 
Constipation 
Diarrhoea 
Nausea 
Vomiting 
Common 
Dry mouth 
Stomatitis 
Uncommon 
Pancreatitis 
Skin and subcutaneous 
disorders 
Very common 
Dry skin 
Pruritus 
Rash 
Erythema 
Common 
Dermatitis acneiform 
Actinic keratosis 
Night sweats 
Hyperkeratosis 
Alopecia 
Palmar-plantar 
erythrodysaesthesia 
Syndrome 
Skin lesion 
Panniculitis 
Skin fissures 
Photosensitivity Reaction 
Musculoskeletal and 
connective 
tissue disorders 
Very common 
Arthralgia 
Myalgia 
Pain in extremity 
Muscle spasms 
Renal and urinary 
disorders 
Common 
Renal failure 
Uncommon 
Nephritis 

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General disorders and 
administration site 
conditions 
Very common 
Fatigue 
Chills 
Asthenia 
Oedema peripheral 
Pyrexia 
Common 
Mucosal inflammation 
Influenza-like illness 
Face oedema 
Investigations 
Very common 
Alanine aminotransferase 
increased 
Aspartate 
aminotransferase 
increased 
Common 
Blood alkaline 
phosphatase increased 
Gamma-
glutamyltransferase 
increased 
Blood creatine 
phosphokinase increased 
a cu SCC: SCC, SCC of the skin, SCC in situ (Bowen's disease) and keratoacanthoma 
b Papilloma, skin papilloma 
c Includes drug hypersensitivity 
d Bleeding from various sites, including intracranial bleeding and fatal bleeding 
 
 
 
Table 4 Adverse reactions reported in the integrated safety population of 
trametinib in combination with dabrafenib (n=641) 
System Organ Class 
Frequency (all grades) 
Adverse Reactions 
Infections and Infestations 
Very Common 
Urinary tract infection 
Nasopharyngitis 
Common 
Cellulitis 
Folliculitis 
Paronychia 
Rash pustular 
Neoplasms benign, 
malignant 
and unspecified (incl cysts 
and 
polyps) 
Common 
Cutaneous squamous cell 
carcinomaa 
Papillomab 
Seborrhoeic keratosis 
Uncommon 
New primary melanoma 
Acrochordon (skin tags) 
Blood and lymphatic 
system 
disorders 
Very common 
Neutropenia 
Common 
Anaemia 
Thrombocytopenia 
Leukopenia 
Immune system disorders 
Uncommon 
Hypersensitivityc 
 
 

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Metabolism and nutrition 
disorders 
Very common 
Decreased appetite 
Common 
Dehydration 
Hyponatraemia 
Hypophosphataemia 
Hyperglycaemia 
Nervous system disorders 
Very common 
Headache 
Dizziness 
Eye disorders 
Common 
Vision blurred 
Visual impairment 
Uncommon 
Chorioretinopathy 
Uveitis 
Retinal detachment 
Periorbital oedema 
Cardiac disorders 
Common 
Ejection fraction decreased 
Uncommon 
Bradycardia 
Unknown 
Myocarditis 
Vascular disorders 
Very common 
Hypertension 
Haemorrhaged 
Common 
Hypotension 
Lymphoedema 
Respiratory, thoracic and 
mediastinal disorders 
Very common 
Cough 
Common 
Dyspnoea 
Pneumonitis 
Gastrointestinal disorders 
Very common 
Abdominal pain 
Constipation 
Diarrhoea 
Nausea 
Vomiting 
Common 
Dry mouth 
Stomatitis 
Uncommon 
Pancreatitis 
Gastrointestinal 
perforation 
Colitis 
Skin and subcutaneous 
disorders 
Very common 
Dry skin 
Pruritus 
Rash 
Erythema 
Common 
Dermatitis acneiform 
Actinic keratosis 
Night sweats 
Hyperkeratosis 
Alopecia 
Palmar-plantar 
erythrodysaesthesia 
syndrome 
Skin lesion 
Hyperhidrosis 
Panniculitis 
Skin fissures 
Photosensitivity Reaction 

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Musculoskeletal and 
connective 
tissue disorders 
Very common 
Arthralgia 
Myalgia 
Pain in extremity 
Muscle spasms 
Renal and urinary 
disorders 
Common 
Renal failure 
Uncommon  
Nephritis 
General disorders and 
administration site 
conditions 
Very common 
Fatigue 
Chills 
Asthenia 
Oedema peripheral 
Pyrexia 
Common 
Mucosal inflammation 
Influenza-like illness 
Face oedema 
Investigations 
Very common 
Alanine aminotransferase 
increased 
Aspartate 
aminotransferase 
increased 
Common 
Blood alkaline 
phosphatase increased 
Gamma-
glutamyltransferase 
increased 
Blood creatine 
phosphokinase increased 
a cu SCC: SCC, SCC of the skin, SCC in situ (Bowen's disease) and keratoacanthoma 
b Papilloma, skin papilloma 
c Includes drug hypersensitivity 
d Bleeding from various sites, including intracranial bleeding and fatal bleeding