A Double Blind Randomised Phase 2 Trial of Docetaxel With or Without AZD6244 in wt BRAF Advanced Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: University of Oxford

 
 
 
 
Page 1 of 42 
 
  
Short title: Docetaxel +/- AZD6244 in Melanoma 
 
A double blind randomised phase 2 trial of 
docetaxel with or without AZD6244 in wt BRAF 
advanced melanoma 
  
 
Protocol Version & date 
Version 6.0, 29 Jul 2014 
OCTO Protocol No: 
OCTO_015 
REC Ref number: 
10/H0604/59 
EudraCT No. 
2009-018153-23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Contact Address 
Clinical Trials and Research Governance (CTRG), University of Oxford, Joint Research Office, 
Block 60, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE 
Tel:  
+44 (0) 1865 572224
Fax:  
+44 (0) 1865 572 228 
 
 
 
 
  
 
 
 
 

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1 
General Contact Information 
 
Chief Investigator:
Professor Mark Middleton 
Participating Centre: 
Oxford 
 
Department of Oncology  
Churchill Hospital  
Oxford  
OX3 7LE 
Tel: 
+44 (0)1865 235315 
Fax: 
+44 (0) 1865 235981 
Email: 
mark.middleton@oncology.ox.ac.uk 
 
Co-Investigator: 
Dr Paul Lorigan 
Participating Centre: 
Christie Hospital 
 
Department of Medical Oncology  
Christie Hospital  
Wilmslow Road 
Manchester 
M20 4BX 
Telephone: 
+44 (0)161 918 7444 
Fax: 
+44 (0)161 446 3299 
Email: 
paul.lorigan@manchester.ac.uk 
 
 
Co-Investigator: 
Dr Mark Harries 
Participating Centre: 
Guy’s Hospital 
 
Department of Medical Oncology  
4th Floor, Bermondsey Wing 
Guy’s Hospital  
Great Maze Pond 
London 
SE1 9RT 
Telephone: 
+44 (0)207 188 4244 
Fax: 
+44 (0)207 188 4271 
Email: 
mark.harries@gstt.nhs.uk 
 
Trials Unit Contact:
Oncology Clinical Trials Office (OCTO) 
 
Department of Oncology 
University of Oxford 
Old Road Campus Research Building 
Roosevelt Drive 
Headington 
Oxford 
OX3 7DQ 
Telephone: 
+44 (0)1865 227191 or 227162 or 227195 
Fax: 
+44 (0)1865 227039 
Email: 
DOC-MEK@octo-oxford.org.uk 
Trial Statisticians 
Ms Sharon Love 
Senior Medical Statistician 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LD 
Telephone:
+44 (0)1865 223441 
Email:
sharon.love@csm.ox.ac.uk 
 
 
 

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Other key contacts: 
 
 
Mutation Analysis 
 
Professor Ian Tomlinson 
Molecular and Population Genetics 
Wellcome Trust Centre for Human Genetics 
University of Oxford 
Old Road Campus 
Headington 
Oxford 
OX3 7BN  
 
Tel: +44(0)1865 287870 
Email: iant@well.ox.ac.uk 
 
 
 
Sample Handling 
 
DOC-MEK Sample Handling Laboratory 
Level 1, Oxford Cancer Centre 
Old Road 
Headington 
Oxford 
OX3 7LE  
 
Tel: +44(0)1865 220557  
Email: labchurchill@oncology.ox.ac.uk 
 
 
Interactive Web Response System (IWRS) – Randomisation and Drug Supply 
 
https://www.cenduitsolutions.com

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TABLE OF CONTENTS 
1 
GENERAL CONTACT INFORMATION ....................................................................... 2 
2 
PROTOCOL SYNOPSIS ............................................................................................. 7 
2.1 
Schedule of Events ............................................................................................................................ 9 
2.2 
Study Flow Chart .............................................................................................................................. 10 
3 
INTRODUCTION ....................................................................................................... 11 
3.1 
Docetaxel mechanism of action ...................................................................................................... 11 
3.2 
AZD6244 and ERK activation .......................................................................................................... 11 
3.3 
AZD6244 and docetaxel ................................................................................................................... 11 
3.4 
Justification for the doses to be used ............................................................................................ 12 
4 
STUDY DESIGN ........................................................................................................ 12 
5 
PATIENT SELECTION .............................................................................................. 13 
5.1 
Screening for BRAF mutation ......................................................................................................... 13 
5.2 
Entry into the main study ................................................................................................................ 13 
5.3 
Patient screening and enrolment .................................................................................................... 15 
5.4 
Randomisation of patients .............................................................................................................. 15 
6 
INVESTIGATIONAL AGENTS .................................................................................. 15 
6.1 
Docetaxel ........................................................................................................................................... 15 
6.2 
AZD6244/Placebo.............................................................................................................................. 15 
6.3 
Criteria for Re-Treatment and Dose Reductions ........................................................................... 16 
6.4 
Concomitant medication and non-drug therapies ........................................................................ 17 
6.5 
Patient evaluability ........................................................................................................................... 19 
7 
PHARMACEUTICAL INFORMATION ....................................................................... 19 
7.1 
IMP Supply ........................................................................................................................................ 19 
7.2 
Preparation ........................................................................................................................................ 19 
7.3 
Drug accountability .......................................................................................................................... 20 
8 
TRIAL ASSESSMENTS AND PROCEDURES ......................................................... 20 

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8.1 
BRAF mutation screening ............................................................................................................... 20 
8.2 
Mutation screening procedures ...................................................................................................... 21 
8.3 
Further Main Study screening procedures .................................................................................... 21 
8.4 
Randomisation Procedures ............................................................................................................. 22 
8.5 
Treatment Period .............................................................................................................................. 22 
8.6 
Follow-up ........................................................................................................................................... 24 
9 
EARLY PATIENT WITHDRAWAL ............................................................................ 24 
9.1 
Code break/Unblinding .................................................................................................................... 24 
10 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS AND 
CORRELATIVE SCIENCE ............................................................................................... 25 
10.1 
Pharmacokinetic (PK) Variable(s) ................................................................................................... 25 
10.2 
Pharmacodynamic (PD) variables................................................................................................... 25 
10.3 
Tumour genotyping, protein analysis and germline genetics ..................................................... 25 
11 
ASSESSMENT OF SAFETY .................................................................................. 25 
11.1 
Adverse Event Definitions ............................................................................................................... 25 
11.2 
Expedited reporting of SAEs and SUSARs .................................................................................... 28 
11.3 
Safety reporting requirements and arrangements ........................................................................ 28 
11.4 
Recording adverse events at the study site .................................................................................. 29 
11.5 
Follow-up of serious adverse events ............................................................................................. 29 
12 
ASSESSMENT OF EFFICACY .............................................................................. 29 
12.1 
Measurement of disease .................................................................................................................. 29 
12.2 
Tumour assessment ......................................................................................................................... 29 
12.3 
Tumour response ............................................................................................................................. 30 
13 
DEFINING THE END OF TRIAL ............................................................................ 30 
14 
STATISTICAL CONSIDERATIONS ....................................................................... 31 
14.1 
Safety ................................................................................................................................................. 31 
14.2 
Patient evaluability ........................................................................................................................... 31 
14.3 
Analysis ............................................................................................................................................. 31 

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14.4 
Analysis timings ............................................................................................................................... 31 
15 
TRIAL ADMINISTRATION ..................................................................................... 31 
15.1 
Regulatory and ethical considerations .......................................................................................... 31 
15.2 
Regulatory Authority approval ........................................................................................................ 32 
15.3 
Trial Monitoring and Quality Assurance ........................................................................................ 32 
15.4 
Records retention ............................................................................................................................. 33 
15.5 
Patient confidentiality ...................................................................................................................... 33 
15.6 
Completion of the Case Report Form (CRF) .................................................................................. 33 
15.7 
Data and Safety Monitoring ............................................................................................................. 34 
15.8 
Clinical study report ......................................................................................................................... 34 
15.9 
Study funding .................................................................................................................................... 34 
15.10 
Indemnity ....................................................................................................................................... 34 
15.11 
Publication policy ......................................................................................................................... 34 
16 REFERENCES ............................................................................................................ 34 
APPENDIX 1: ECOG PERFORMANCE SCALE ............................................................. 36 
APPENDIX 2: MEASUREMENT OF DISEASE - MODIFIED RECIST CRITERIA ........... 37 
APPENDIX 3: MEDICATIONS INTERACTING SIGNIFICANTLY WITH CYP3A4 AND 
CYP1A2 ........................................................................................................................... 42 
 
 
 
____________ 

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2 
Protocol Synopsis 
Title of study: 
A double blind randomised phase 2 trial of docetaxel with or without AZD6244 in 
wt BRAF advanced melanoma
Trial Name
DOC-MEK 
Short Title
Docetaxel +/- AZD6244 in melanoma
Chief Investigator: 
Professor Mark Middleton  
Sponsor:
University of Oxford 
OCTO Protocol No.
OCTO_015 
EudraCT Number
2009-018153-23 
REC Ref Number
 
Aims: 
To determine the efficacy and tolerability of the combination of the selective MEK 
inhibitor AZD6244 with docetaxel in patients with wild-type BRAF metastatic 
melanoma. 
Scientific rationale 
ERK1/2 is constitutively active in melanoma cells regardless of BRAF or NRAS 
status, presenting a potential target for treatment. Phosphorylated ERK is 
important for melanoma as it plays key roles in cell cycle entry, invasion and 
angiogenesis, as well as in resistance to apoptosis.  
AZD6244 is a highly selective allosteric inhibitor of MEK1/2. Treatment with 
AZD6244 leads to suppression of pERK levels in melanoma in a manner 
independent of BRAF and NRAS mutation status. Single agent therapy of 
melanoma with AZD6244 has been disappointing. In a phase 2 trial of AZD6244 
6/104 patients achieved a partial response, including in a wt BRAF wt NRAS 
patient. AZD6244 and docetaxel have demonstrated synergy in a variety of 
animal xenograft models, including colorectal cancer (HCT-116, SW-620), 
NSCLC (A549) and melanoma (1025Lu). 
Clinical rationale 
Current treatment for metastatic melanoma is unsatisfactory. No agent has been 
shown to improve survival compared with supportive care, and classical cytotoxic 
agents produce responses in a minority (between 5 and 20%) of patients. 
Docetaxel has been evaluated in phase 2 trials in melanoma, producing 
response rates of 6-14%, in line with a number of cytotoxic agents.  
A phase 1 study of the combination of AZD6244 and docetaxel has 
recommended 75 mg BD of AZD6244 in combination with docetaxel 75 mg/m2 
q21 days for further study. Adverse events were consistent with the monotherapy 
toxicity profiles. To date the combination has been given to 12 patients with 
melanoma: 1 had a complete response; 1 a partial response; and 4 had stable 
disease beyond 6 cycles of treatment (18+ weeks) indicating clinical activity 
worthy of further study.
Primary Endpoint:
Progression free survival 
Secondary 
Endpoints: 
Objective response rate.  
Progression free survival at 6 months 
Safety of the AZD6244/docetaxel combination 
Overall survival. 
Study Design: 
A randomised, double-blind placebo controlled phase 2 trial.  Randomisation 1:1 
between treatment arms: either docetaxel 75mg/m2 IV and placebo given bd, or 
AZD6244 75mg bd daily with docetaxel 75mg/m2 IV. Docetaxel will be 
administered every 3 weeks for a maximum 6 cycles, but AZD6244/placebo may 
be continued beyond this, until disease progression.  
Patient Numbers: 
80 patients (40 per treatment arm) will be recruited to the study.  
Target Population:
Chemonaive patients with metastatic cutaneous melanoma, with tumours wild 
type for BRAF. 
Main eligibility / 
exclusion criteria 
Inclusion Criteria 
 
≥ 16 years of age, written informed consent 
 
Histologically confirmed, wild type BRAF, metastatic melanoma. 
 
Unresectable Stage III or Stage IV metastatic melanoma. 
 
Measurable disease as defined by modified RECIST criteria.  
 
Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1.  

Adequate haematological, hepatic and renal function.

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 
Adequate cardiac function (NYHA 0-1). 
 
No evidence of brain metastases or treated brain metastasis with no 
evidence of relapse on cerebral MRI, or stable off treatment for 3 months. 
 
Life expectancy > 12 weeks. 
 
LDH  2xULN. 
 
Exclusion criteria  
 
Radiotherapy or systemic melanoma therapy within 28 days prior to starting 
treatment.  
 
Prior DNA damaging agents or BRAF or MEK inhibitors for metastatic 
melanoma 
 
Pregnancy or breastfeeding woman 
 
Grade ≥ 2 peripheral neuropathy at study entry 
 
Known severe hypersensitivity to drugs formulated in polysorbate 80 
 
Ocular or mucosal malignant melanoma  
 
Another active malignancy within the past five years  
 
Clinically significant and uncontrolled major medical condition(s).  
 
Refractory nausea and vomiting, chronic gastrointestinal diseases (eg, 
inflammatory bowel disease) or significant bowel resection that would 
preclude adequate absorption of AZD6244. 
 
Taking medication known to interact significantly with CYP3A4. 
Trial dose and 
administration
Docetaxel will be administered intravenously every 3 weeks at a dose of 75 
mg/m2. AZD6244 75mg or placebo will be given orally twice a day. 
Duration on study 
Patients will receive up to 6 cycles of docetaxel. 
Patients will receive AZD6244/placebo until disease progression or unacceptable 
toxicity. 
Study Procedures 
and frequency 
Complete physical examination at screening, on C1D1, C1D8, C1D15, C2D1, 
C2D8 and day 1 of every subsequent cycle. Blood for haematology and 
biochemistry will be taken at each of these visits. A 12 lead ECG will be 
performed at screening and day 1 of each cycle.  Disease assessment by CT 
scanning using modified RECIST criteria at 9 and 18 weeks after randomisation, 
then every 3 months +/- 7 days until disease progression.  
Criteria for 
evaluation 
Efficacy 
Disease progression will be monitored by modified RECIST. 
Safety 
Safety and toxicity will be reported by using CTCAE (version 4). 
Genotyping 
BRAF mutation analysis will be performed on previously collected melanoma 
samples or on fresh biopsy specimens. 
Statistical methods 
The primary objective of this study will be to compare the efficacy of AZD6244 in 
combination with docetaxel, versus docetaxel alone, in first line patients with wt 
BRAF advanced cutaneous melanoma, by assessing progression free survival. 
Analysis will be performed when approximately 58 progression events have 
occurred.  If the true Hazard Ratio (HR) is 0.57 (likely to correspond to a 75% 
prolongation of PFS), this analysis will have approximately 80% power to 
demonstrate a statistically significant difference for PFS, assuming a 1-sided 
10% significance level.  
 
Study Site(s)
Between 15 and 20 centres across the UK, under the auspices of the NCRI 
Melanoma Clinical Study Group 
Duration of 
recruitment
Approximately 12 months 
End of study
Last patient last visit 
Funding: 
The study will be funded according to the terms of the NCRN-AZ alliance, with 
AstraZeneca underwriting the excess treatment costs of docetaxel used in the 
study. 

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2.1 
Schedule of Events 
Visit
1
2
3
4
5
6
7
8
9
10
11
12+
Off Treatment Visits
Cycle
0
0
1
1
1
2
2
3
4
5
6
7
N/A
N/A
N/A
Day
N/A 
-14 to -1
1 
8 
15 
22 
29 
43 
64 
85 
106 
 
N/A 
30 days 
post Tx
Every 3 
months
Visit description 
Mutation 
Screening
Main study 
screening
Baseline 
Treatment 
Stop 
treatment
Post study 
visit 
Follow up1
Visit window(days)
N/A 
 
N/A 
+/- 2 
+/- 2 
+/- 2 
+/- 2 
+/- 2 
+/- 7 
+/- 7 
+/- 7 
+/-7 
Mutation status consent
X
Main study consent
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Treatments
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam 
 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Disease Assess.
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Haematology and 
Biochemistry
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG3
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Docetaxel administration
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
AZD6244/placebo
Twice daily dosing
Urinalysis
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CT scan
 
Baseline4
 
 
 
 
 
 
X5 
 
X 
X 
 
 
X5 
Blood sample6
X
 
                                               
 
1 Survival status only may be recorded 
2 A physical examination is not required at baseline if the screening visit is within 3 days of commencing treatment 
3 ECG must be performed pre dose and 2 hours post dose on day 1 (visit 3).  
4 Baseline CT within 28 days of commencing treatment. This must include a contrast study of the head (an MRI head is acceptable as an alternative)  
5 Disease assessment by modified RECIST will be recorded at the end of cycles 3 & 6, and every 3 months thereafter until disease progression is recorded. 
6 Blood sample for genetic analysis may be taken at Main Study Screening if BRAF Mutation Screening not required. 

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2.2 
Study Flow Chart 
 
 
 
 
 
 
 
Screening visit 1  
Consent for BRAF mutation assessment  
Screening visit 2 (day -14 to -1) 
If wild type BRAF and no obvious exclusions, then consent 
to main study and proceed with full screening 
Randomisation 
Patients assigned to receive docetaxel/AZD6244 or 
docetaxel/placebo 
Day 1 baseline visit (3) 
Treatment commences with docetaxel IV q3w and 
AZD6244/placebo PO bd
Day 8 and 15 follow up visits (4 and 5) 
Safety assessment and physical examination 
Visits at day 22, 29, 43, 64, 85 and 106.  
Safety assessment, physical examination and 3 weekly 
treatment with docetaxel (to 6 cycles), & re-supply of 
AZD6244/placebo.   
Tumour assessments using modified RECIST every 9 
weeks while on chemotherapy and every 3 months 
thereafter
Withdrawal of study treatment 
Follow up visit after 30 days 
Date of death recorded
Continue clinical assessment and disease assessment by modified RECIST every 3 
months until disease progression 

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3 
INTRODUCTION 
In the developed world the incidence of melanoma has been increasing, with the highest noted in the 
southern hemisphere. In the UK, melanoma rates have risen more than any other cancer. Melanoma affects 
over 10,000 people every year and now represents the most common cancer in young adults. Early 
detection of melanoma leads to treatment in the form of surgical excision, but the disease metastasises in 
approximately 15% of patients. Current treatment for metastatic melanoma is unsatisfactory. No agent has 
been shown to improve survival compared with supportive care, and classical cytotoxic agents produce 
responses in a minority (between 5 and 13%) of patients. Despite these dismal figures dacarbazine remains 
the standard of care. Docetaxel has been evaluated in phase 2 trials in melanoma, producing response rates 
of 6-14% (Aamdal et al., Eur J Cancer 30A: 1061), in line with a number of cytotoxic agents.  
 
One of the most important developments in melanoma has been the discovery that over 40% of patients 
harbour activating mutations in BRAF, principally V600E, an observation confirmed in a recent phase 2 
clinical trial population (Board et al, Br J Cancer 101:1724). Recently, promising results have been observed 
with PLX4032, an agent targeting the activating V600E mutation in BRAF. In an early phase trial 25 of 38 
patients with V600E BRAF responded to treatment at pharmacodynamically active doses (Chapman, 
European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 5). PLX4032 is now being 
evaluated in patients with metastatic melanoma harbouring mutated oncogenic BRAF in an international 
phase 3 trial. 
 
New therapies are still needed for melanoma, as the utility of PLX4032 and related drugs remains uncertain 
until definitive trial results are available. Even if these bear out the early promise outlined above, effective 
therapy for the ~60% of patients without the V600E BRAF mutation will still be lacking.  
 
3.1 
Docetaxel mechanism of action 
Docetaxel acts by promoting the assembly of tubulin into stable microtubules and inhibits their disassembly 
which leads to a marked decrease of free tubulin. Subsequent pathways to cell death are unclear and vary 
between cell types. In melanoma cells docetaxel induces apoptosis via pathways that are dependent on 
activation of caspase-2, which initiates mitochondrial dependent apoptosis by activation of Bax (Mhaidat et 
al., Mol Cancer Ther 6:752). Docetaxel induces activation of both JNK and ERK1/2, but not p38 mitogen-
activated protein kinase or Akt kinases. Apoptosis is dependent on activation of JNK, which is required for 
phosphorylation and inactivation of bcl-2 and activation of Bax. Conversely, activation of ERK1/2 results in 
degradation of the BH3-only protein Bim and phosphorylation of Bad, inhibiting apoptosis (Mhaidat et al., 
Clin Cancer Res 13:1308). Taxane resistance can occur as a result of constitutive and/or drug-induced 
activation of the Ras-raf-MEK-ERK axis. 
 
3.2 
AZD6244 and ERK activation 
ERK1/2 is constitutively active in melanoma cells regardless of their BRAF or NRAS status, presenting a 
potential target for treatment in this population. Phosphorylated ERK is important for melanoma because it 
plays key roles in cell cycle entry, invasion, and possibly angiogenesis, as well as in resistance to apoptosis 
(Smalley, Int J Cancer 104: 527). AZD6244 is a highly selective allosteric inhibitor of MEK1/2. Treatment with 
AZD6244 leads to suppression of pERK levels in melanoma in a manner independent of BRAF and NRAS 
mutation status (Haass et al., Clin Cancer Res, 14:230). Single agent therapy of melanoma with AZD6244 
has been disappointing. In a phase 2 trial of AZD6244 6/104 patients achieved a partial response (Dummer 
et al., Proc ASCO 2008), including in a wt BRAF wt NRAS patient. A randomized phase 2 trial (NCRN063) is 
exploring AZD6244 in combination with dacarbazine in mutant BRAF melanoma.  
 
3.3 
AZD6244 and docetaxel 
Our interest is in exploring the potential for MEK inhibition to overcome taxane resistance in melanoma. 
AZD6244 and docetaxel have demonstrated synergy in a variety of animal xenograft models, including 
colorectal cancer (HCT-116, SW-620 figure 1), NSCLC (A549) and melanoma (1025Lu figure 2) (Wilkinson et 
al., AACR 2008, abstract 4012). 

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Figure 1. Effect of AZD6244 and/or 
docetaxel in a SW620 colorectal cancer 
xenograft model 
 
 
 
 
 
 
 
 
 
 
Figure 2. Effect of AZD6244 (30mg/kg daily po)  
and/or docetaxel (15mg/kg iv 3x per week) in a  
1205Lu melanoma xenograft model  
(from Haass, ref above) 
 
 
 
 
 
 
 
 
 
3.4 
Justification for the doses to be used 
A phase 1 study of the combination of AZD6244 and docetaxel has been conducted (AstraZeneca study 
D1532C00004). The 75 mg BD dose of AZD6244 in combination with docetaxel 75 mg/m2 q21 days was 
recommended for further study. The most frequently reported adverse events were diarrhoea, fatigue, 
nausea, peripheral oedema, rash, vomiting, mucosal inflammation, neutropenia and constipation. Adverse 
events were consistent with the monotherapy toxicity profiles. To date the combination has been given to 12 
patients with melanoma: 1 had a complete response; 1 a partial response; 4 had stable disease beyond 6 
cycles of treatment (18+ weeks) indicating clinical activity worthy of further study.  
 
4 
Study Design 
This is a randomised, double-blind, placebo-controlled multi-centre study. Eighty patients (forty in each of 
two arms) will be randomised with stratification for M stage (M1c vs M1a, M1b or M0) and performance 
status (0 vs 1). Patients will receive docetaxel with placebo or docetaxel with AZD6244. 
 
5
10
15
20
25
30
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Tumour volume (cm3) +/- SEM
Day after implant
 Control
 AZD6244-25mg/kg
 Taxotere-15mg/kg
 Combo

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Clinical study Objectives and Endpoints 
 
Primary objective 
Endpoints 
To assess the efficacy of AZD6244 in 
combination with docetaxel, compared with 
docetaxel alone, in first line patients with wild 
type BRAF advanced malignant melanoma 
Progression free survival 
Secondary objective 
Endpoints 
To further assess the efficacy of AZD6244 in 
combination with docetaxel, compared with 
docetaxel alone, in first line patients with wild 
type BRAF advanced malignant melanoma 
Overall survival (OS). 
Objective response rate (ORR)  
Progression free survival at 6 months (PFS) 
 
To assess the safety and tolerability of 
AZD6244 in combination with docetaxel 
compared with docetaxel alone. 
Adverse events using CTCAE v4.0 
Vital signs and weight 
Biochemistry, haematology and urinalysis 
Physical examination 
ECG  
Exploratory objectives 
Endpoints 
To assess the impact of tumour 
characteristics on response to docetaxel 
therapy with or without AZD6244 
Immunohistochemistry of proteins in the 
MAPkinase pathway 
Genotyping of tumours 
 
 
5 
Patient Selection 
The Investigator will determine patient eligibility based on the following criteria: 
 
5.1 
Screening for BRAF mutation 
Patients will be eligible for screening for BRAF mutation status provided that: 
 
1. They give written informed consent to screening for the BRAF mutation.  
2. They are able to provide a tumour sample or are willing to have a fresh biopsy taken.  
3. The Investigator anticipates that there is a reasonable expectation that they will satisfy the inclusion 
criteria in 5.2 below (NB formal screening for the main study should not be performed until the BRAF 
status of the patient is known). 
Patients whose BRAF mutation status is already known through screening for, or participation in, previous 
studies, and who are known to be wt may proceed directly to screening for the main study. Otherwise 
mutation status will be assessed centrally in Oxford (see section 8.1). 
 
5.2 
Entry into the main study 
 
5.2.1 Inclusion criteria 
A patient will be eligible for inclusion in the main study if all of the following criteria apply:  
 
4. Aged  16 years  
5. Able to provide evidence from an accredited laboratory of wt BRAF status for their melanoma, or 
ascertainment of wt BRAF status from a sample of melanoma provided for mutational analysis in 
Oxford (see section 8.1).  
6. Unresectable stage 3 or 4, histologically proven cutaneous or unknown primary melanoma  

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7. At least 1 lesion, not previously irradiated, that can be accurately measured on CT or MRI as defined 
by modified RECIST criteria 
8. ECOG performance score of 0 or 1.  
9. Life expectancy of at least 12 weeks. 
10. The patient is willing to give consent to the main study and able to comply with the protocol for the 
duration of the study, including scheduled follow-up visits and examinations. 
11. Haematological and biochemical indices within the ranges shown below.  
Lab Test 
Value required 
Haemoglobin (Hb) 
>10g/dL 
White Blood Count (WBC) 
> 3x109/L 
Platelet count 
> 100,000/μL 
Absolute Neutrophil count 
> 1.5x109/L; 
Serum bilirubin 
≤ 1.2 x ULN 
AST (SGOT) or ALT 
≤ 2.5 x ULN 
LDH 
≤ 2 x ULN 
Creatinine clearance (Cockcroft-Gault) 
>50 ml/min 
 
 
5.2.2 Exclusion criteria 
A patient will not be eligible for the trial if any of the following criteria apply: 
 
1. Any anti-cancer therapy (including radiotherapy and participation in other clinical trials) within 28 
days prior to Day 1.  
2. Prior DNA damaging agents or cytotoxic chemotherapy for metastatic melanoma. 
3. Any unresolved toxicity from prior anti-cancer therapy that is greater than CTCAE grade 2. 
4. Pregnancy or breastfeeding women. Female patients must have a negative urinary or serum 
pregnancy test or have evidence of post-menopausal status (defined as absence of menstruation for 
> 12 months, bilateral oophrectomy or hysterectomy). 
5. Grade ≥2 peripheral neuropathy at study entry. 
6. Patients of reproductive potential who are not willing to use adequate contraceptive measures for the 
duration of the study (both male and female patients) 
7. Known severe hypersensitivity reactions to docetaxel or other drugs formulated in polysorbate 80 
8. Ocular or mucosal malignant melanoma  
9. Another active malignancy within the past five years.  
10. Evidence of brain metastases, unless surgically resected/stereotactic radiosurgery treated brain 
metastasis with no evidence of relapse on cerebral MRI, or treated brain metastasis and stable off 
treatment, including steroids, for 3 months. 
11. Clinically significant and uncontrolled major medical condition(s): such as active infection, bleeding 
diathesis.  
12. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. 
13. Cardiac conditions, including uncontrolled hypertension (BP>160/100 despite treatment), heart 
failure NYHA class 2 or above, prior or current cardiomyopathy, myocardial infarction within 6 
months or angina requiring nitrate therapy more than once a week. 
14. Previous treatment with EGFR, ras, raf or MEK inhibitors. 
15. Inability to swallow capsules, refractory nausea and vomiting, chronic gastrointestinal diseases (eg, 
inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption. 
16. Taking medication that significantly induces or inhibits CYP3A4 (see appendix 3). 
 

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5.3 
Patient screening and enrolment 
Patients will be recruited from those referred to oncology services for management of advanced melanoma.  
Screening and study enrolment logs will be maintained by each site clinical study team.  Before entering a 
patient onto the study the Principal Investigator or designated representative will confirm eligibility. If in any 
doubt the Oncology Clinical Trials Office must be consulted. 
 
Patients will be randomised using an IWRS (see section 8.4) 
  
5.4 
Randomisation of patients 
Eligible patients will be randomised 1:1 to receive Docetaxel with Placebo or Docetaxel with AZD6244, 
stratifying for M status (M1c vs M1a or b or M0) and Performance Status (0 vs 1).  Every effort should be 
made to ensure that only eligible patients are randomised.  If a patient is randomised in error, the study site 
should contact OCTO as soon as possible and if necessary treatment should be stopped.  Patients 
randomised in error should be followed up for disease progression and for survival. For patients randomised 
in error, and who do not start study treatment, replacement patients will be recruited and randomised. 
 
6 
Investigational agents 
The Investigational Medicinal Products in this trial are docetaxel, AZD6244 and Placebo.  Docetaxel 
(Taxotere)7 has a Marketing Authorisation for the treatment of several cancers (as described in the Summary 
of Product Characteristics) but is not authorised for use in melanoma.  It is therefore being used as an IMP in 
this trial.  AZD6244 is a new chemical agent developed by AstraZeneca, and is provided in capsule form.  
Placebo capsules are supplied by AstraZeneca. 
 
6.1 
Docetaxel 
Patients will receive docetaxel 75 mg/m2, rounded to the nearest 10 mg, based on the most recent body 
surface area, as a 1 hour IV infusion in 250ml of either 5% glucose solution or 0.9% sodium chloride 
solution.  Standard pre-medication with steroids should be given, consisting of dexamethasone 8 mg b.d. for 
3 days starting 1 day prior to docetaxel administration. Treatment will be given on day 1 and every 3 weeks 
for up to 6 cycles.  The dose of docetaxel may be reduced or delayed if necessary as described in section 
6.3.1. There will be no adjustments or dose capping for missing limbs and no dose capping for larger 
patients. 
 
Patients should be observed closely for hypersensitivity reactions especially during the first and second 
infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of 
docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If 
hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not 
require interruption of therapy. Hypersensitivity reactions should be managed according to local protocols, 
and docetaxel may be re-introduced according to the scheme described in 6.3.1. However, severe reactions, 
such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation 
of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should 
not be re-challenged with docetaxel, but may continue with AZD6244/placebo within the study. 
 
6.2 
AZD6244/Placebo 
Patients will be allocated AZD6244/placebo by bottle number. They will receive 75mg AZD6244 or placebo 
orally twice a day on a continuous schedule.  The AZD6244/placebo will be supplied in white HDPE bottles 
containing capsules of 25mg strength.  At each visit, sufficient capsules will be provided for the period until 
the patient’s next scheduled visit.  It is not possible to specify capsules numbers in each bottle as availability 
of the AZD6244 and/or placebo may vary during the trial. 
 
Capsules should be taken whole and not opened or crushed.  They should be taken on an empty stomach 
(no food or drink for 2 hours before or 1 hour after treatment), with approximately 240ml of water.  Doses 
should be taken approximately 12 hours apart.  Wherever possible doses should not be missed but if a dose 
is missed then the next dose should be taken at the allotted time and the missed dose should not be made 
                                                
 
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up. Patients are permitted to continue to take AZD6244/placebo until they experience disease progression, 
in the absence of significant toxicity. If any patients are still on AZD6244/placebo at the time the final 
analysis is performed and the study is unblinded, any patients who are in the active arm will be offered the 
opportunity to continue on open label AZD6244. Any patients who are on placebo will be taken off IMP and 
offered standard care. 
 
The end of study assessment will take place 30 days after the last AZD6244/placebo administration.  If any 
adverse events attributable to either of the study drugs are still present, then the patient will be followed up 
appropriately until resolution or stabilisation of the AE(s), unless the patient starts another anti-tumour 
treatment. 
 
If patients have not experienced disease progression at the time of the end of study assessment every effort 
should be made to follow them until disease progression, or the start of another anti-tumour therapy. 
 
6.3 
Criteria for Re-Treatment and Dose Reductions 
Patients may receive second and subsequent doses of docetaxel on the scheduled day of treatment 
provided that they have an absolute neutrophil count >1.5x109/L and a platelet count >100x109/L, and no 
drug-related non-haematological toxicity of grade 3 or above. 
 
6.3.1 Dose reduction of docetaxel. 
Adverse events considered related to the administration of docetaxel are listed in the relevant product 
information sheet.  A reduction in the dose of docetaxel should be considered if any of the following apply in 
the preceding cycle: 
 
 
Grade 3 or 4 neutropenia complicated by sepsis (temperature >38.5oC or documented infection), 
 
Grade 4 neutropenia > 7 days duration, 
 
Grade 4 thrombocytopenia, or grade 3 thrombocytopenia complicated by haemorrhage, 
 
Grade 3 or 4 non-haematological toxicities that cannot be adequately controlled by optimization of 
supportive therapy (except fatigue of less that 2 weeks duration, changes in alkaline phosphatase 
and LDH, hyperglycaemia related to temporary steroid use and alopecia), 
 
Grade 3 or 4 peripheral sensory neuropathy of greater than 2 weeks duration. 
 
>2 week delay in re-treating with docetaxel 
 
Treatment should not be reintroduced until the toxicity has resolved to grade 1 or less. Where there is a 
delay in re-treating with docetaxel subsequent visits will be defined by the start of each cycle of treatment 
(e.g. visit 9 would still be at the start of cycle 4, and later than the planned day 64). However scan times do 
not shift and continue in accordance with the  randomisation date rather than cycles of treatment received. 
 
In the case of neutropenic sepsis or grade 4 neutropenia greater than 7 days, docetaxel can be restarted at 
the full dose, when appropriate but with G-CSF support (centres should follow local guidelines).  If 
neutropaenia recurs despite G-CSF, then the docetaxel should be reduced to 50 mg/m2.  If G-CSF support 
cannot be offered local policies for support will apply. If the neutropaenia then recurs then the docetaxel 
should be stopped. 
 
In the case of other toxicities, a dose reduction in docetaxel to 50 mg/m2 should be applied. No further dose 
reductions in docetaxel are permitted in the study. 
 
6.3.2 Dose reduction of AZD6244/placebo 
Adverse events considered related to AZD6244 are fatigue, dermatitis (acne form), diarrhoea, nausea and 
periphery oedema. More detail can be found in the Investigator Brochure. 
 
Treatment with AZD6244 should be withheld for any grade 3 or 4 (CTCAE criteria) or otherwise intolerable 
toxicity that cannot be adequately managed with optimal supportive care, if considered related to the study 
drug.    
 

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Treatment may be resumed once the toxicity improves to CTCAE grade 1 or baseline, or in the case of a 
skin rash to CTCAE grade 2.  At the discretion of the Investigator, treatment can resume at the same dose: 
however if this is not likely to be tolerated then the dose should be reduced in the following stepwise manner, 
from 75mg b.d. to 75 mg o.d. to 50 mg b.d. to 50 mg o.d.  If the drug is not tolerated at this level then the 
drug should be discontinued. The scheme for dose reductions is summarised overleaf. 
 
NB once a dose reduction has occurred then the patient must remain at that dose and not 
be increased back to a previous dose level.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4 
Concomitant medication and non-drug therapies 
Concomitant therapies may be given as medically indicated, and will be documented at each follow up visit. 
However the following advice should be noted; 
 
 
Patients should avoid changing any drugs that may affect the metabolism of AZD6244 or docetaxel, 
particularly CYP3A4 and CYP1A2 inhibitors and inducers, unless considered to be in the best 
interests of the patient. 
 
Patients should avoid taking Vitamin E in doses that exceed 100% of the RDA (15mg). 
 
Patients on coumarin anticoagulants such as warfarin should have careful INR monitoring for the 
duration of the study. 
 
Patients should not have live attenuated or yellow fever vaccines.  However, administration of the 
seasonal influenza and H1N1 (‘swine flu’) vaccines is not contraindicated. 
 
Patients should take care with sun exposure and take adequate precautions. 
 
Steroid and anti-emetic premedication for administration of docetaxel should be given in line with local policy.  
For example, dexamethasone 8mg twice a day may be given on the day before, day of and day after 
treatment with metoclopramide 10 mg to 20 mg tds.  
 
Grade 3 or 4 toxicity has resolved to ≤ Grade 1,  
or Grade 2 if dermatological.
Dose reduction to 75 mg od if necessary
Further AE (same) 
Further AE 
(different) 
Toxicity has resolved to ≤ Grade 1,  
or Grade 2 dermatological. 
Dose reduction to 50 mg bd if necessary
Dose reduction to 50 mg od if necessary 
If a dose reduction has 
already occurred, the 
investigator has the 
discretion to continue at 
the same dose or go 
down to the next dose 
level as appropriate

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6.4.1 Conditions for palliative radiotherapy 
The patient may have palliative radiotherapy while on study for symptomatic purposes providing that the 
AZD6244 is stopped for 3 days prior to and following treatment.  The field should be as small as possible 
and not involve more than 20% of the bone marrow.  The symptoms should be investigated to ensure that 
they do not constitute progressive disease.  The lesions will no longer be evaluable for the purposes of the 
study, and if there is no longer disease that can be measured using modified RECIST following radiotherapy, 
then the patient should be followed for progression and overall survival only. 
 
6.4.2 Prohibited medication 
Patients should not be prescribed any other anti-cancer or investigational drugs while participating in this 
study 
 
6.4.3 Management of overdose 
To date, no subject has reported an overdose with AZD6244.  There is currently no known antidote with 
AZD6244.  Patients should be admitted for careful monitoring, and management should be supportive and 
tailored to symptoms as they arise. 
 
If a patient does overdose, either accidentally or deliberately, this should be reported as an AE regardless of 
whether the patient experienced symptoms. 
 
Overdosing with Docetaxel should be managed in line with local policy. 
 
6.4.4 Management of hypersensitivity reactions 
Hypersensitivity to docetaxel is a recognized complication, and may present with hypotension, facial flushing, 
back pain, dyspnoea, laryngeal and facial oedema and urticaria.  Emergency management should be in line 
with local policy.  The docetaxel should be stopped, and oxygen, adrenaline, hydrocortisone, antihistamines 
and appropriate ventilatory and circulatory support administered if necessary. 
 
Depending on the severity of the reaction, at the Investigator’s discretion and with appropriate monitoring 
and availability of resuscitation equipment, the patient may be rechallenged with docetaxel following a 
hypersensitivity reaction.  The following rechallenge schedule may be adopted 
 
 
Dexamethasone 20mg iv 3 hours before administration on the day of treatment and 20mg iv 30 
minutes prior to docetaxel administration 
 
Ranitidine 50 mg iv 30 minutes prior to docetaxel 
 
Chlorphenamine 10mg iv stat 30 minutes prior to docetaxel. 
 
Docetaxel given at 10% of the rate ie 25 ml per hour for 2 hours.  If no further reaction is seen, then 
the rate may be increased to 50 ml per hour for 1 hour, then 75 ml per hour, then 100 ml per hour to 
complete the infusion.   
 
If less than 10% of the dose was administered initially, then rechallenge may take place with the full dose of 
docetaxel.  If more than 10% was administered then the chemotherapy should be represcribed with an 
appropriate dose reduction.  If the rechallenge is more than 72 hours after the initial dose, then haematology 
and biochemistry needs to be reassessed to determine suitability.   
 
On subsequent cycles following a rechallenge the same schedule should be followed in line with local policy. 
 
If hypersensitivity to docetaxel recurs despite full premedication then the docetaxel should be stopped.  
 
6.4.5 Management of skin toxicity 
The skin toxicity seen with AZD6244 has yet to be fully investigated.  The management of skin toxicity is 
based on the consensus guidelines produced for other targeted agents thought to produce a similar pattern 
of skin toxicity. 
 

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Grade 
Action 
Grade 1 
Regular emollients and oatmeal based creams eg Aveeno 
Topical steroids e.g. 1% hydrocortisone 
Topical antibiotics e.g. clindamycin gel 
Oral antihistamines for itch 
Avoid sun exposure 
Grade 2 
Continue above plus consider topical pimecrolimus  
Oral antibiotics i.e. doxycycline 100 mg bd 
Grade 3 
Stop AZD6244 and allow rash to resolve to grade 2 or better.  
Consider dose reduction as outlined in the algorithm in 6.3.2. 
Consider superinfection eg staph aureus, take swabs and consider oral 
antibiotics or topical mupirocin.   
Consider oral steroids, prednisolone 20mg daily in severe cases   
 
6.5 
Patient evaluability 
All patients who receive at least one dose of docetaxel and/or AZD6244/placebo and who have post-dose 
data available will be evaluable for the safety analysis.  Efficacy will be analysed on an intention-to treat-
basis and therefore any patient who is randomized within the trial will be included in the analysis.   
7 
Pharmaceutical Information 
7.1 
IMP Supply  
AZD6244/placebo will be supplied, appropriately labelled in accordance with all applicable regulatory 
requirements, by AstraZeneca to study sites and dispensed by the Pharmacy Department in the appropriate 
hospital trust.  Docetaxel will be sourced locally in the same way as standard treatment and prescribed in 
accordance with local regulations.  
 
A patient’s first bottle will be allocated and shipped at randomisation. Resupplies will be managed through an 
Interactive Web Response System (IWRS). The web based system will facilitate randomisation to treatment, 
stratification and automated supply management of the AZD6244/placebo to the sites. Subsequent patient 
study medication assignment will also be managed through the IWRS. 
 
Any patients who remain on active treatment once the final analysis has been performed will be allocated 
open label bottles of AZD6244. The open label bottles of AZD6244 will not be managed through the IWRS 
and will be dispensed by the Pharmacy Department in the appropriate hospital Trust in quantities determined 
by the Investigator. Sites will request re-supply of open label AZD6244 by contacting the trial team in OCTO.  
 
The cost of Docetaxel will be reimbursed as detailed in the Clinical Trial Agreement between Sponsor and 
NHS Trust. 
 
7.1.1 Handling and storage 
Only patients enrolled in the trial may receive the trial drug supplies in accordance with this protocol and 
under the supervision of the Investigator.  All supplies must be stored in a secure, limited access storage 
area.   
 
7.2 
Preparation 
 
7.2.1 Formulation, Method of Reconstitution and stability 
AZD6244/placebo will be supplied as 25 mg Hyd-Sulfate capsules in white high density polyethylene (HDPE) 
bottles.  At each visit patients will receive sufficient capsules for treatment until the next scheduled visit. 
 
Docetaxel is formulated as a concentrate for solution for infusion or as a concentrate and solvent for solution 
for infusion depending on the brand/generic form.  The concentrate is a clear colourless,to pale yellow or 
pale yellow to brownish yellow solution depending on the brand/generic form.Docetaxel will be reconstituted 
in 250 ml of 0.9% Sodium Chloride or 5% glucose in line with local policies (refer to the instructions in the 

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SmPC for the particular brand/generic form being used at site).  Once reconstituted, docetaxel to be handled 
as per local practice. 
 
7.2.2 Labelling  
The responsible Pharmacy will ensure that docetaxel supplies are appropriately labelled to give the following 
information and in accordance with all applicable regulatory requirements.   
 
Batch number  
Active medication strength  
Dosing instructions  
Storage instructions  
Investigator contact address 
Name of sponsor 
“For clinical trial use only” and “Keep away from children” 
 
Note that emergency contact details will be supplied to the patient separately. 
 
7.2.3 Administration 
AZD6244/placebo is administered orally as three 25 mg capsules in the morning and three 25 mg capsules 
in the evening.  AZD6244/placebo must be taken on an empty stomach (no food or drink for 2 hours before 
or 1 hour after treatment) with 240 ml of water.  Doses should be taken 12 hours apart where possible. The 
dose can be taken up to 3 hours after the scheduled time. If missed, the dose should be ignored and the 
next dose taken at the scheduled time. 
 
Docetaxel is administered into a peripheral vein over 1 hour. 
 
7.2.4 Vein Extravasation /Accidental Spillages and Occupational Safety 
Vein extravasation and accidental spillages should be dealt with according to hospital policy.   Docetaxel is 
an exfoliant cytotoxic agent and likely to cause inflammation and skin shedding but not deep tissue damage. 
The product is not expected to pose an occupational safety risk to site staff under normal conditions of use 
and administration.  
 
7.3 
Drug accountability 
The Principal Investigator is responsible for investigational product accountability, reconciliation, and record 
maintenance throughout the course of the study. This responsibility may be delegated to designated 
pharmacy staff who must maintain accurate records of all trial drug receipts from the supplier, dispensing to 
trial patients, and the disposal of all unused drug. This inventory must be available for review by 
representatives of the sponsor, Regulatory Authority or Chief Investigator on request.  
 
Empty or partially used vials or returned unused capsules will be properly disposed of by pharmacy in 
accordance with local practice.  
 
On completion of the trial, the Chief Investigator (or designee) will instruct pharmacy in the arrangements for 
the destruction of any unused study drug. 
 
8 
Trial assessments and procedures 
A summary of the study assessments and procedures is given in section 2.1.  Details of all protocol 
evaluations and investigations will be recorded in the patient medical record for reconciliation with the study 
Case Record Folder. 
 
8.1 
BRAF mutation screening 
The consent process will be conducted in a stepwise manner.  Patients will be given two separate consent 
forms.  The first will outline the principles and rationale of evaluating BRAF mutation status (Consent Form 
A). In order to limit the time that patients have to wait to obtain their mutation status, and in recognition that 
this usually involves sourcing archival biopsy material, they will be permitted to give consent to mutation 

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screening without the usual 24 hour period for consideration, if they so desire. At this visit patients will be 
asked to provide a 10mL blood sample (collected in EDTA) for genotyping (Consent Form B). 
 
Patients submitting to mutation screening will be logged with the Oncology Clinical Trials Office in Oxford in 
order to obtain a screening number before a sample is sent. A sample from their tumour will be dispatched 
to: 
 
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Sample Handling Laboratory, Level 1 
Oxford Cancer and Haematology Centre 
Churchill Hospital 
Oxford 
OX3 7LE 
 
The sample should be accompanied by a despatch note detailing the screening number, any local identifying 
numbers and source of the tissue. 
 
If a BRAF mutation is not detected from initial testing because the sample is deemed by the laboratory to be 
of poor quality (defined as poor fixation, less than 1% cells in sample, less than 50 cells in sample or 
inadequate DNA preparation), then one further sample may be analysed.  If the results remain inconclusive 
then the patient will not be eligible for randomisation to the trial. 
 
Where patients already have knowledge of their BRAF mutation status they must be logged with the 
Oncology Clinical Trials Office in the normal way in order to obtain a screening number.  The report detailing 
their mutation status as wt for BRAF must be provided to the Office to allow them to proceed to screening for 
the main trial. 
 
8.2 
Mutation screening procedures 
Once the patient has consented to the BRAF mutation screening phase demographic information and 
medical and surgical history will be recorded, but no further study-specific investigations will be made until 
mutation status is known. 
 
8.3 
Further Main Study screening procedures 
 
Once the BRAF mutation status is known and shown to be wild type, then the following screening 
procedures will be performed within 14 days of dosing unless otherwise stated. 
 
 
Main study informed consent (Consent Form C) 
 
Disease staging 
 
Concomitant medications and previous anti cancer therapy 
 
Smoking status 
 
Tumour evaluation according to RECIST guidelines: CT scan of the chest abdomen and pelvis and 
other imaging of known sites of disease if appropriate.  Baseline imaging must be performed within 
28 days of commencing treatment 
 
CT or MRI of the brain. 
 
Assessment of ECOG performance status 
 
Physical examination and vital signs 
 
Blood samples for haematology and clinical biochemistry, including LDH 
 
Urinalysis 
 
Pregnancy test, if applicable 
 
Single ECG 
 
Overall assessment of patient eligibility 

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Collection of AEs commences after signing Consent Form C. 
 
Eligible patients will then be randomised to the study. 
 
8.4 
Randomisation Procedures 
 
Randomisation is completed via an IWRS system:https://www.cenduitsolutions.com 
Patients will be randomised to one of two arms as shown below: 
 
Each patient will be assigned a unique identifying number and first bottle number for AZD6244/placebo.  
 
8.5 
Treatment Period 
The following procedures will be performed throughout the treatment period. At each visit the Investigator will 
make an assessment of the clinical disease status of the patient to inform decision making, but objective 
radiological assessment will be as specified below: 
 
Day 1  
Visit 3 
Physical Examination 
Vital signs 
Document Concurrent therapy 
Haematology – FBC 
Biochemistry* – to include: U&Es, LFTs and LDH 
Urinalysis 
Baseline AEs and performance status (PS)  
Administration of Docetaxel 
Dispensing of AZD6244/placebo 
ECGs pre dose and 2 hrs post dose  
Day 8  
Visit 4 
Physical Examination, vital signs and PS 
Document Concurrent therapy  
Haematology – FBC  
Biochemistry* – to include U&Es, LFTs 
Urinalysis  
Record Adverse Events 
Day 15  
Visit 5 
Physical Examination 
Vital signs 
Haematology – FBC  
Biochemistry* – to include U&Es, LFTs 
Urinalysis  
Record Adverse Events 

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Day 22  
Visit 6 
Physical Examination, vital signs and PS 
Document Concurrent therapy  
Weight 
Haematology – FBC  
Biochemistry* – to include: U&Es, LFTs and LDH 
Urinalysis 
Record Adverse Events  
Administration of Docetaxel 
Dispensing of AZD6244/placebo 
 
Day 29  
Visit 7 
Physical Examination 
Vital signs 
Haematology – FBC  
Biochemistry – to include: U&Es, LFTs  
Urinalysis  
Record Adverse Events 
Day 43    Visit 8 
Day 64    Visit 9 
Day 85    Visit 10 
Day 106  Visit 11 
Physical Examination, vital signs and PS 
Document Concurrent therapy  
Weight 
Haematology – FBC  
Biochemistry* – to include: U&Es, LFTs and LDH 
Urinalysis 
Record Adverse Events 
Administration of Docetaxel 
Dispensing of AZD6244/placebo 
Assessment of tumour response immediately before visit 9 
Visit 12 + 
Physical Examination, vital signs and PS 
Document Concurrent therapy  
Weight 
Haematology – FBC  
Biochemistry* – to include: U&Es, LFTs and LDH 
Urinalysis 
Record Adverse Events 
Dispensing of AZD6244/placebo 
End of treatment 
Physical Examination, vital signs and PS 
Document Concurrent therapy  
Weight 
Haematology – FBC  
Biochemistry* – to include U&Es, LFTs and LDH 
Urinalysis 
Record Adverse Events 
30 days post 
treatment. 
Physical Examination, vital signs and PS 
Document Concurrent therapy  
Weight 
Haematology – FBC  
Biochemistry* – to include U&Es, LFTs and LDH 
Urinalysis 
Record Adverse Events 

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* U and Es to include Sodium, Potassium, Calcium, Urea, Creatinine, Phosphate, and LFTs to include 
Bilirubin, Alkaline Phosphatase, ALT or AST, albumin, GGT and total protein. 
 
8.6 
Follow-up 
Information will be sought on patient status at least every 3 months after cessation of all therapy and will be 
monitored for resolution of any toxicity including laboratory assessments as required. Disease assessment 
using modified RECIST will take place every 3 months until disease progression is documented. Once 
disease progression has occurred, then further clinical follow up is at the Investigator’s discretion: for the 
purposes of the study survival status must be recorded every 3 months. Following unblinding and final 
analysis of the trial data, no further follow-up data will be collected for patients who have already been 
withdrawn from treatment. 
If the patient reaches 12 months off treatment without evidence of disease progression by modified RECIST 
criteria, then CT and/or MRI scans can be performed according to local practice until disease progression is 
documented. Any patients who remain on active treatment following final analysis will be followed for 
adverse events only and no further data will be collected for the study. Sites will report any SAEs (apart from 
those that are exempt as per protocol) to OCTO until 30 days post last dose of treatment.  
9 
Early patient withdrawal 
If a patient is withdrawn early the end of study assessments should be performed and recorded (as above) 
as soon as possible and ideally on the day the decision is made. Patients who withdraw from treatment 
without progressing should be followed until disease progression. The reasons for study withdrawal must be 
recorded in the medical records and CRF. Patients who are removed from study treatment due to AEs 
(clinical or laboratory) will be treated and followed according to accepted medical practice. All pertinent 
information concerning the outcome of such treatment must be recorded in the CRF. 
The following are justifiable reasons for the Investigator to withdraw a patient from study: 
 
Unacceptable toxicity. 
 
Adverse event requiring discontinuation. 
 
Unforeseen events: any event that in the judgement of the Investigator makes further participation 
inadvisable. 
 
Withdrawal of consent. 
 
Serious violation of the study protocol (including persistent patient attendance failure and persistent 
non-compliance with the prescribed medication).
 
Withdrawal by the Investigator for clinical reasons not related to the study. 
With exception of withdrawal of consent (unless the patient agrees to the information being collected) 
patients should be followed for disease progression and overall survival. 
 
Early patient withdrawal must be logged in the IWRS to ensure that drug resupplies are stopped. 
 
9.1 
Code break/Unblinding 
The treatment code will be broken at trial closure for all patients. In the rare event that a patient requires 
emergency code break, site staff are to do the following;  
During office hours (Monday to Friday, 9:00-17:00 - GMT/BST) contact OCTO on 0800 389 1629. The 
request will be reviewed by Chief Investigator (or his designee).   
 
While waiting for a decision from the clinical review, treating clinicians should withhold the AZD6244/placebo 
and treat the medical problem in the most appropriate manner with all the supportive care required. It should 
always be assumed that the patient is on the active arm of the trial (i.e. receiving AZD6244).  
If a codebreak is agreed OCTO staff will contact Fisher Clinical Services and obtain the relevant details.  
These will then be provided to the study site. 

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Patients who have had the treatment code broken will receive no further treatment in the study but will be 
followed up as per protocol.  Code breaking should be avoided wherever possible. 
 
10 Pharmacokinetic and Pharmacodynamic Assessments and correlative science 
10.1 Pharmacokinetic (PK) Variable(s) 
Pharmacokinetic assessments are not planned in this study. 
10.2 Pharmacodynamic (PD) variables 
Pharmacodynamic assessments are not planned in this study. 
10.3 Tumour genotyping, protein analysis and germline genetics  
Consent will be requested from patients to retain tumour samples for future research, once BRAF mutation 
status has been determined. This will not be a requirement for participation in the main study. In addition, 
patients will be asked to provide a specimen of whole blood for DNA extraction and future genetic analyses. 
Genetic analysis will consist of evaluation of mutations deletions and insertions in genes other than BRAF 
that affect the function of the MAPkinase pathway. To date these include NRAS, PTEN, AKT, MEK, which 
will be the focus of initial analyses. 
 
Whole blood samples should be stored at -70OC, and sent in batches as notified by OCTO to: 
 
DOC-MEK, Sample Handling Laboratory, Level 1, Oxford Cancer and Haematology Centre, 
Churchill Hospital, Oxford, OX3 7LE. 
 
11 Assessment of Safety 
The Investigator will monitor each subject for clinical and laboratory evidence of adverse events on a routine 
basis throughout the study. Adverse Event Monitoring starts from the time the patient receives any of the 
research procedures until they complete the trial The Investigator will assess and record in the case report 
form (CRF) any drug related adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course, duration and outcome, relationship of the adverse event to study drug, 
and any action(s) taken. For serious adverse events not considered "probably related" to study drug, the 
Investigator will provide an "Other" cause of the event. For adverse events to be considered intermittent, the 
events must be of similar nature and severity. Adverse events, whether in response to a query, observed by 
site personnel, or reported spontaneously by the subject will be recorded.  All adverse events will be followed 
to a satisfactory conclusion. 
 
Should an Investigator become aware of any drug-related SAEs following withdrawal from the study, these 
must also be reported as stated below. 
 
All adverse events reported into OCTO will be processed following OCTO standard operating procedures. 
 
11.1 Adverse Event Definitions 
 
11.1.1 Adverse Event 
An Adverse Event or experience (AE) is any untoward medical occurrence in a clinical investigation patient, 
temporally associated with the administration of an investigational medicinal product (IMP) or a comparator 
product, whether or not considered related to the IMP or a comparator product. An AE can therefore be any 
unfavourable and unintended sign, symptom, disease (new or exacerbated) and /or significant abnormal 
laboratory or physiological observation temporally associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. An AE includes but is not limited to: 
 
 
Significant or unexpected worsening or exacerbation of the condition/indication under study thought 
by the Investigator to indicate lack of the expected treatment efficacy. N.B. disease progression per 
se is not an AE. 
 
A clinically significant worsening of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 

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 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or a concurrent 
medication (overdose per se, whether accidental or intentional should not be reported as an 
AE/SAE). 
 
Other reportable events that must be treated as AEs are as follows: 
 
Any pregnancy occurring in a patient or a patient’s partner during occurring within six months of the 
last trial agent administration. These should be reported (even if the patient was withdrawn from the 
study) in the same timelines as a serious adverse event (SAE).  The outcome of a pregnancy should 
be followed up carefully and any abnormal outcome of the mother or the child should be reported. 
 
 Any newly identified malignancy, occurring after first administration of study agent in subjects 
participating in this clinical trial.  
 
Any SAE that could be related to the protocol procedures, and which could modify the conduct of the 
trial. 
 
Examples of an AE do not include a/an: 
 
Medical / surgical procedure (e.g., endoscopy, appendectomy) being performed for a pre-existing 
condition which was planned prior to study entry 
 
Situations where an untoward medical occurrence did not occur (social and/or convenience hospital 
admission). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
 
11.1.2 Adverse Drug Reaction (ADR) 
An Adverse Drug Reaction is an AE which is considered to be causally related to any dose of the IMP. This 
means that a causal relationship between the IMP and the AE is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. An adverse drug reaction, the nature or severity of which, is not consistent 
with applicable product information is said to be an unexpected adverse drug reaction. 
 
11.1.3 Serious Adverse Events (SAEs) 
A Serious Adverse Event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
 
Results in death 
 
Is life-threatening 
 
[NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe.] 
 
 
Requires in-patient hospitalisation or prolongs existing inpatient hospitalisation 
 
[Note: In general, hospitalisation signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalisation are 
AEs. If a complication prolongs hospitalisation or fulfils any other serious criteria, the event is serious. When 
in doubt as to whether hospitalisation occurred or was necessary, the AE should be considered serious.] 
 
 
Results in persistent or significant incapacity or disability 
 
[Note: this definition means a substantial disruption of a person’s ability to conduct normal life functions. It 
does include experiences of relatively minor medical significance or accidental trauma (e.g. sprained ankle) 
which do not constitute a substantial disruption.] 
 
 
Is a congenital anomaly or birth defect 
 
Is any other medically important event 

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[Note: A medically important event is defined as an event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above. Any new primary cancer must be reported as an 
SAE.]. 
 
11.1.4 Disease-Related Events or Outcomes not requiring expedited SAE reporting 
An event that is part of the natural course of the disease under study (i.e., disease progression or admission 
for standard treatment) should not be reported as an SAE. However, if the progression of the underlying 
disease is greater than that which would normally be expected, or if the Investigator considers that there may 
be a causal relationship between the IMP or protocol design/procedures and the disease progression, then it 
must be reported as per section 11.2 below. 
 
11.1.5 Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal 
assessments (e.g., ECGs, X-rays and scans) that are judged by the Investigator as clinically significant will 
be recorded as AEs or SAEs if they meet the definitions given above. By definition, all grade 4 laboratory 
abnormalities will be reported as SAEs. Clinically significant abnormal laboratory findings or other 
abnormal assessments that are detected during the study or are present at baseline and significantly worsen 
following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with the disease being studied, 
unless judged by the Investigator as more severe than expected for the patients condition, or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs. The 
Investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant. 
 
11.1.6 Determining adverse event causality 
The relationship of an AE to docetaxel or AZD6244/placebo will be determined as follows: 
Probably
• 
Starts within a time related to the study drug administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s 
clinical state. 
*Possibly 
• 
Starts within a time related to the study drug administration and 
• 
A causal relationship between the study drug and the adverse event is at 
least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the study drug 
is not likely to have had an association with the observed effect. 
Unrelated 
• 
The AE is definitely not associated with the study drug administered 
* Note that unless otherwise defined, the term ‘drug-related’ includes ‘possibly’ 
 
The Investigator must endeavour to obtain sufficient information to determine the causality of the 
adverse event (i.e. relation to surgery, study drug, other illness, progressive malignancy etc) and 
must provide his/her opinion of the causal relationship between each AE and study drug. This may 
require instituting supplementary investigations of significant AEs based on their clinical judgement 
of the likely causative factors and/or include seeking a further opinion from a specialist in the field of 
the AE. 
 
11.1.7 Expectedness 
Expected AEs are AEs that have been assessed as expected events for the IMPs, based upon previous 
experience in man. AEs that are considered expected in this trial are based on data in humans. The list of 
expected AEs for the Investigational Medicinal Product(s) in this trial can be found in the protocol section 
6.3.2 or the Summary of Product Characteristics (for docetaxel) and Investigator Brochure (for AZD6244). 
 

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11.1.8 Suspected Unexpected Serious Adverse Drug Reaction (SUSARs) 
A SUSAR is a suspected, unexpected, serious adverse reaction. SUSARs therefore are suspected to be at 
least possibly related to the study agent and fulfil the definition of a SAE, the nature and severity of which are 
not consistent with the applicable product information. All SUSARs related to an IMP must be reported to the 
Medicines and Healthcare products Regulatory Agency (MHRA) and the Main REC within specified time 
periods. 
 
In addition, other safety issues also qualify for expedited reporting where they might materially alter the 
current risk-benefit assessment of an IMP or be sufficient to change the IMP administration or the overall 
conduct of the trial. For instance: 
• 
Single case reports of an expected serious adverse reaction with an unexpected outcome. 
• 
An increase in the rate of occurrence of an expected serious adverse reaction, which is judged to be 
clinically important. 
• 
Post study SUSARs that occur after the patient has completed a clinical trial and are reported by the 
Investigator to the Sponsor. 
• 
New event relating to the conduct of the trial or the development of the IMP likely to affect the safety 
of the subjects. 
• 
In the event that a participant or his/her partner becomes pregnant whilst taking part in a clinical trial 
or during a stage where the fetus could have been exposed to the medicinal product (in the case of 
the active substance or one of its metabolites having a long half life).  The pregnancy should be 
followed up by the Investigator (via the patient’s healthcare professional) until delivery. If the 
pregnancy results in an abnormal outcome, which the healthcare professional considers might be 
due to the drug, this should be treated as an expedited report. 
 
11.2 Expedited reporting of SAEs and SUSARs 
The following SAE expedited reporting requirements apply regardless of the Investigator’s assessment of the 
causality or expectedness of the SAE. All Serious AEs should be reported on the trial Serious Adverse Event 
Report Form (see SAE Report Form and completion guidelines). 
 
Reports must be faxed within one working day of site staff becoming aware of event to: 
 
The Oncology Clinical Trials Office (OCTO) - +44 (0) 1865 227038 
 
Each separate episode must be recorded on a separate SAE Report Form. For example, if an AE resolves 
completely or resolves to baseline and then worsens again, this must be recorded as a separate AE. The 
NCI CTCAE Version 4.0 must be used to grade each AE, and the worst grade recorded. 
 
The SAE Report Form must be completed as thoroughly as possible with all currently available details of the 
event and the Investigator’s assessment of causality at the time of the initial report. The Investigator (or a 
medically qualified designee) must sign the form. To ensure the SAE report is forwarded within the 
designated time frames, the Investigator will not wait to receive additional information before sending the 
initial notification. The form will be updated when additional information is received. 
 
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added on 
the fax cover sheet when sending the SAE Report Form. 
The Investigator team shall ensure that all SAE reports (including follow-up reports of new information, 
responses to queries and changes to the assessment of expectedness or causality) are transmitted to the 
trials office.  
 
11.3 Safety reporting requirements and arrangements 
The Annual Progress Report, as required by NRES, will be prepared by OCTO and submitted to the main 
REC within 30 days of the anniversary of ethical approval for the trial.  Annual Safety Reports will be 
prepared by OCTO in collaboration with the Chief Investigator and submitted to the MHRA and main REC 
within 60 days of the anniversary of MHRA approval, as required.  
 
Copies of the annual progress report and the annual safety report will be sent to the sponsor and to 
participating sites to forward to R and D as per local requirements. 
 

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11.3.1 Expedited Safety Reporting 
OCTO is responsible for the identification and expedited reporting of SUSARs to the Medicines and 
Healthcare products Regulations Agency (MHRA) and the Main Research Ethics Committee (REC) as 
required under the applicable UK GCP legislation. Fatal or life-threatening SUSARs must be reported to the 
MHRA and the Main REC within 7 calendar days of the Sponsor receiving the report. Follow up information 
for fatal or life-threatening SUSARs must be reported to the MHRA and REC within 8 calendar days of 
submitting the initial report. All other SUSARs are reportable within 15 calendar days of receipt. Therefore 
expedited reporting of SAEs by the Investigator is crucial to the Sponsor meeting these timelines. The Chief 
Investigator will ensure that all Investigators are kept informed as new safety profile information becomes 
available. 
 
11.3.2 Annual Progress and Safety Reports (ASRs) 
The Oncology Clinical Trials Office is responsible for providing periodic trial progress reports as required to 
the Regulatory Authority, the Sponsor and Ethics Committee. Unless otherwise instructed, Annual Progress 
Reports will be submitted to the ethics within 30 days of the anniversary of the ethics favourable opinion and 
the ASR and Annual Safety Reports (ASR) will be submitted in parallel to the MHRA and responsible 
Research Ethics Committee within 60 days of the anniversary of the date of MHRA approval. 
 
11.4 Recording adverse events at the study site 
All reportable SAEs and ADRs (Adverse Drug Reactions) must be recorded on the patient CRF. All 
concomitant medications and any therapy used to treat the event must be recorded in the medical record. 
Copies of the original SAE Report Forms, together with the fax cover sheet and transmission confirmation (if 
available) will be filed in the Investigator Site File. Each SAE report must be entered into the SAE Log form 
held in the Investigator Site File. 
 
11.5 Follow-up of serious adverse events 
Follow up will continue until all the necessary safety data for the event has been gathered. Any serious 
adverse event that is ongoing when a subject completes his/her participation in the trial must be followed 
until any of the following occurs: 
• The event resolves or stabilizes; 
• The event returns to baseline condition or value (if a baseline value is available); 
• The event is attributed to other agent(s) or to factors unrelated to study conduct. 
If new or amended information on a previously reported SAE becomes available, the Investigator should 
report this to the Sponsor on a new SAE Report Form using the completion guidelines. In addition, the 
sponsor may make requests for further information to the study site at regular intervals. Requested follow-up 
information should be reported to in a timely manner and as soon as possible after receipt of the follow up 
request. For fatal or life-threatening SUSARs, follow-up information should be reported as soon as possible, 
as follow up for these cases is reportable to the MHRA and Main REC within eight calendar days of the initial 
report being sent. 
 
 
12 Assessment of Efficacy 
12.1 Measurement of disease 
All patients must have at least 1 lesion that is measurable using RECIST in a field that has not previously 
been treated by radiotherapy.  Disease must be measured according to modified RECIST given in Appendix 
2. 
12.2 Tumour assessment 
A clinical and radiological evaluation of malignancy, as judged appropriate by the Investigator, and in line 
with the protocol, must be performed before starting the study treatment.  The same methods that detect 
lesions at baseline will be used to follow these lesions throughout the study.  To ensure compatibility, the 
radiological assessments used to assess response must be performed using identical techniques.  Imaging 
based evaluation is preferred to evaluation by clinical examination when both methods have been used to 
assess the anti-tumour effect of a treatment. 

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12.2.1 Baseline evaluations: 
These will include radiological measurements of the extent of disease by CT scan, or MRI scan where 
applicable. Fluorescence angiography will be performed to evaluate the extent of any optical lesions. All 
areas of disease present must be mentioned (even if specific lesions are not going to be followed for 
response) and the measurements of all measurable lesions must be recorded on the scan reports.  Any non-
measurable lesions must be stated as being present.  For clinical measurements, documentation by colour 
photography including a ruler to estimate the size of the lesion is recommended.  
 
12.2.2 Evaluations during treatment and at off-study 
Tumour assessment will be repeated as per the schedule given at sections 2.1 and 2.2, or more frequently if 
clinically indicated.  All lesions measured at baseline must be measured at subsequent disease 
assessments, and recorded on the scan reports.  All non-measurable lesions noted at baseline must be 
reported as present or absent. 
 
The Principal Investigator must ensure that the radiologists are aware of the requirement to follow up and 
measure every target lesion mentioned at baseline and comment on the non-target lesions in accordance 
with modified RECIST criteria. 
 
12.3 Tumour response 
To be assigned a status of CR or PR, changes in tumour measurements must be confirmed by two 
consecutive observations.  To be assigned a status of stable disease (SD), follow-up measurements must 
have met the SD criteria at least once and at least six weeks after study treatment is started. 
 
Should rapid tumour progression occur before the completion of nine weeks treatment the patient will be 
classified as having early progression (EP). 
 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it under 
another response category, e.g., when baseline and/or follow-up assessment is not performed or not 
performed appropriately.  
 
The applicable overall response category for each visit that includes disease assessment must be recorded 
in the medical record for inclusion in the CRF. 
 
12.3.1 Other definitions of outcome 
Toxic death: 
Any death to which drug toxicity is thought to have a major contribution. 
Early death:  
Death during the first three weeks of treatment that is not a toxic death. 
Progression free survival:  
The interval from the day of randomisation until disease progression or 
death in the absence of RECIST progression. 
Overall survival:  
 
The interval between the day of randomisation and death. 
 
 
13 Defining the End of Trial  
The ‘end of trial’ is defined as the last visit of the last patient undergoing the trial.   
It is the responsibility of the Chief Investigator to inform the Main REC, the Sponsor and the Regulatory 
Authority within 90 calendar days of the ‘end of the trial’ that the study has closed. 
 
The sponsor and the Chief Investigator reserve the right to terminate the trial at any time. In terminating the 
study, they must ensure that adequate consideration is given to the protection of the patient’s best interests. 
In particular, where patients are still receiving AZD6244/placebo when the above conditions are met, 
consideration must be given to ensuring continued drug supply. 
 

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14 Statistical considerations  
80 patients will be recruited to the study. A detailed statistical analysis plan will be drawn up prior to breaking 
of the blind. Analysis will be performed when approximately 58 disease progression/death events have 
occurred. The trial is planned to recruit for 12 months and follow-up all patients for at least 3 months after 
last patient recruitment. If the true Hazard Ratio (HR) is 0.57 (likely to correspond to a 75% prolongation of 
progression free survival (PFS)), this analysis will have approximately 80% power to demonstrate a 
statistically significant difference for PFS, assuming a 1-sided 10% significance level. If a 1-sided p<0.1 is 
observed for the comparison of PFS between AZD6244 in combination with docetaxel, versus docetaxel, the 
results will be regarded as promising (but not definitive) as there is a less than 1 in 10 probability that such a 
result could have been detected if there was truly no treatment effect.   
14.1 Safety 
All patient receiving a study dose will be assessed for toxicity.  Safety variables will be summarised by 
descriptive statistics, with patients grouped according to treatment received.  SAEs and ADRs will be 
summarised by incidence rates and classified by the worst severity grade observed.  Laboratory data will be 
presented by dose level at each observation time.  Values outside normal limits will be identified and 
summarised by frequency distribution.  Laboratory variables will be described using the NCI CTCAE (Version 
4.0). 
 
14.2  Patient evaluability 
The trial will be assessed on an intention-to-treat basis, being grouped according to the treatment they were 
assigned. Thus, all patients randomised to receive treatment within the study will be evaluable for response. 
 
14.3 Analysis 
The primary aim of PFS will be analysis by Cox Regression Analysis using the randomisation stratifying 
factors as covariates. A p value of ≤0.1 will be considered significant and worthy of a further trial. 
 
14.4 Analysis timings 
The primary aim will be analysed when we have all patients recruited, followed up for at least 3 months and 
58 PFS events.  
The final analysis of the secondary and post hoc aims will be completed as determined in the statistical 
report. 
 
15 Trial Administration 
15.1 Regulatory and ethical considerations 
The Sponsor and Principal Investigator will ensure that this protocol will be conducted in compliance with the 
UK Clinical Trials Regulations8, the ICH guidelines of Good Clinical Practice (GCP)9 and the applicable 
policies of the University of Oxford. Together, these implement the ethical principles of the Declaration of 
Helsinki (1996) and the regulatory requirements for clinical trials of an investigational medicinal product 
under the European Union Clinical Trials Directive.  
 
15.1.1 Ethical conduct of the trial and ethics approval 
The Investigator will ensure that the protocol, patient information sheet, consent form, GP Letter and any 
other information that will be presented to potential trial patients (e.g. advertisements or information that 
supports or supplements the informed consent) are reviewed and approved by an appropriately constituted, 
independent Research Ethics Committee (REC).  
 
                                                
 
8 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
9 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, 
adopted by CPMP July 1996. 

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15.1.2 NHS Research Governance and sponsorship 
The Investigator is responsible for applying for local Trust management approval to conduct the trial in 
accordance with local arrangements and policies. Trust approval and indemnity must be confirmed in writing 
before patient recruitment commences at an Investigator site. 
 
The University of Oxford will provide written confirmation of Sponsorship. The Chief Investigator will 
authorise the trial commencement once satisfied that all arrangements and approvals for the proper conduct 
of the trial are in place. A separate study delegation agreement, setting out the responsibilities of the Chief 
Investigator, the Oncology Clinical Trials Office and the Sponsor will be put in place between the parties. 
 
15.2 Regulatory Authority approval 
This study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency (MHRA) 
Clinical Trials Authorisation (CTA). MHRA approval to conduct the study will be obtained prior to initiating the 
study.  
 
15.2.1 Protocol amendments 
Amendments are changes made to the research after a favourable ethical opinion has been given. A 
‘substantial amendment’ is an amendment to the terms of the MHRA CTA application, the REC application, 
or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: 
 
 
the safety or physical or mental integrity of the subjects of the trial; 
 
the scientific value of the trial; 
 
the conduct or management of the trial; or 
 
the quality or safety of the investigational medicinal product(s) used in the trial. 
 
Non-substantial amendments are those where the change(s) involve only minor logistical or administrative 
aspects of the study, such as a change in contact details. 
 
 The Chief Investigator shall determine whether an amendment is substantial with reference to current 
applicable guidance and policies.  All substantial amendments will be submitted to the sponsor for approval. 
Once approval has been obtained from the sponsor the substantial amendments will be submitted to the 
responsible REC, the MHRA and the host (NHS) Trust for approval and/or for information as appropriate. 
Written documentation of the Ethics Committee ‘favourable opinion’ (and MHRA and Trust approval as 
deemed appropriate) must be received before a substantial amendment can be implemented. The only 
exceptions are for changes necessary to eliminate an immediate hazard to study patients. 
 
It is the Chief Investigator’s responsibility to update patients (or their authorised representatives, if 
applicable) whenever new information (in nature or severity) becomes available that might affect the patient’s 
willingness to continue in the trial.  The Chief Investigator must ensure this is documented in the patient’s 
medical notes and the patient is re-consented. 
 
15.2.2 Informed consent 
It is the responsibility of the Investigator, or a person designated by the Investigator to obtain written 
informed consent from each individual participating in this study after adequate explanation of the aims, 
methods, objectives, anticipated benefits and potential hazards of the study.  The content and process of 
obtaining informed consent will be in accordance with the applicable GCP Regulatory and ethical 
requirements. Consent will be obtained before any protocol specific procedures are performed. 
 
Optional consent for additional research  
Where suitable patients will be invited to allow their tumour biopsy sample to be used in future research and 
to provide whole blood for DNA extraction, but this will not be a requirement for participation. 
 
15.3 Trial Monitoring and Quality Assurance 
OCTO is responsible for monitoring the trial in order to verify that (ICH GCP section 5.18):  
 
The rights and wellbeing of the human subjects are protected.  
 
The reported trial data are accurate, complete and verifiable from source documents.  

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 
The conduct of the trial is in compliance with the approved protocol and GCP.  
Monitoring will be performed in accordance with the applicable OCTO policies and guidelines. These may 
include activities designed to: 
 
Initiate the study and check progress periodically  
 
Review the essential trial documentation and study data collected.  
 
Conduct source document verification if required.  
 
Identify any issues and address their resolution 
 
Confirm proper closure of the clinical study site at the end of the clinical phase 
 
Monitor the study sample handling laboratories activities and facilities  
 
The sponsor or OCTO may conduct quality assurance audit to assure compliance with protocol and ICH-
GCP.  The Regulatory agency may conduct a regulatory study inspection.  Such audits/inspections can 
occur at any time during or after completion of the study.  If an audit or inspection occurs, the Investigator 
and host institution(s) agree to allow auditors/inspectors direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to discuss findings and any relevant issues.  
 
15.4 Records retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate records 
to enable the conduct of a clinical trial and the quality of the research data to be evaluated and verified.  
These essential documents (as detailed in Section 8 of the ICH GCP Guidelines)  must be stored in such a 
way that ensures that they are readily available, upon request, to the sponsor or the Regulatory Agency, for 
the minimum period required by national legislation or for longer if needed.  The medical files of trial subjects 
shall be retained in accordance with national legislation and in accordance with the host institution policy. 
 
15.5 Patient confidentiality 
All records identifying the patients will be kept confidential and to the extent permitted by the 
laws/regulations, will not be made publicly available. Only the patient number and patient initials will be 
recorded in the case report form.  Before sending out any other document (e.g. a pathologist report, scan, 
copy medical record or study log) the Investigator site research team will check for and obliterate any 
information that could uniquely identify the patient. Study findings stored on a computer will be stored in 
accordance with local data protection laws. The Investigators will maintain a list to enable patients’ records to 
be identified. The patients will be informed in writing that:  
 
Members of the research team will need access to their records to collect information. Representatives of the 
sponsor, Chief Investigator, study monitors, Regulatory Agency and the Ethics Committee may inspect their 
medical records to verify information collected. All personal information made available will be handled in the 
strictest confidence and in accordance with local data protection laws.  When the results of the study are 
published, the identity of the patients will remain confidential.  
 
15.6 Completion of the Case Report Form (CRF) 
 A Case Report Form (CRF) will be completed for each patient enrolled into the trial. If a patient is withdrawn 
early, the reason will be noted on the CRF.  If a patient is withdrawn from the study because of an AE, 
thorough efforts should be made to document the outcome. The CRF will not contain any source data. All 
appropriate laboratory data, summary reports and Investigator observations will be transcribed into the CRF 
from the relevant medical record(s).  
 
OCTO staff will enter patient data into the database at regular intervals and raise data queries. Queries 
concerning the source data or medical interpretation will be resolved and documented by authorised 
members of the clinical study team. Corrections [whether to the source data or to data query listing for entry 
into the eCRF must only be made by striking out any errors, with a single stroke, and not by using correction 
fluid. The incorrect figure must remain visible and the correction should be initialled and dated by the person 
authorised by the Investigator to make the correction.  A reason for the change or correction should be given 
as appropriate. This cycle will be repeated as necessary until the patient data are declared clean. 
 
The Investigators (or their deputies) are responsible for ensuring the accuracy and completeness of the key 
trial data for their patients. They should sign the CRFs off prior to data lock and analysis. The Investigator 
approved CRFs will be archived with the trial master file.  

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15.7 Data and Safety Monitoring 
An independent Data & Safety Monitoring Committee (DSMC) is now established for this trial, following a 
safety concern in another trial notified to us by AZ.  The committee met soon after the safety concern was 
raised and 6 months later to assess the toxicity and SAE by treatment arm.  The committee has endorsed 
the analysis plan outlined above. 
 
 
15.8 Clinical study report 
All clinical data will be presented at the end of the study on final data listings.  The data manager and 
statistician will prepare a clinical study report based on the final data listings. The report will be submitted to 
the Investigator(s) for review and signature to confirm that it accurately represents the data collected during 
the course of the study. At this point the trial data will be locked for analysis and publication. The Chief 
Investigator will provide the Trial Steering Committee, sponsor, responsible Research Ethics Committee with 
a copy of the final clinical report once available. 
 
15.9 Study funding 
This trial is being organised by the Oncology Clinical Trials Office (OCTO) at the University of Oxford and is 
being funded by an educational grant from Astra-Zeneca.   Any additional NHS clinical service support costs 
of patient care while on-study should be met by the host medical institution. 
 
15.10 Indemnity 
Arrangements for NEGLIGENT harm. 
The University has arrangements in place to provide for harm arising from participation in the study for which 
the University is the Research Sponsor. NHS indemnity operates in respect of the clinical treatment which is 
provided. 
  
Arrangements for NON-NEGLIGENT harm 
The University has arrangements in place to provide for non-negligent harm arising from participation in the 
study for which the University is the Research Sponsor.  
15.11 Publication policy 
The Chief and Co-Investigators (the Investigators) will retain ownership of all data arising from this trial. The 
intention is to publish this research in a specialist peer reviewed scientific journal on completion of the study. 
The results may also be presented at scientific meetings and/or used for a thesis.  The Investigators will be 
involved in reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising 
from the trial and retain final editorial control. Authors shall acknowledge the study sponsor and funding 
bodies as appropriate.  
 
16 References 
 
Aamdal et al 1994 
Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials 
Group. Eur J Cancer 30A:1061-1064. 
 
Board et al 2009 
Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) 
advanced melanoma phase II study. Br J Cancer 101:1724-30. 
 
Chapman et al 2009 
Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF selective 
inhibitor PLX4032. Eur J Cancer 7(3) supplement page 5. 
 
Dummer et al 2008 

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AZD6244 (ARRY-142886) vs temozolomide in patients with advanced melanoma: an open label, 
randomised, multi-centre phase II study.  Presented at the 44th American Society of Clinical Oncology 
Annual Meeting, 30 May–3 June 2008.  Abstract number 9033. 
 
Haass et al 2008 
The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase inhibitor AZD6244 (ARRY-
142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin 
Cancer Res 14:230-239. 
 
Mhaidat et al 2007 (1) 
Docetaxel-induced apoptosis in melanoma cells is dependent on activation of caspase-2. Mol Cancer Ther 6: 
752-761. 
 
Mhaidat et al 2007 (2) 
Docetaxel-induced apoptosis of human melanoma is mediated by activation of c-Jun NH2-terminal kinase 
and inhibited by the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase 1/2 pathway. 
Clin Cancer Res 13: 1308-1314. 
 
Smalley 2003 
A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 104:527-532. 
 
Therasse et al 2000 
New guidelines to evaluate the response to treatment in solid tumors.  J National Cancer Institute 
2000;92:205-216. 
 
Wilkinson et al 2008 
Activity of the MEK 1/2 inhibitor AZD6244 (ARRY-142886) in combination with standard and approved 
therapies: impact of in vivo sequencing of drug administration.  Presented at the 99th American Association 
for Cancer Research Annual Meeting, San Diego; 12-16 April, 2008.  Abstract number 4012. 

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APPENDICES 
 
APPENDIX 1: ECOG PERFORMANCE SCALE 
Activity Performance Description 
Score 
 
 
Fully active, able to carry out all on all pre-disease performance without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g. light housework, office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
2 
 
 
Capable of only limited self-care.  Confined to bed or chair more than 50% of waking hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
 
4 
 
 
 
 
 

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APPENDIX 2: MEASUREMENT OF DISEASE - MODIFIED RECIST CRITERIA 
 
This appendix details the implementation of modified RECIST guidelines for the DOC-MEK study for the 
assessment of tumour burden (Therasse et al., 2000 J National Cancer Institute 2000;92:205-216) 
. 
 
Definition of measurable, non-measurable, target and non-target lesions 
Only patients with measurable disease at baseline should be included in the study.  Measurable disease is 
defined by the presence of at least one measurable lesion that has not been previously irradiated.  If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
 
Measurable: 
 
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 10 mm with spiral Computed Tomography (CT) scan or as ≥20 mm with 
conventional techniques (Conventional CT, Magnetic Resonance Imaging (MRI), and which have 
not previously been irradiated 
 
Exception applies to lymph nodes lesions: lymph node must be >15 mm in short axis when 
assessed by CT scan (slice thickness 5 mm). 
Non-measurable: 
 
All other lesions, including small lesions (longest diameter <20 mm with conventional techniques 
or <10 mm with spiral CT scan) 
 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal disease, 
ascites, pleural / pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, 
abdominal masses that are not confirmed and followed by imaging techniques, cystic lesions. 
 
Previously irradiated lesions 
 
Brain metastasis. 
 
Target lesions: 
 
A maximum of 10 measurable lesions (with a maximum of 5 lesions per organ), representative of 
all lesions involved suitable for accurate repeated measurement, should be identified as target 
lesions (TL) at baseline. 
Non-Target lesions: 
 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Methods of measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
 
A summary of the methods to be used for modified RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted. 
 
 
 
Table 1: 
Summary of methods of assessment 

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Target Lesions  
Non-Target lesions and New Lesions 
CT (preferred) 
MRI 
 
CT (preferred) 
MRI 
Clinical examination  
X-ray, Chest X-ray 
Ultrasound 
Endoscopy and laparoscopy 
 
CT and MRI  
CT and MRI are generally considered to be the best currently available and reproducible methods to 
measure TL selected for response assessment and to assess NTL and new lesions. In the study it is 
recommended that CT examinations of the chest, abdomen and pelvis be used to assess tumour burden at 
baseline and follow-up time points. CT examination with intravenous (iv) contrast media administration is the 
preferred method.  MRI should be used where CT is not feasible or it is medically contra-indicated.  For brain 
lesion assessment, MRI is the preferred method. 
Clinical examination  
Clinical examination will not be used as part of RECIST assessment for TL. Clinically detected lesions can 
be selected as target lesions if they are assessed by CT or MRI scans. Clinical examination can be used to 
assess NTL and to identify the presence of new lesions. 
X-ray 
Chest X-ray assessment will not be used as part of RECIST assessment for TL as they will be assessed by 
CT examination or MRI examination.  Chest X-ray can, however, be used to assess NTL and to identify the 
presence of new lesions. Plain X-ray may be used as a method of assessment for bone non-target lesions 
and for confirmation of new bone lesions. 
Ultrasound  
Ultrasound examination will not be used as part of RECIST assessment for TL as it is not a reproducible 
method and does not provide an accurate assessment of tumour size.  Ultrasound examination can, 
however, be used to assess NTL and to identify the presence of new lesions. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used as part of RECIST assessment for TL as they are not validated 
in the context of tumour measurements.  However, endoscopy and laparoscopy can be used for assessment 
of NTL and to identify the presence of new lesions.  
Isotopic bone scan  
Isotopic bone scans will not be used to assess bone lesions as part of RECIST assessment due to 
insufficient specificity. Bone lesions identified on an isotopic bone scan and confirmed by CT, MRI or X-ray at 
baseline should be recorded as NTL and followed by the same method as per baseline assessment.  If new 
bone lesions or worsening bone symptoms occur and a bone scan is performed, then worsening of disease 
needs to be confirmed by CT, MRI or X-ray. 
PET scan  
PET scans will not be used for assessment of tumour response, as PET evaluations do not form part of the 
RECIST framework. 
Tumour response evaluation 
Schedule of evaluation 
All baseline tumour assessments must adequately assess tumour burden and should be performed no more 
than 28 days before the start of study treatment and ideally should be performed as close as possible to the 
start of study of treatment.  Any other sites at which new disease is suspected should also be adequately 
imaged at follow-up.  Follow-up assessments will be performed at Week 9, Week 18, and every 12 weeks 
thereafter. If an unscheduled radiological and/or clinical tumour assessment is performed, and the 
patient has not progressed, the next scheduled tumour assessment should still be performed at the 
planned time.  This schedule is to be followed in order to minimise any unintentional bias caused by some 
patients being assessed at a different frequency than other patients. 
Target lesions (TL) 
Documentation of target lesions 
A maximum of 10 measurable lesions (with a maximum of 5 lesions per organ), representative of all lesions 
involved, should be identified as TL at baseline.  Target lesions should be selected on the basis of their size 

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(lesions with the longest diameter) and their suitability for accurate repetitive measurements. An exception 
will apply for lymph nodes assessment for which the short axis will be measured and followed at 
baseline and at follow-up time-points. The site and location of each TL should be documented as well as 
the longest diameter (LD) of each TL.  All measurements should be recorded in metric notation using a ruler, 
calipers, or electronic calipers etc.  At baseline the sum of the LD for all TL will be calculated & reported as 
the baseline sum LD.  At follow-up visits the sum of the LD for all TL will be calculated & reported as the 
follow-up LD.   
 
Special cases: 
 
If a TL splits into two or more parts, then the sum of the LDs of those parts is recorded 
 
If two or more TL merge then the LD of the combined lesion should be recorded for one of the 
lesions and 0 mm recorded for the other lesion(s) 
 
If a TL becomes too small to measure accurately, then an estimate as close to the size as 
possible should be provided.  The minimum size that can be recorded for a single lesion is 5 mm 
 
If a TL cannot be measured accurately due to it being too large, provide as close an estimate as 
possible of the size of the lesion 
 
For TL measurable in 2 or 3 dimensions, always report the longest diameter 
 
When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc., during the 
study, the size of the TL should still be provided where possible. 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumour visit response for TL 
at the investigational site. 
 
Table 2: 
Overall visit response for target lesions 
Complete Response (CR)
Disappearance of all TL since baseline
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of TL, taking as 
reference the baseline sum LD
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of TL, taking as 
reference the smallest sum LD recorded since the treatment 
started
Not Evaluable (NE) 
Only relevant if any of the TL were not assessed or not evaluable 
or had a lesion intervention
 
Non-target lesions (NTL) 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.  
Measurements are not required for these lesions, but their status should be followed at subsequent visits.  At 
each visit an overall assessment of the NTL response should be recorded by the Investigator.  This section 
provides the definitions of the criteria used to determine and record overall response for NTL at the 
investigational site at each visit. 
 
Table 3: 
Overall visit response for non-target lesions 
Complete Response (CR)
Disappearance of all NTL since baseline
Incomplete 
Response 
(IR)/ 
Stable Disease (SD)
Persistence of one or more NTL  
Progression (PD) 
Unequivocal progression may be due to an important progression 
in one lesion only or in several lesions.  In all cases the 
progression must be clinically significant for the physician to 
consider changing (or stopping) therapy 
Not Evaluable (NE) 
Only relevant when one or some of the NTL have not been 
assessed and in the Investigator’s opinion they are not able to 

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provide an evaluable overall NTL assessment
Not Applicable (NA)
Only relevant if there are no NTL at baseline
 
New Lesions 
Details of any new lesions will also be recorded with the date of assessment.  Progression based on 
appearance of new lesions will be recorded if one of the following is applicable: 
 
New soft-tissue lesions measuring ≥10 mm in longest diameter 
 
For new lymph nodes lesions, the shorter axis should be above 15 mm to be classed as a new 
lesion. 
If the Investigator is in doubt as to whether progression has occurred, particularly with response to NTL or 
the appearance of a new lesion, it is advisable to continue treatment until the next scheduled assessment or 
sooner if clinically indicated and reassess the patient’s status.  If the lesion is still present it should be 
recorded as a new lesion on the date it was first observed. 
 
Evaluation of Date of Progression and Best Overall Response 
The best overall response is the best response recorded from the start of treatment until disease 
progression. Date of progression and best overall response will be derived as part of the study analysis from 
TL measurements, overall assessment of NTL and presence/absence of new lesions. 
 
Table 4: 
Overall visit response 
Target lesions
Non-Target lesions
New Lesions*
Overall response
CR 
CR (or NA) 
No 
CR
CR 
IR/SD 
No 
PR
PR 
CR, IR/SD (or NA) 
No 
PR
SD  
CR, IR/SD (or NA) 
No 
SD
PD 
Any 
Yes or No 
PD
Any 
PD 
Yes or No 
PD
Any 
Any 
Yes 
PD
NE 
Non-PD 
No 
NE
Non-PD 
NE 
No 
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease 
IR = incomplete response, NE = not evaluable, NA = not applicable, * = see criteria above 
Confirmation of response  
In the DOC-MEK study, confirmation of response (CR or PR) is determined by the study protocol to be 
performed at the next scheduled RECIST assessment following the date the criteria for response were first 
met.  If a confirmation scan is performed earlier than the scheduled scan, every attempt should be made to 
perform the subsequent scans at their scheduled time points. 
 
 
Specifications for radiological imaging 
The following is recommended for use in DOC-MEK.   
 
CT Scan 
CT scans of the neck, thorax, abdomen, and pelvis should be contiguous throughout the anatomical region 
of interest. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  CT 
examination with IV contrast media administration is the preferred method. Contrast agent timing should be 
aimed at the portal-venous phase of the liver.  In patients in whom the abdomen and pelvis have been 
imaged, oral contrast agents should be given to distinguish the bowel from other soft tissue masses.  A 
consistent method should be used on subsequent examinations for any given patient. 
If iodine contrast media is medically contraindicated at baseline, or at any time during the course of the 
study, then the recommended methods are: CT thoracic examination without contrast and abdominal and 

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pelvis MRI with contrast.  If MRI cannot be performed then CT without iv contrast is an option for the thorax, 
abdomen and pelvis examination.  For brain lesions assessment, MRI is the preferred method. 
All window settings should be included in the assessment, particularly in the thorax where lung and soft 
tissue windows should be considered.  When measuring lesions, the TL should be measured on the same 
window setting for repeated examinations throughout the study.  All images from each examination should 
be included in the assessment and not “selected” images of the apparent lesion. 
MRI Scan 
MRI is entirely acceptable and capable of providing images in different anatomical planes.  It is important 
therefore that when it is used lesions must be measured in the same anatomical plane using the same 
imaging sequences on subsequent examinations. For a particular patient the same scanner should be used 
during the study assessment. However, CT is the imaging modality of choice. 
 
 

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 APPENDIX 3: MEDICATIONS INTERACTING SIGNIFICANTLY WITH 
CYP3A4 AND CYP1A2 
 
The following medications/foodstuffs are to be avoided during the course of the study. This list is 
not exhaustive, and advice should be sought from the trials office where there is doubt. The 
definition of a strong inhibitor used is one that causes a > 5-fold increase in the plasma AUC 
values or more than 80% decrease in clearance. 
 
 
CYP3A4 Inhibitors
CYP3A4 Inducers
aprepitant 
clarithromycin 
diltiazem 
erythromycin 
fluconazole 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole 
nefadozone 
nelfinavir 
ritonavir 
saquinavir 
telithromycin 
verapamil
barbiturates 
carbamazepine 
efavirenz 
glucocorticoids 
modafinil 
nevirapine 
phenobarbitol 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St John’s wort 
troglitazone 
CYP1A2 Inhibitors
CYP1A2 Inducers
fluvoxamine 
ciprofloxacin