Clinical trial NCT01586624
Conditions: Cancer Non Small Cell Lung Cancer
Keywords: Phase I Drug evaluation Oncology Vandetanib Selumetinib Dose escalation Clinical trial Vascular Endothelial Growth Factor (VEGFR) inhibitor Epidermal Growth Factor Receptor (EGFR) inhibitor Mitogen Activated Kinase (MEK) inhibitor Non small cell lung cancer
Sponsor: Cancer Research UK
Start date: 2012-01-10; Completion date: 2020-06-11
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether using two drugs together called vandetanib and selumetinib is effective in the treatment of cancer. The first part of this study will include patients with any solid tumour and the second part of this study will include only patients with non small cell lung cancer. The four main aims of this clinical study are to find out:

* If the two drugs can be given safely to patients when given together.
* The maximum dose that can be given safely to patients.
* More about the potential side effects of the drugs and how they can be managed.
* What happens to vandetanib and selumetinib inside the body.

Detailed description:
The purpose of this Phase I study is to establish a safety and toxicity profile of combining two study drugs; vandetanib, a VEGFR (Vascular Endothelial Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor) inhibitor, with selumetinib a MEK (Mitogen Activated Kinase) inhibitor.

This is the first time the drugs have been used together. These types of drugs have shown an effect in non small cell lung cancer (NSCLC).

The study is in two parts; the dose escalation phase and the expansion phase.

In the dose escalation phase, 42-50 patients will receive different doses of vandetanib and increasing doses of selumetinib to establish a safe dose to recommend for the next stage of the study. Patients with any solid tumour will be eligible.

In the expansion phase, up to 30 patients will receive the dose recommended in the previous phase. Only patients with NSCLC will be eligible for this part of the study.

The expansion phase will look at further evaluating the safety of the drug combination and the anti-tumour activity. Patients in this cohort will be requested to also consent to have additional imaging assessments and optional tumour biopsies.

Study treatment is administered orally; vandetanib tablets once daily and selumetinib capsules once daily (OD)/twice daily (BD). Cycle 1 is 42 days long. Subsequent cycles are 28 days in length. Patients will receive a total of 6 cycles of the combination treatment. If the patient has not progressed after six cycles, they may be treated for further cycles following approval from the sponsor.

Arms: arm 1: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 2: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 3: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 4: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 5: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 6: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 7: Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. arm 8: Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase.
Interventions: intervention 1: Vandetanib, Selumetinib intervention 2: Vandetanib, Selumetinib intervention 3: Vandetanib, Selumetinib intervention 4: Vandetanib, Selumetinib intervention 5: Vandetanib, Selumetinib intervention 6: Vandetanib, Selumetinib intervention 7: Vandetanib, Selumetinib intervention 8: Vandetanib, Selumetinib
Intervention descriptions: intervention 1: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 2: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 3: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 4: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 5: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 6: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 7: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. intervention 8: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.

Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.

Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Protocol documents:
Prot_000.pdf: 
ClinicalTrials.gov  
Document Cover Page 
 
NCT No.: NCT02761915 
 
09 June 2021 
Protocol No.: CRUKD/11/001 
 
 
 
ClinicalTrials.gov Upload Document Cover Page 
NCT Number 
NCT01586624 
EudraCT Number 
2011-000627-33 
Sponsor Protocol Number CRUKD/11/001 
Official Title 
A Cancer Research UK Phase I dose escalation trial of the 
oral VEGFR and EGFR inhibitor, Vandetanib in 
combination with the oral MEK inhibitor, Selumetinib 
(VanSel-1) in solid tumours (dose escalation) and NSCLC 
(expansion cohort). 
 
 
Documents, Version & 
Date 
Protocol Version 13.0, dated 26 January 2018 
 




 
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CRUKD/11/001 Protocol version 13.0 FINAL  26Jan2018 
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© Cancer Research UK  
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PARTICIPATING INVESTIGATORS AND CENTRES: 
Contact details for participating investigators and centres can be found in the Trial Master 
File (TMF) contact list. 
PROTOCOL VERSION HISTORY: 
Version No. 
Issue Date 
Reason for update 
1.0 
15August2011 
Initial version submitted for ethics and regulatory approval. 
2.0 
19December2011  
Updated safety information regarding medications known to prolong QTc 
interval. 
Updated guidance regarding renal function assessment at elig bility. 
Administrative changes. 
3.0 
19May2012 
Revised interval between treatment of patients 1 and 2 at each dose 
level. 
Time windows for PK sampling time points. 
Inclusion of measurement of CPK levels throughout study. 
4.0 
18October2012 
Revision of DLT criteria regarding hypertension. 
Clarification of expansion cohort patient group (inclusion criteria). 
Clarification of exclusion criteria. 
5.0 
06March2013 
Non substantial amendment 
Clarification of additional Cohort 4. 
6.0 
02April2013 
Addition of additional ophthalmological eye monitoring and associated 
dose modification.   
Revised medically important SAE reporting to include eye changes. 
7.0 
17October2013 
Investigation of alternative vandetanib doses. 
Clarification of inclusion criteria  INR value). 
Patient evaluability for dose escalation. 
Increase in patient numbers recruited to dose escalation phase. 
Non substantial amendments  
8.0 
30May2014 
Update information relating to: 
Selumetinib exposure and patients of Asian ethnicity. 
Vitamin E exposure. 
LVEF guidelines. 
Dose modifications. 
Plus Non substantial amendments. 
9.0 
12November2014 
Investigation of an increased maximum dose of vandetanib and 
alternative dosing schedules.  
Non substantial amendments. 
10.0 
07July2015 
Addition of new site. 
Revision to total patient numbers. 
Revision to exclusion criteria. 
Update to precautions for treatment. 
Non substantial amendments. 
11.0 
18November2015 
Change to inclusion criteria (previous treatments) 
Non substantial amendments. 
12.0 
10May2016 
Exclusion criteria revision re: previous EGFR inh bitor treatment. 
Dose modification update relating to suspected ILD. 
Precautions for treatment update relating to ILD.  
Non substantial amendment relating to RECIST update to v1.1.  
13.0 
26January2018 
Selumetinib capsules colour change.  
Clarification regarding study reporting schedule.  
 
To note: NCI CTCAE version used throughout this protocol is version 4.02. 
 


 
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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ........................................................................................11 
1.1 
Full title ..........................................................................................................11 
1.2 
Clinical trial objectives and endpoints ............................................................11 
1.3 
Design ...........................................................................................................12 
1.4 
Administration schedule .................................................................................13 
1.4.1 
Vandetanib administration ................................................................13 
1.4.2 
Selumetinib administration ...............................................................13 
1.4.3 
Treatment period – Cycle length ......................................................13 
1.4.4 
Treatment group ...............................................................................14 
1.4.5 
Expected accrual ..............................................................................14 
2 
INTRODUCTION ....................................................................................................15 
2.1 
Background ...................................................................................................15 
2.2 
Investigational medicinal product ...................................................................15 
Structure of Vandetanib and Selumetinib .......................................................15 
2.2.1 
Vandetanib .......................................................................................16 
2.2.1.1 
Drug class ..........................................................................16 
2.2.1.2 
Preclinical Experience ........................................................16 
2.2.1.3 
Clinical Experience .............................................................17 
2.2.1.4 
Clinical Pharmacokinetics ...................................................17 
2.2.1.5 
Safety .................................................................................17 
2.2.1.6 
Efficacy ...............................................................................18 
2.2.2 
Selumetinib ......................................................................................19 
2.2.2.1 
Preclinical Experience ........................................................19 
2.2.2.2 
Clinical Experience .............................................................20 
2.2.2.3 
Clinical Pharmacokinetics ...................................................20 
2.2.2.4 
Safety .................................................................................21 
2.2.2.5 
Efficacy ...............................................................................21 
2.3 
Rationale for the proposed trial ......................................................................22 
2.3.1 
Proposed Combination Hypothesis for Vandetanib and Selumetinib 22 
2.3.2 
Combination Non-Clinical Anti-Tumour Activity ................................23 
2.3.3 
Clinical experience of Vandetanib and Selumetinib Combination .....24 
2.3.4 
Possible toxicities based on single agent studies .............................24 
2.3.5 
Supportive combination class data ...................................................25 
2.3.6 
Marketing Experience.......................................................................26 
3 
TRIAL DESIGN ......................................................................................................27 
3.1 
Clinical trial objectives and endpoints ............................................................27 
Primary objectives and endpoints ..................................................................27 
3.1.1 
Definition of dose limiting toxicity ......................................................28 
3.1.2 
Definition of maximum tolerated dose ..............................................29 
3.1.3 
Patient evaluability ...........................................................................30 
3.2 
Design of the clinical trial ...............................................................................30 
3.2.1 
Dose escalation ................................................................................30 
3.2.2 
Expansion cohort .............................................................................31 
3.2.3 
Study duration ..................................................................................32 


 
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4 
PATIENT SELECTION ...........................................................................................33 
4.1 
Eligibility criteria .............................................................................................33 
4.1.1 
Inclusion criteria ...............................................................................33 
4.1.2 
Exclusion criteria: .............................................................................34 
4.2 
Patient enrolment ...........................................................................................35 
5 
TREATMENT ..........................................................................................................37 
5.1 
Selection of the Phase I starting dose and schedule ......................................37 
5.1.1 
Selection of Vandetanib dose ...........................................................37 
5.1.2 
Selection of Selumetinib dose ..........................................................38 
5.2 
Dosing schedule/treatment schedule .............................................................38 
5.2.1 
Dose escalation phase. ....................................................................38 
5.2.2 
Expansion cohort. ............................................................................39 
5.3 
Dose escalation schedule ..............................................................................40 
5.3.1 
Intra-patient dose escalations ...........................................................41 
5.3.2  
Expansion of dose level(s) ...............................................................41 
5.4 
Dose modifications.........................................................................................42 
5.4.1 
Dose interruptions ............................................................................42 
5.4.1.1 Management of vandetanib and selumetinib toxicity .................42 
5.4.2 
Dose reductions ...............................................................................44 
5.4.2.1 
Vandetanib and Selumetinib dose reduction .......................44 
5.4.2.2 
Selumetinib dose reduction ................................................45 
5.5 
Missed doses .................................................................................................46 
5.6 
Duration of treatment .....................................................................................46 
5.7 
Replacement of patients ................................................................................47 
5.8 
Concomitant medication and treatment ..........................................................47 
5.9 
Precautions for treatment ...............................................................................47 
6 
PHARMACEUTICAL INFORMATION ....................................................................50 
6.1 
Supply of Vandetanib and Selumetinib...........................................................50 
6.2 
Pharmaceutical data ......................................................................................50 
6.2.1 
Formulation of Vandetanib and Selumetinib .....................................50 
6.2.2 
Storage conditions ...........................................................................51 
6.2.3 
Stability of Vandetanib and Selumetinib ...........................................51 
6.2.4 
Dispensing of Vandetanib and Selumetinib ......................................51 
6.2.5 
Vandetanib and Selumetinib administration ......................................51 
6.2.6 
Vandetanib and Selumetinib Accountability ......................................51 
7 
INVESTIGATIONS SCHEDULE .............................................................................53 
7.1 
Pre-treatment evaluations ..............................................................................53 
7.1.1 
Obtaining written informed consent ..................................................53 
7.1.2 
Evaluations within four weeks (28 days) ...........................................54 
7.1.3 
Evaluations within two weeks (14 days) ...........................................54 
7.1.4 
Evaluations within one week (seven days) .......................................54 
7.2 
Evaluations during the trial .............................................................................55 
7.2.1 
Evaluations during Cycle 1 ...............................................................56 




 
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10.1 Measurement of disease ................................................................................80 
10.2 Timing and type of tumour assessments ........................................................80 
10.3 Tumour response ...........................................................................................81 
11 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT SCHEDULE82 
12 
DEFINING THE END OF TRIAL .............................................................................83 
13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................84 
13.1 Presentation of data .......................................................................................84 
13.2 Safety ............................................................................................................84 
13.3 Pharmacokinetics ..........................................................................................85 
13.4 Pharmacodynamics .......................................................................................85 
13.5 Anti-tumour activity ........................................................................................86 
14 
ADMINISTRATION .................................................................................................88 
14.1 Protocol deviations and amendments ............................................................88 
14.2 Completion of the electronic case report form (eCRF) ...................................88 
14.3 Trial performance and monitoring ..................................................................89 
14.4 Source document verification .........................................................................89 
14.5 Clinical study report .......................................................................................90 
14.6 Record retention ............................................................................................90 
14.7 Ethical considerations ....................................................................................90 
14.8 Indemnity .......................................................................................................91 
14.9 Publication policy and press releases ............................................................91 
15 
REFERENCES .......................................................................................................92 
16 
APPENDICES ........................................................................................................95 
16.1 WHO PERFORMANCE SCALE .....................................................................95 
16.2 DECLARATION OF HELSINKI ......................................................................96 
16.3 MEASUREMENT OF DISEASE .....................................................................99 
16.4 NEW YORK HEART ASSOCIATION (NYHA) SCALE ................................. 110 
16.5 MANAGEMENT OF SKIN TOXICITY ........................................................... 111 
16.6 MANAGEMENT OF QTc PROLONGATION ................................................ 113 
16.7 INVESTIGATION OF ASYMPTOMATIC DECREASES IN LVEF. ................ 114 
16.8 MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL AND/OR INDUCE 
TORSADES DE POINTES ........................................................................... 115 
 
 


 
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LIST OF ABBREVIATIONS 
A 
ABPI 
Association of the British Pharmaceutical Industry  
 
AE 
adverse event 
 
AKT 
serine/threonine protein kinase 
 
ALP 
alkaline phosphatase 
 
ALT 
alanine aminotransferase 
 
ANC 
absolute neutrophil count 
 
aPTT 
Activated partial thromboplastin time 
 
AST 
aspartate aminotransferase 
 
AUC 
area under the curve 
B 
BAD 
biologically active dose 
 
BD 
Bis die (twice daily) 
 
BP 
blood pressure 
 
bpm 
beats per minute 
 
BDBRAF 
v-Raf murine sarcoma viral oncogene 
 
BSA 
body surface area 
C 
0C 
degrees Celsius 
 
CDD 
Centre for Drug Development  
 
CDM 
Clinical Data Manager 
 
cfDNA 
Circulating free DNA 
 
CI 
Chief Investigator (formerly Co-ordinating Investigator) 
 
CLT 
total body clearance 
 
Cmax 
maximum observed plasma concentration 
 
CNS 
Central nervous system 
 
CPK 
Creatine phosphokinase 
 
CR 
complete response 
 
CRA 
Clinical Research Associate 
 
eCRF 
electronic case report form 
 
CR-UK 
Cancer Research UK 
 
CSM 
Clinical Study Manager 
 
CSR 
Clinical Study Report 
 
CT 
computerised tomography 
 
CTA 
clinical trial authorisation 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
calendar day 
 
DCE - MRI 
Dynamic contrast enhanced magnetic resonance imaging 
 
DCF 
data clarification form 
 
DCR 
disease control rate 
 
DLT 
dose limiting toxicity 
 
DNA 
Deoxyribonucleic acid 
 
DWI 
Diffusion weighted imaging 
E 
ECG 
electrocardiogram 
 
ECHO 
echocardiogram 
 
EDC 
electronic data capture 
 
EDTA 
ethylene diamine tetra-acetic acid 
 
EGFR 
Epidermal growth factor receptor 
 
EMA 
European Medicines Agency 
 
EORTC 
European Organisation for Research and Treatment of Cancer 
 
EPD 
early progressive disease 
 
ERK 
extracellular signal regulated kinases 
F 
FDA 
Food and Drug Administration 
 
FDG 
fluorodeoxyglucose 


 
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FU 
Formulation Unit 
G 
GCP 
Good Clinical Practice 
 
g/dL 
gram(s) per decilitre 
 
GFR 
Glomerular filtration rate 
 
GLDH 
Glutamate dehydrogenase 
 
GMP 
Good Manufacturing Practice 
 
GTAC 
Gene Therapy Advisory Committee 
H 
Hb 
haemoglobin 
 
HCG 
human chorionic gonadotropin 
 
HDPE 
High-density polyethylene 
 
HIV 
human immunodeficiency virus 
 
HPMC 
hydroxypropylmethylcellulose 
I 
IAUC 60 
Initial area under curve taken up to 60 seconds 
 
IB 
Investigator Brochure 
 
IC50 
half maximal inhibitory concentration 
 
ICH GCP 
International Conference on Harmonisation of Good Clinical 
Practice 
 
ILD 
interstitial lung disease 
 
IMP 
investigational medicinal product 
 
INR 
International normalised ratio 
 
ITF 
Investigator Trial File 
 
IUD 
Intrauterine device 
K 
KRAS 
Kirsten rat sarcoma oncogene 
 
Ktrans 
Volume transfer across a capillary wall 
L 
LVEF 
left ventricular ejection fraction 
M 
MAD 
maximum administered dose 
 
MAP 
Mitogen activated protein kinase 
 
MEK 
Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase 
 
mg/m2 
milligram per square metre 
 
MHRA 
Medicines and Healthcare products Regulations Agency  
 
MRI 
magnetic resonance imaging 
 
msec 
millisecond 
 
MTD 
maximum tolerated dose 
 
MUGA 
Multi gated acquisition scan 
N 
NCI 
National Cancer Institute 
 
NSCLC 
Non Small Cell Lung Cancer 
O 
OD 
Omne in die (once daily) 
 
OCT 
Optical coherence tomography 
P 
PD 
progressive disease 
 
PDF 
Portable document format 
 
PFS 
Progression Free Survival 
 
PO 
Per os (by mouth) 
 
PET 
Positron emission tomography 
 
PI 
Principal Investigator 
 
PK 
pharmacokinetic 
 
PR 
partial response 
 
PSRB 
Protocol, Safety and Review Board 
 
PV 
Pharmacovigilance 
Q 
QC 
quality control 
 
QP 
Qualified Person 
 
QT 
 
measure of the time between the start of the Q wave and the 
end of the T wave in the heart's electrical cycle 
 
QTc 
QT interval corrected for heart rate 


 
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R 
REC 
Research Ethics Committee 
 
RECIST 
Response Evaluation Criteria in Solid Tumours 
 
RET 
 ‘rearranged in transformation’ (kinase) 
 
RPM 
revolutions per minute 
 
RP2D 
Recommended Phase II dose 
 
RT 
radiotherapy 
S 
SAE 
serious adverse event 
 
SD 
stable disease 
 
SGDCF 
site generated data clarification form  
 
SDV 
source data verification 
 
SOP 
standard operating procedure  
 
SPC 
Summary of Product Characteristics 
 
SUSAR 
suspected unexpected serious adverse (drug) reaction 
 
SUV 
Standardised  uptake value 
T 
T1/2 
terminal elimination half-life 
 
Tmax 
time to reach Cmax 
 
TPGS 
alpha-tocopheryl succinate esterified to polyethylene glycol 
1000 [PEG 1000] 
U 
ULN 
upper limit of normal 
 
USM 
urgent safety measure 
 
UV 
ultra violet 
V 
VSS 
steady state volume of distribution 
 
ve 
Extracellular, extravascular volume 
 
VEGF-A  
Vascular endothelial growth factor -A 
 
VEGFR 
Vascular endothelial growth factor  receptor 
 
VOI 
Volume of interest 
 
vp 
Blood plasma volume 
W 
WFI 
Water for Injection 
 
WBC 
white blood cell 
 
WHO 
World Health Organisation 
 
 
 


 
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PROTOCOL SIGNATURES 
 
Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my 
responsibilities as an Investigator under the UK Clinical Trials Regulations1, the guidelines of 
Good Clinical Practice (GCP)2, the Declaration of Helsinki (Appendix 2), the applicable 
regulations of the relevant NHS Trusts and the trial protocol.  I agree to conduct the trial 
according to these regulations and guidelines and to appropriately direct and assist the staff 
under my control, who will be involved in the trial, and ensure that all staff members are 
aware of their clinical trial responsibilities. 
 
Investigator's Name: 
 
 
 
 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
 
 
Sponsor Signature: 
ON BEHALF OF SPONSOR, CENTRE FOR DRUG DEVELOPMENT OF CANCER RESEARCH UK: 
 
NAME: 
 
 
 
 
 
DIRECTOR OF CENTRE FOR DRUG 
DEVELOPMENT  
 
 
 
SIGNATURE: 
 
 
 
DATE: 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any 
subsequent amendments to it. 
2 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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1.4 
Administration schedule 
1.4.1 
Vandetanib administration 
Vandetanib is administered orally as a tablet formulation. 
Vandetanib will be given at 300 mg once daily (od) for four days (to rapidly reach the 
approximate steady state dose of 100 mg od) followed by 10 days at 100 mg od.  Dose 
loading of vandetanib will only occur once at the beginning of the study treatment (Cycle 1).  
Following the dose loading phase, the steady state dose will be maintained through 
subsequent cycles.  
Based on emerging data from the study, the vandetanib loading dose and steady state dose 
may also be increased.   Once or twice daily dosing will be considered. 
1.4.2 
Selumetinib administration 
Selumetinib is administered orally as a capsule (hyd sulfate) formulation. 
Selumetinib will be administered once (od) or twice a day (bd).  Administration will start (on 
Day 15) following completion of 14 days of treatment with vandetanib as a single agent 
(Cycle 1 only).   
For subsequent cycles, patients will receive 100 mg od vandetanib from Day 1 in 
combination with selumetinib for 28 days.  The starting dose will be 25 mg bd. 
Cohorts of up to 6 patients will receive escalating doses of selumetinib (25, 50 and 75 mg 
bd).  
Based on emerging data from the study, once daily selumetinib dosing may be considered if 
twice daily dosing results in unacceptable toxicity. 
Once the RP2D and schedule of the combination of vandetanib and selumetinib has been 
determined, approximately 30 NSCLC patients will be treated at this dose in the expansion 
cohort.  
1.4.3 
Treatment period – Cycle length 
Cycle 1 will consist of 42 days.  This includes the 14 days of vandetanib alone plus the 28 
days of combination treatment. 
Subsequent cycles will be of 28 days in length and consist of continuous combination 
treatment with vandetanib and selumetinib at steady state from Day 1.  There is no planned 
interval between cycles.  Patients may continue to receive the combination therapy in the 
absence of disease progression or unacceptable toxicity. 


 
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1.4.4 
Treatment group 
Approximately 42-50 patients with any solid primary tumour will be entered into the dose 
escalation phase of the study.  Approximately 30 patients with NSCLC will be entered into 
the expansion cohort.  
1.4.5 
Expected accrual 
It is expected that approximately 42-50 patients will be required to complete the dose 
escalation phase and approximately 30 patients will be required to complete the expansion 
cohort.  However additional patients may be required if any patients fall into the categories 
listed in Section 5.7 ‘Replacement of patients’. 
 


 
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2 
INTRODUCTION 
2.1 
Background 
Lung cancer is the second most common cancer in the UK (Cancer Research UK, Cancer 
Stats 2011) and is increasing in incidence globally (International Agency for Research on 
Cancer, Globocan, 2008). More than 38,000 new cases are diagnosed each year in the UK 
resulting in lung cancer being the cause of more than one in five cancer deaths (Cancer 
Research UK, Cancer Stats 2011). Thus the disease has a major impact on mortality and 
morbidity on a global scale.  
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of new cases of lung 
cancer (Cancer Research UK, Cancer Stats 2011). A minority of patients present with early 
stage disease amenable for surgery which is the only treatment that offers a realistic chance 
of cure. For patients with metastatic disease the first-line treatment option is usually 
systemic therapy and symptom management including radiotherapy. The choice of first line 
therapy depends on performance status, histology and predictive molecular markers.  
Despite advances made in earlier diagnosis, staging and treatment option, patients with 
advanced NSCLC still have a poor prognosis, with a median survival time of 8 to 11 months 
and a 1 year survival rate of 30% (Cancer Research UK, Cancer Stats 2011).  
Consequently, there is an urgent requirement to identify and develop new, effective 
treatment options for this disease. 
Advances have been made in the design and development of agents directed against novel 
molecular targets in NSCLC, including the epidermal growth factor receptor (EGFR) tyrosine 
kinase activity (Mok et al 2009), vascular endothelial growth factor (VEGF) signalling 
(Sandler et al 2006), anaplastic lymphoma kinase (ALK) gene re-arrangements and 
extracellular regulated kinases (ERK) that have the potential for improving clinical outcome.  
Agents that target EGFR and VEGF signalling have demonstrated some benefit in the 
treatment of NSCLC but are limited by development of tumour resistance mechanisms that 
utilise alternative growth stimulatory pathways. As validated techniques for detailed analysis 
of the activity of signal transduction pathways are applied to the investigation of targeted 
agents it is possible to investigate new combination strategies in order to maximise the 
therapeutic potential of novel targeted agents. We present here the rationale for combined 
targeting of EGFR, VEGF and MEK. We will describe how the safety of this approach will be 
evaluated and the strategy for testing the hypothesis, at the molecular level, that such an 
approach is effective in NSCLC.   
2.2 
Investigational medicinal product 
Structure of Vandetanib and Selumetinib 
Details of the physical and chemical characteristics of vandetanib and selumetinib, the two 
investigational medicinal products (IMPs), are provided in the two investigator brochures.  
Please refer to Section 6.0 for further details on both IMPs.  


 
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2.2.1 
Vandetanib 
2.2.1.1 
Drug class 
Vandetanib is an inhibitor of EGFR tyrosine kinase, a receptor tyrosine kinase that is 
activated by binding of a range of structurally related ligands (i.e., EGF and transforming 
growth factor α [TGFα]).  Over-expression of EGFR by tumour cells has been found to 
correlate with poor prognosis in a range of malignancies (e.g., bladder, breast, colorectal, 
gastric, head and neck, lung, ovarian and renal cancers), and some tumour cells produce 
large amounts of EGFR ligands (e.g., TGFα), which induce autocrine-stimulated tumour 
proliferation.  In addition Vandetanib is a potent inhibitor of VEGFR-2 tyrosine kinase that is 
expected to inhibit VEGF-driven angiogenesis and, as a consequence, constrain solid 
tumour growth.  Since angiogenesis is necessary for the growth and metastasis of all solid 
tumours, and VEGF is believed to have a pivotal role in this process, vandetanib treatment 
may have broad-spectrum clinical use.  Vandetanib also has activity against oncogenic RET 
kinases, which are activated in certain cancers, e.g. medullary thyroid cancer. 
2.2.1.2 
Preclinical Experience 
An extensive non-clinical package exists for vandetanib.  A summary of the main toxicology 
studies are presented in Section 4.3 of the current version of the vandetanib IB.  In 
summary, vandetanib had an IC50 of 0.4 μM in the hERG assay.  In canine Purkinje fibre 
studies, vandetanib caused a concentration-dependent increase in action potential duration 
at concentrations of 1 µM and greater.  Vandetanib also elevated systolic and diastolic blood 
pressure in rats and dogs.  In studies of the pharmacokinetics of vandetanib, absolute 
bioavailability following oral solution dosing to rats and dogs was approximately 90% and 
30% respectively.  Absorption was slow with Cmax occurring 3 to 8 hours post-dose.  
Vandetanib showed high clearance and high volume of distribution in both species.  
Toxicokinetics were dose proportional at low doses with a less than proportion increase in 
exposure observed at higher doses.  Vandetanib was shown to bind to both human serum 
albumin and AAG.  Following dosing with [14C]vandetanib to the rat, radioactivity was 
rapidly and extensively distributed with the highest concentrations in the gastrointestinal 
tract, liver, spleen, adrenal glands and other glandular tissues; radioactivity penetrated into 
the CNS.  Vandetanib was shown to be a weak inhibitor of P450 2D6 and 2C8 and a 
moderate inducer of P450 1A2, 2C9 and 3A4.  Faecal excretion was the predominant route 
of elimination after oral dosing (50 to 60% in the rat and 80% in the dog); evidence of 
enterohepatic recirculation was also observed. 
Extensive toxicology studies have been performed using vandetanib; these include multiple-
dose studies of up to 6 months in rats and 9 months in dogs, genetic toxicology studies and 
reproductive toxicology studies.  In rat studies the muzzle region showed dose-related acute 
folliculitis and epidermal micro-abscess formation at higher doses; this was considered to be 
a consequence of EGF receptor inhibition.  Elevated plasma ALT, AST and GLDH activities, 
hepatocellular necrosis and acute cholangitis were seen at the higher doses of vandetanib.  
Histopathological and ultrastructural changes, consistent with the induction of 
phospholipidosis, were also recorded.  Similar changes were not seen in the 1 month or 9 
month dog studies where gastrointestinal tract toxicity was the dose-limiting finding.  In 1 


 
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month rat and dog toxicity studies dose-related dysplasia was observed in the epiphyseal 
growth plates of the femorotibial joint in rats and in the femur of dogs.  These effects on 
intestinal function and bone formation were considered to be a consequence of on target 
VEGFR and EGFR inhibition.  Vandetanib demonstrated significant effects on all stages of 
female reproduction but no effects on male fertility in rats. 
2.2.1.3 
Clinical Experience 
Vandetanib has been extensively investigated in the clinic.  As of 26 May 2010, more than 
4000 patients have been exposed to vandetanib including 8 Phase I, 12 Phase II and 5 
Phase III patient studies (current version of the vandetanib IB).  Studies have evaluated both 
vandetanib as a monotherapy and in combination with a range of other cancer therapeutics.  
The majority of patients in the vandetanib studies to date have had NSCLC.  Refer to the 
vandetanib Investigators Brochure for detailed summaries.  Vandetanib has not been given 
in combination with selumetinib before. 
2.2.1.4 
Clinical Pharmacokinetics 
The PK of vandetanib is linear.  The steady state exposure is reached at day 28 with a once-
daily dosing.  The absorption is slow with a median time to maximum plasma concentration 
(tmax) of 4 to 10 hours.  The slow clearance (total plasma clearance after an oral dose (CL/f) 
of 11 L/h) and the large volume of distribution (3000 L) give a long terminal half-life (t1/2) of 
about 10 to 19 days.  Vandetanib is eliminated both in the faeces and in urine.  Therefore, in 
patients with mild and moderate renal impairment the exposure is increased by about 1.5-
fold and by 2-fold in patients with severe renal impairment.  Hepatic impairment or food has 
no effect on exposure.  In healthy volunteers, the CYP3A4 inhibitor, itraconazole did not 
modify the exposure to vandetanib but the CYP3A4 inducer rifampicin significantly reduced 
by about 40% the exposure to vandetanib. 
2.2.1.5 
Safety 
The CRUKD/11/001 study will explore a maximum total dose of 300mg with the option of 
increasing this up to 600mg (300mg bd during the loading phase only) should the safety 
profile of the combination with selumetinib be acceptable at the lower doses.   
Vandetanib has been explored at several doses up to 1200mg od (healthy volunteers) with 
minimal symptoms. In cancer patients, chronic dosing of 600mg od has resulted in diarrhoea 
and other AEs.   
Vandetanib has a very long half-life for a small molecule meaning that several weeks dosing 
are required to reach the 300mg od steady state plasma levels.   In the CRUKD/11/001 
study, a total dose of up to 600mg (as 300mg bd) can be administered at the start of the 
loading dose phase (Days 1 and 2) before reverting back to a maximum of 300mg od.  This 
two day 600mg “dose loading” should allow plasma levels approximating the 300mg od 
steady state level to be reached within a few days thereby reducing the period during which 
the patient has sub pharmacodynamic plasma levels of Vandetanib. Given the extended half 
life of vandetanib (10-19 days), it is unlikely that two days of 600 mg administration would 


 
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result in the severity of toxicity seen in the chronic dosing setting and therefore have any 
safety impact on patients.  
Vandetanib has an acceptable safety profile at a daily dose of 300 mg once a day (od) as 
demonstrated in previous studies (see current vandetanib IB).  The most common adverse 
events (AEs) have been related to the skin (e.g., rash, acne, pruritis), the gastrointestinal 
tract (e.g., nausea, diarrhoea) and nervous system (e.g., fatigue).  Cardiac AEs have also 
been observed including QTc prolongation in approximately <2% of patients treated with 100 
mg vandetanib in combination with chemotherapy, and in approximately 5% to 10% of 
patients treated with 300 mg vandetanib depending on the study.  The QTc prolongation was 
managed by dose interruption followed by dose reduction.  It is estimated that Torsades de 
Pointes occurs in approximately 0.1-1% of patients receiving 300 mg vandetanib.  These 
events were dose-dependent, and can be managed with appropriate monitoring and 
management.  From a randomised, placebo controlled Phase III study administering 300mg 
vandetanib (D4200C00058), in patients with medullary thyroid cancer (MTC), other adverse 
events included headache, dysgeusia, gastrointestinal disorders (including diarrhoea, 
nausea, vomiting, abdominal pain), rash, hypertension, weight decreased, decreased 
appetite, anorexia, corneal micro-opacities which rarely affected vision that were noticed in 
some patients after a few months of treatment with vandetanib; refer to the vandetanib IB for 
detailed summaries of AEs. 
2.2.1.6 
Efficacy 
Thirteen Phase II studies investigated the efficacy of vandetanib in patients with advanced or 
metastatic solid tumours or patients who had failed therapy (medullary thyroid cancer [MTC] 
(2), prostate cancer (1), colorectal cancer (2), breast cancer (3), NSCLC (4), small cell lung 
cancer (1)). 
In Phase II NSCLC studies, there was an increase in progression-free survival (PFS) for 
patients treated with vandetanib compared to gefitinib (median PFS 11 weeks vs. 8.1) 
[6474IL/0003] (Natale et al 2009), patients treated with vandetanib plus docetaxel compared 
to docetaxel alone (approx 18 weeks vs 12) [6474IL/0006] (Heymach et al 2007).  However, 
in a study comparing patients treated with vandetanib in addition to paclitaxel plus 
carboplatin with paclitaxel plus carboplatin alone, the median PFS was similar in both groups 
(24.0 weeks vs. 23.1) [6474IL/0007]. In a randomized double-blind dose-finding study, the 
objective response rate was 17.6% in the 100-mg group, 5.6% in the 200-mg group and 
16.7% in the 300-mg group [D4200C00039]. 
In Phase III NSCLC studies (see current version of the vandetanib IB), there was a 
statistically significant advantage in PFS and time to deterioration of disease-related 
symptoms (TDS) for the addition of vandetanib to docetaxel compared with docetaxel alone 
(D4200C00032) (Herbst et al 2009).  There was a trend for PFS in favour of vandetanib in 
combination with pemetrexed compared with pemetrexed alone, although this did not reach 
statistical significance (D4200C00036) (De Boer et al 2009), but the combination showed a 
statistically significant advantage in the disease control rate (DCR).  Neither study showed a 
significant advantage in overall survival (OS) as a consequence of adding vandetanib to 


 
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standard chemotherapy.  In a comparison with erlotinib, PFS and OS were similar for 
vandetanib (D4200C00057).  There was a statistically significant improvement for 
vandetanib over placebo (both in combination with best supportive care [BSC]) for PFS and 
DCR; however, OS was similar for vandetanib and placebo (D4200C00044).  In a Phase III 
study in patients with unresectable locally advanced or metastatic MTC for whom no 
standard therapeutic option was available.  (D4200C00058), there was a statistically 
significant improvement in PFS for vandetanib compared with placebo. The AVAiL study 
which combined bevacizumab with carboplatin/paclitaxel also did not show an increase in 
overall survival but did show an increase in PFS (Reck et al 2009). 
2.2.2 
Selumetinib 
Drug class 
Selumetinib is an orally bioavailable, selective, non-competitive MEK inhibitor.  MEK is a 
critical kinase in the mitogen-activated protein (MAP) kinase signal transduction pathway for 
many growth factor receptors including EGFR.  Cell signalling through growth factor 
receptors and protein kinases plays an essential role in cell survival, proliferation and 
differentiation.  One of the most important and best understood MAP kinase pathways is the 
RAS/RAF kinase pathway.  In proliferative diseases dysregulation of the growth factor 
receptor-RAS/RAF MAP kinase pathway leads to uncontrolled cell proliferation and, 
eventually, tumour formation.  It is anticipated that inhibition of MEK activity should inhibit 
transduction of the mitogenic signals from multiple pathways, resulting in an effect on tumour 
proliferation, differentiation and survival (Adjei et al 2008). 
2.2.2.1 Preclinical Experience 
An extensive non-clinical package exists for selumetinib.  A summary of the main toxicology 
studies are presented in Section 4.3 of the current version of the selumetinib IB.  In 
summary, selumetinib has been investigated non-clinically as free base and as Hyd-Sulfate 
salt.  No significant safety pharmacology findings were reported in minipig cardiovascular 
studies or in rat behavioural, pulmonary and gastrointestinal function/tolerability studies.  
Absorption of selumetinib free base was moderate to high at low doses in rat, dog and 
monkey.  Following dosing of the free base, there was evidence of dose-limiting absorption 
in mouse, rat, monkey and minipig.  However, exposure from selumetinib Hyd-Sulfate salt 
increased approximately in proportion with dose in mouse and monkey and allowed higher 
exposures to be achieved in monkey than the free-base.  In mouse toxicity studies a 
pharmacologically active metabolite, N-desmethyl selumetinib, was detected at plasma 
concentrations greater than 10% parent in some dose groups and is approximately 3 to 5 
times more potent than the parent compound.  Selumetinib was a weak direct inhibitor of 
CYP2C9 and a weak inducer of CYPs 3A, 1A and 2C9.  CYP1A2 was the enzyme primarily 
responsible for the formation of the N-desmethyl metabolite although selumetinib was also a 
substrate for 2C19 and 3A4.  In rat, monkey and mouse excretion was predominantly via the 
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2.2.2.2 
Clinical Experience 
Seven Phase I or II studies have evaluated selumetinib monotherapy both as a free base 
suspension (5 studies) or as Hyd-Sulfate capsule formulation (2 studies).  Three Phase I or 
II studies have investigated the selumetinib Hyd-Sulfate capsule formulation in combination 
with a wide range of other cancer therapeutics.  Refer to the selumetinib Investigators 
Brochure for detailed summaries. The MTD of selumetinib Hyd-Sulfate salt capsule was 75 
mg bd.  Selumetinib has not been given in combination with vandetanib before. 
2.2.2.3 
Clinical Pharmacokinetics  
The pharmacokinetics of selumetinib were approximately dose proportional for both 
formulations.  Selumetinib had a tmax of 1.5 hours, and t1/2 of 5 to 7 hours.  Clearance 
(CL/F) and steady-state volume of distribution (Vss/F) remained largely consistent across 
the dose range studied.  N-desmethyl selumetinib PK profile was largely similar to 
selumetinib, but exposures were much lower.  The plasma pharmacokinetic parameters for 
selumetinib and selumetinib N-desmethyl were similar after single and multiple dosing, 
suggesting minimal accumulation over time.  A food effect study involving administration of 
selumetinib to patients with advanced solid malignancies under fasting conditions and with a 
high-fat meal indicated a statistically significant effect of food on the exposure of selumetinib.  
Geometric least squares mean (Glsmean), Cmax and area under the plasma concentration-
time curve (AUC) were reduced by 62% and 19%, respectively, under fed conditions.  
Therefore selumetinib should be taken with water on an empty stomach for 2 hours prior to 
dosing and 1 hour after dosing. 
2.2.2.3.1 
Exposure in subjects of Asian ethnicity 
The pharmacokinetics of selumetinib were investigated in study D1532C00086, conducted in 
the UK involving healthy volunteers of Asian ethnicity (defined as being born in an Asian 
country, and expatriate for not longer than 5 years, and with maternal and paternal 
grandparents of Asian ethnicity).  The subjects who received Selumetinib in Study 
D1532C00086 were of the following ethnicities:  Japanese, Chinese, Filipino, Malay, 
Malaysian, Maldivian, Singaporean, Thai, Indian and Vietnamese, and it is not known in 
these groups whether Selumetinib exposure will be similar to Western subjects or to 
subjects of the specific Asian ethnicities included in Study D1532C00086. 
The pharmacokinetic findings from study D1532C00086 do not support excluding subjects of 
Asian ethnicity from studies of Selumetinib.  However, as it is possible that Asian subjects 
may experience higher Selumetinib plasma exposure (than would be expected in Western 
subjects receiving the same dose of selumetinib), there could be a potential for a higher risk 
of adverse events.  
The number of Asian patients with advanced cancer who have received treatment with 
selumetinib is very low.  Emerging information from ongoing study D1532C00067 of 
Japanese patients receiving selumetinib + docetaxel for second-line treatment of NSCLC 
suggests that febrile neutropenia may occur more commonly in Japanese patients (3 of 8 
patients treated, although comparative data in Japanese patients receiving docetaxel 


 
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monotherapy is not available) than might be predicted from studies conducted in Western 
subjects. 
Patients of Asian ethnicity are not excluded from studies evaluating selumetinib. However, 
when considering enrolling an individual of Asian ethnicity to a selumetinib clinical study, 
investigators should make a clinical judgment as to whether the potential risk of experiencing 
higher selumetinib plasma levels outweighs the potential benefit of treatment with 
selumetinib.  The Patient Information and Consent form for studies of selumetinib includes 
information on the possibility of higher selumetinib plasma levels and occurrence of adverse 
events in Asian subjects than in subjects who are not of Asian origin.  Investigators should 
be aware of the potentially higher risk of adverse events when monitoring patients of Asian 
ethnicity receiving treatment in clinical studies of selumetinib. 
 
2.2.2.4 
Safety 
The maximum tolerated dose (MTD) of selumetinib was 100 mg bd as a free-base 
suspension and 75 mg bd as a Hyd-Sulfate salt capsule.  Safety data have been evaluated 
from four Phase I studies and four Phase II monotherapy studies.  The most frequently 
reported AEs in Phase II monotherapy studies with the free-base suspension formulation 
and Phase I monotherapy studies of both formulations were fatigue, dermatitis acneiform, 
nausea, diarrhoea, vomiting and peripheral oedema.  Small mean increases in systolic and 
diastolic blood pressure have been observed in patients on selumetinib.  No clinically 
significant trends were observed for pulse rate in any study.  Review of ECG) parameters 
demonstrated no evidence of QTc prolongation.  A trend towards elevated liver 
transaminases has been observed in patients who received bd dosing of selumetinib.  The 
majority of transaminase elevations reported either remained within normal limits or 
increased by no more than a single Common Terminology Criteria (Version 3) for Adverse 
Events (CTCAE) grade.  There was a trend towards a small mean decrease in albumin and 
in some patients an increase in serum phosphate that was observed after initiation of 
selumetinib.  Refer to the current version of the selumetinib IB for detailed summaries of 
AEs. 
2.2.2.5 
Efficacy 
There were no significant differences in the primary endpoints of four Phase II monotherapy 
studies (see current version of the selumetinib IB) comparing selumetinib free-base 
suspension formulation with standard chemotherapy regimes in melanoma, pancreatic 
cancer, colorectal cancer, or NSCLC [D1532C00003, D1532C00008, D1532C00011 and 
D1532C00016]. 
However, objective responses were seen in both the melanoma and NSCLC studies.  In the 
Phase II melanoma study (D1532C00003) (Dummer et al 2008) 6 partial responses were 
noted in patients treated with selumetinib (out of 104 patients enrolled), 5 of which were in 
patients with the BRAF mutation.  In the Phase II NSCLC study (D1532C00016), 2 patients 
treated with selumetinib (out of 40 enrolled) had a partial response (mutation status 
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One patient in the Phase I Study D1532C00005 treated with selumetinib capsule formulation 
(75 mg bd) had a complete response (out of 31 patients enrolled).  This patient had a 
BRAF+ melanoma.  In another Phase I study with selumetinib capsule formulation assessing 
the effect of food on the dosing with selumetinib (D1532C00020), 2 patients with melanoma 
had a partial response (out of 28 patients enrolled). 
2.3 
Rationale for the proposed trial 
2.3.1 
Proposed Combination Hypothesis for Vandetanib and Selumetinib 
The proposed combination hypothesis is that combined inhibition of VEGF, EGF and MEK 
signalling in an unselected NSCLC patient population (refractory to first-line therapy) may 
deliver greater benefit than inhibition of any of these targets alone. 
The primary aim of the expansion cohort is to demonstrate the effective targeting of EGFR, 
VEGF and MEK signal transduction through pharmacodynamic end points. The study is not 
powered sufficiently to deliver definitive clinical efficacy data and thus it is not essential to 
enrol a homogenous patient population. However, it would be important to have imaging and 
biomarker evidence to test the rationale of multiple pathway inhibition. Inclusion of patients, 
for example, who have had previous EGFR targeted therapy (and would normally be 
resistant to EGFR Tyrosine Kinase Inhibitors (TKIs)) and those who are EGFR TKI naïve 
and properly informed would be helpful. Having a less restrictive inclusion criteria would also 
significantly enhance the recruitment rate. 
Inhibition of EGFR signalling has been shown to benefit NSCLC patients with activating 
mutations in the EGFR tyrosine kinase domain or those with high EGFR gene copy number 
(Mok et al.; 2009).  There is mounting evidence that NSCLC patients with mutant KRAS are 
less likely to respond to EGFR signalling inhibition (Roberts et al.; 2010).  The correlation is 
even more clear-cut in metastatic colorectal cancer where patient tumours containing KRAS 
mutations clearly do not respond to treatment with the anti-EGFR monoclonal antibodies 
cetuximab or panitumumab.  This resistance is presumed to be due to the activation of 
pathways downstream of RAS such as MEK/ERK being driven by the mutant KRAS rather 
than the EGFR.  Conversely, preclinical data indicates that tumour cell lines and human 
tumour xenografts with BRAF or KRAS gene mutations tend to be sensitised to MEK 
inhibition, because of their constitutive activation and dependency on ERK pathway 
signalling.  However, some tumour cell lines have been identified (head and neck squamous 
cell carcinoma and colorectal carcinoma cells) that lack BRAF or KRAS gene mutation yet 
retain sensitivity to MEK inhibition, and these also tend to be sensitive to EGFR tyrosine 
kinase inhibitors. 
VEGF signalling is believed to be a pivotal angiogenic factor that can induce the growth, 
survival and permeability of tumour blood vessels, required to support the progression of 
solid tumour disease.  The monoclonal antibody bevacizumab that specifically sequesters 
VEGF-A, has been shown to improve survival in NSCLC patients when combined with 
standard paclitaxel and carboplatin chemotherapy (Sandler et al.; 2006).  Clinical data from 
patients with metastatic colorectal cancer suggest that the response to VEGF inhibition is 
not influenced by KRAS gene status. 


 
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Consequently, combined inhibition of VEGF signalling, EGFR signalling and MEK signalling  
may deliver benefit in NSCLC patients. 
2.3.2 
Combination Non-Clinical Anti-Tumour Activity 
The addition of MEK inhibition to inhibition of either EGFR or VEGFR signalling was initially 
studied by examining selumetinib in combination with gefitinib (a selective EGFR tyrosine 
kinase inhibitor) or cediranib (a potent VEGFR tyrosine kinase inhibitor without activity 
against EGFR).  A combination efficacy study of selumetinib and gefitinib was performed in 
vivo using an A549 human NSCLC model (KRAS mutant).  The A549 tumour cell line is 
comparatively insensitive to monotherapy treatment with selumetinib or gefitinib alone, and 
when grown as a human tumour xenograft, demonstrates only modest sensitivity to 
treatment with either agent.  However, a combination of selumetinib and gefitinib 
demonstrates a greater anti-tumour effect in this tumour xenograft model than either agent 
alone.  A combination efficacy study of selumetinib and cediranib was performed in a Calu-6 
human NSCLC model (KRAS mutant).  This tumour line is sensitive to monotherapy 
treatment with selumetinib but not to treatment with an EGFR tyrosine kinase inhibitor 
(gefitinib), both in vitro and in vivo.  Calu-6 tumour xenografts are also sensitive to treatment 
with a VEGFR tyrosine kinase inhibitor, such as cediranib, in vivo.  When selumetinib and 
cediranib were dosed concomitantly in this model, the combination demonstrated a greater 
anti-tumour effect than either agent alone.  Similar results have also been reported with this 
combination in orthotopic lung cancer models using NCI-H441 and NCI-H460 cells (both 
KRAS mutant) (Takahashi et al, 2011, Poster 629, AACR).  However, in none of these 
studies was a direct statistical comparison of either monotherapy versus the combination 
performed and it is unclear if the combination efficacy was additive or synergistic relative to 
the two monotherapies. 
Taken together the above three studies suggest that inhibition of MEK in combination with 
inhibition of either EGFR or VEGFR signalling and may give enhanced efficacy over either 
agent as a monotherapy.  A similar or greater antitumour effect could therefore be expected 
for the combination of selumetinib with the dual EGFR and VEGFR inhibitor vandetanib.  
The efficacy of this combination was therefore examined in the A549 human NSCLC model 
(KRAS mutant).  Although this tumour model is comparatively insensitive to selumetinib or 
gefitinib monotherapy, it does respond significantly to vandetanib – which can be attributed 
to inhibition of VEGF signalling.  Dose groups were vehicle control selumetinib alone 
(25 mg/kg, PO once daily), vandetanib alone (25 mg/kg, PO once-daily), and a combination 
of selumetinib (25 mg/kg, PO once daily) plus vandetanib (25 mg/kg, PO once-daily).  
Growth inhibition was calculated from the start of treatment by comparison of the mean 
change in tumour volume for control and treated groups.  The addition of selumetinib to 
vandetanib was found to induce a 35% increased anti-tumour effect versus vandetanib alone 
(Figure 1.)  The tumour growth inhibition in the combination group was significantly greater 
(p<0.005; two-tailed t-test) than that in the vandetanib group. 


 
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Figure 1. 
Effect of administration of selumetinib (AZD6244; 25 mg/kg; orally once-daily), 
vandetanib (AZD6474; 25 mg/kg; orally once-daily), or a combination of the two, 
in on tumour size in A549 human NSCLC tumour xenografts. 
 
***P<0.0005 relative to vehicle control.  To remove any size-dependency prior to statistical evaluation, data was log-
transformed prior to statistical evaluation using a one-tailed two-sample t test.; one-tailed t-test 
When body weights were examined, treatment with selumetinib did not induce weight loss 
relative to the control group and weight loss in animals receiving a combination of 
selumetinib and vandetanib was comparable to the weight loss observed with vandetanib 
alone.  Two out of ten animals in the combination group were sacrificed early due to bloated 
abdomens and subsequently found to have fluid within their peritoneal cavity at autopsy.  
Such an effect has been observed as a consequence of amyloidosis at a low level in 
untreated athymic mice and the two cases in the combination arm of this study may be an 
exacerbation of this condition.  Further studies investigating the toxicology of vandetanib and 
selumetinib in combination have not been conducted due to the late stage patient population 
in the trial.  This is in accordance with the Note for guidance on non-clinical evaluation for 
anti-cancer pharmaceuticals (EMEA/CHMP/ICH/646107/2008; 2008). 
2.3.3 
Clinical experience of Vandetanib and Selumetinib Combination 
Vandetanib and selumetinib have not been given in combination to patients. 
2.3.4 
Possible toxicities based on single agent studies 
AEs related to the skin, gastrointestinal system, cardiovascular systems and fatigue are 
commonly observed with both agents. 
Clinical administration of both agents has been associated with skin toxicities with dermatitis 
acneiform and photosensitivity reaching CTCAE (version 3.0) Grade ≥3 in vandetanib and 
the former also being the most common AE in selumetinib trials.  The co-administration of 
vandetanib and selumetinib may result in a higher frequency or intensity of these 
dermatological adverse events, especially dermatitis acneiform and rash.  Similarly, 
administration of both agents has been associated with gastrointestinal adverse events and 


 
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the co-administration of vandetanib and selumetinib may result in a higher frequency or 
intensity of these gastrointestinal adverse events, especially nausea and vomiting. 
Cardiovascular adverse events in Phase III trials of vandetanib include hypertension, deep 
venous thrombosis, pulmonary thrombosis, pulmonary haemorrhage, peripheral ischaemia 
and cerebrovascular events.  Hypertension is considered to be a class effect for VEGF 
pathway inhibitors.  Prolongation of the QTc interval, using Bazett’s correction, was seen in 
Phase II studies.  Two cases of torsade de pointes (both reversible and non-fatal) have been 
reported out of more than 4000 patients who have received vandetanib.  No significant 
changes in heart rate were observed.  Hypertension has also been observed in clinical 
studies of selumetinib.  Some patients receiving selumetinib have been observed to develop 
asymptomatic decreases in left ventricular ejection fraction (LVEF) in the absence of obvious 
confounding comorbidities.  Patients receiving selumetinib frequently report the development 
or worsening of oedema, particularly at peripheral sites or the face.  The underlying 
aetiology of the oedema and fluid accumulation adverse events is unclear at present.  There 
is currently no evidence to suggest that the oedema is due to congestive cardiac failure.  
The co administration of vandetanib and selumetinib may result in a higher frequency or 
intensity of these cardiovascular adverse events, especially hypertension. 
In addition studies of vandetanib monotherapy occurrences of dyspnoea, pneumonia and 
interstitial lung disease were reported in some cases CTCAE (version 3.0) Grade ≥3.  There 
is also data from a pharmacoethnicity study suggesting that interstitial lung disease may 
occur more often in patients from Japan than in patients from elsewhere.  Dyspnoea and 
interstitial lung disease have been reported in patients receiving selumetinib, although the 
majority of these events have occurred in patients with lung/pleural disease due to their 
underlying malignancy.  The combination of two agents with this finding may result in a 
higher frequency or intensity of these adverse events. 
The gastrointestinal AE’s observed with both agents does raise the possibility of an 
interaction of the combination on the absorption one or both agents.  Additionally both 
vandetanib and selumetinib have been shown to induce CYP3A4 and selumetinib is a 
substrate of CYP3A4 raising the possibility of metabolic interaction.  Pharmacokinetics of 
both agents and the two most abundant metabolites of each will be performed during the 
study to detect any such interactions. 
2.3.5 
Supportive combination class data 
Preliminary clinical data are available for a combination study of selumetinib with the EGFR 
inhibitor erlotinib.  A total of 48 patients received treatment with selumetinib in combination 
with erlotinib 100 mg once daily (Study D1532C00004).  Doses of 50 mg bd and 75 mg bd 
selumetinib were explored in combination with erlotinib however the combination of 
selumetinib 50 mg bd and erlotinib to be non-tolerated (due to Grade 3 rash and diarrhoea).  
The tolerability of once daily dosing of selumetinib 50, 100 or 150 mg was subsequently 
explored in combination with erlotinib.  All patients who received chronic administration of 
selumetinib 150 mg bd and erlotinib experienced either Grade 2 or 3 adverse events of rash 
and/or diarrhoea and/or mucositis, which required dose interruptions and reductions in some 
patients; therefore, this dose combination was not recommended for use in clinical trials.  


 
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The most common AE across all selumetinib doses were diarrhoea and rash.  There was no 
evidence of a PK interaction between selumetinib and erlotinib. 
A preliminary review of the available safety data indicated that the adverse event profile for 
the combination of selumetinib with erlotinib is consistent with the individual monotherapy 
profiles for these agents.  Selumetinib 100 mg once daily is the recommended dose for 
combination with erlotinib 100 mg once daily. 
2.3.6 
Marketing Experience 
Selumetinib had not received marketing approval in any country or region (at the time of 
development of this protocol). In 2015, the FDA granted Orphan Drug Designation for 
selumetinib, for the treatment of uveal melanoma. 
Regulatory submissions for vandetanib in combination with chemotherapy in patients with 
advanced NSCLC were submitted to the FDA and the EMA in June 2009 and withdrawn in 
October 2009. 
The FDA and the EMA accepted regulatory submissions for review of vandetanib in the 
treatment of patients with advanced medullary thyroid cancer (MTC) in September 2010. 
Vandetanib has recently received FDA marketing approval (100 mg and 300 mg tablets) for 
treatment of symptomatic or progressive medullary thyroid cancer in patients with 
unresectable locally advanced or metastatic disease. 
 






 
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• 
Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection) with Grade 3 or 4 neutropenia (absolute neutrophil count 
[ANC] <1.0 x 109/L and fever ≥38.5oC); 
• 
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutropenia 
(ANC <1.0 x 109/L)  
• 
Thrombocytopenia Grade 4: a) for ≥5 days *See footnote, or b) associated with 
active bleeding, or c) requiring platelet transfusion. 
• 
Grade 3 or 4 toxicity to organs other than the bone marrow including Grade 3 and 
Grade 4 biochemical AEs. 
• 
Grade 4 diarrhoea 
• 
Any drug related toxicity that causes a treatment interruption for > 2 weeks (14 
successive days).  If a patient is deemed fit to restart treatment on Day 15 then this is 
not a DLT. 
• 
QTc prolongation >500 msec 
• 
Grade 4 hypertension. 
• 
Persistent hypertension (defined as blood pressure >160/100 mmHg) sustained for 
>1 week despite optimal therapy. 
 
EXCLUDING: 
• 
Grade 3 nausea 
• 
Grade 3 or 4 vomiting in patients (who have not received optimal treatment
 with anti-emetics) 
• 
Grade 3 skin toxicity (and patients are receiving supportive measures to manage 
toxicity) 
• 
Grade 3 diarrhoea in patients (who have not received optimal treatment with anti 
diarrhoeals) 
• 
Alopecia (any grade) 
 
* Note: In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full 
blood count must be performed within 5 days of the onset of the event to determine if 
a DLT has occurred.  Continue to monitor the patient closely until resolution to Grade 
3 or less. 
Should any change be made to the grade or causality of an AE during the trial that may alter 
its DLT status, the Centre for Drug Development (CDD) must be informed immediately as 
this may affect dose escalation decisions. 
3.1.2 
Definition of maximum tolerated dose  
The MTD will be determined as the dose level below that at which two of up to six patients at 
the same dose level experience DLT in the first cycle of treatment (as defined in Section 
3.1.1). 
The maximum administered dose (MAD) could also equal the MTD in the event that dose 
escalation is stopped before two DLTs are observed at a given dose level due to the 
expectation that higher dose levels would be too toxic to administer to patients.  The 
recommended dose for the expansion cohort evaluation will be determined following 
discussion of all the relevant toxicity data between the Sponsor (to include review by the 


 
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Protocol Safety and Review Board)  and the Study Team, including the Chief Investigator 
and participating investigators. 
3.1.3 
Patient evaluability 
Dose escalation: 
All patients who meet the eligibility criteria and receive at least one dose of the combination 
treatment (vandetanib and selumetinib) will be evaluable for safety assessment. 
Patients who receive fewer than 21 of 28 daily doses of the combination treatment in Cycle 1 
(for reasons other than toxicity) will not be evaluable for dose escalation decisions. 
Expansion cohort: 
All patients who meet the eligibility criteria and receive at least one dose of the combination 
treatment (vandetanib and selumetinib) will be evaluable for safety assessment.  
All patients who meet the eligibility criteria receive at least one cycle* of vandetanib and 
selumetinib and have a baseline assessment of disease will be evaluable for response.  To 
be assigned a status of complete response (CR) or partial response (PR), changes in 
tumour measurements must be confirmed by repeat measurements performed no less than 
four weeks after the response criteria are met.  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 the initial dose of the combination treatment is given. 
*To be evaluable for response, a patient must receive a minimum 21/28 daily doses of the 
combination treatment in Cycle 1. 
3.2 
Design of the clinical trial 
This is a Phase I, multi-centre, dose escalation study (any solid tumour) with an expansion 
cohort (NSCLC).  
3.2.1 
Dose escalation 
The final number of patients recruited to this phase will depend on the number of dose 
escalations required to reach the RP2D.  
In the dose escalation stage of the study, the Sponsor reserves the right to investigate 
alternative doses of vandetanib and selumetinib in response to emerging safety data. 
Recruitment into cohorts will follow a “rolling-six” design.  Dose assignment for each cohort  
will be carried out, using all available data, by the Sponsor in conjunction with the CI and 
PI(s).  Cohorts of three to six patientswill be entered at each dose level.   
If one out of three patients experience a DLT (as defined in Section 3.1.1, up to six patients 
will be treated at that dose.   
If one out of up to six patients experience a DLT, dose escalation will continue.   




 
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an optional biopsy sampling schedule.  It is expected that a minimum of 20 patients will 
complete the full imaging schedule and a minimum of 10 patients will consent to be biopsied.  
Patients who undergo the additional biopsies may also complete the full imaging schedule if 
further evaluable lesions are identified. 
Imaging will be performed to measure tumour vascularisation and metabolism using FDG-
PET 
  These 
functional imaging assessments will take place pre and post treatment with single agent 
vandetanib and following combination treatment with selumetinib. 
 
    
 
    
Progression free survival will be assessed at 12 weeks and one-year survival will also be 
recorded. 
3.2.3 
Study duration 
Following completion of recruitment to the dose escalation phase, the data will undergo 
review and assessment by the Sponsor. The Sponsor will confirm the decision to proceed to 
the expansion cohort. 
The recruitment period of the dose escalation phase could increase pending the addition of 
further cohorts to investigate alternate doses of the study drug combination.   
Patients can continue on study treatment on observation of SD, PR or CR therefore time on 
study for patients cannot be defined. Patients may continue to receive the combination 
therapy in the absence of disease progression or unacceptable toxicity.  If the patient has 
not progressed after 6 cycles, they may be treated for further cycles after a formal written 
request has been made to and written approval received from the Sponsor.  




 
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9. Ability to swallow and retain oral medications. 
10. Written (signed and dated) informed consent and be capable of co-operating with treatment, and 
follow-up 
 
4.1.2 
Exclusion criteria: 
1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy 
during the previous 4 weeks (6 weeks for investigational medicinal products) before treatment. 
2. Patients who have been withdrawn from treatment with agents that target EGFR because of 
unacceptable toxicity (prior treatment with these agents is allowed) and those patients who have 
had an EGFR dose reduction by 50% or more (dose modifications as per standard clinical 
practice is allowable and is not considered a reduction e.g. afatinib administration). 
3. Expansion cohort only: Prior treatment with any agent that targets MEK or VEGFR or VEGF  
4. Any prior exposure to RAS or RAF inhibitors 
5. Ongoing toxic manifestations of previous treatments.  Exceptions to this are alopecia or certain 
Grade 2 toxicities, which in the opinion of the Investigator and the Centre for Drug Development 
(CDD) should not exclude the patient.  
6. Symptomatic brain metastases (patients must be stable for >3 months post RT treatment) or 
spinal cord compression. 
7. Patients with interstitial lung disease. 
8. Pregnant or lactating women are excluded. Female patients with the ability to become pregnant 
who have a negative serum or urine pregnancy test before enrolment and agree to use two of the 
following three highly effective forms of combined contraception (oral, injected or implanted 
hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with 
spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six 
months afterwards are considered eligible.  
9. Male patients with partners of child-bearing potential (unless they agree to take measures not to 
father children by using one form of highly effective contraception [condom plus spermicide] 
during the trial and for six months afterwards).  Men with pregnant or lactating partners should be 
advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent 
exposure to the foetus or neonate. 
10. Major surgery from which the patient has not yet recovered. 
11. At high medical risk because of non-malignant systemic disease including active uncontrolled 
infection. 
12. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus 
(HIV). 
13. Cardiac conditions as follows: 
• 
Clinically significant cardiovascular event within 3 months prior to entry to 
include: 
o 
Myocardial infarction  
o 
Angina requiring use of nitrates more than once weekly 
o 
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Eligible patients must be enrolled in the EDC system before they start treatment with 
vandetanib.  If the patient is eligible the patient number will be automatically allocated during 
the enrolment process.   
Dose level allocation will be confirmed to the Investigator (and team as applicable) by the 
CDD following patient enrolment. 
 


 
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5 
TREATMENT 
5.1 
Selection of the Phase I starting dose and schedule 
5.1.1 
Selection of Vandetanib dose 
Initially vandetanib will be dose loaded at 300 mg od for four days (to rapidly reach the 
approximate steady state dose of 100 mg od) followed by 10 days at 100 mg od. The dose 
loading will achieve the steady state plasma concentration at a faster rate than would be 
possible using 100 mg od tablets.  The steady state plasma concentration will then be 
maintained by dosing once daily with 100 mg.  
Dose loading the vandetanib for the first four days of the study is a novel approach which 
has not been performed in clinical trials using vandetanib before.  
In vandetanib monotherapy trials, it was observed that 28 days of 100 mg od administration 
was required before a steady state of vandetanib was achieved.   The length of time to 
achieve steady state is a concern, especially in the expansion cohort which will recruit 
NSCLC patients.  Disease progression in this group of patients can be rapid. To reduce the 
time between starting vandetanib and achieving steady state a novel administration 
schedule has been proposed to reach the steady state of vandetanib within 14 days and 
allow administration of the combination treatment.   The loading dose of 300 mg od 
vandetanib has been explored in monotherapy trials and has been found to be tolerable to 
patients (please see current version of vandetanib IB).  
The vandetanib dose at steady state is based on the experience of previous clinical trials 
(refer to the vandetanib IB for detailed summaries of previous trials), which showed 
acceptable tolerability and safety profile at the selected dose level.  
Steady state doses of 200 or 300mg od vandetanib will be considered based on emerging 
data during the study. 
Should the steady state dose of 300mg od be explored, an increased ‘loading phase’ total 
dose of vandetanib may be considered i.e. 600mg (300md bd) for two days before reverting 
back to 300mg od. This two day 600mg “dose loading” should allow for plasma levels 
approximating the expected 300mg od steady state level to be reached within a few days 
thereby reducing the period during which the patient has sub pharmacodynamic plasma 
levels of Vandetanib. Steady state will therefore be reached within 14 days as in previous 
cohorts.  Pharmacokinetic modelling of the proposed regimens using a 200 or 300 mg dose 
of vandetanib has been performed and the appropriate loading phase of vandetanib has 
been established for both doses should a decision be made to increase the vandetanib 
dose.  
 


 
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5.1.2 
Selection of Selumetinib dose 
The starting dose of selumetinib has been selected as 25 mg bd.   The starting dose of 25 
mg bd is two dose levels below the highest dose of the Hyd-sulfate capsule form explored in 
previous clinical trials (refer to the selumetinib Investigator Brochure (IB) for detailed 
summaries of previous trials), 75 mg bd, which showed an acceptable tolerability and safety 
profile.  
This is the first time the combination of vandetanib and selumetinib will be used in humans.  
Therefore a reduced starting dose of selumetinib has been selected followed by dose 
escalation to 50 mg bd and then 75 mg bd.  Selumetinib 100 mg od is the recommended 
dose in combination with erlotinib (EGFR inhibitor) (Study D1532C00004, see current 
selumetinib IB) therefore once daily administration of selumetinib may be considered on 
observation of unacceptable toxicity under twice daily administration (see Section 3.2).  
 
5.2 
Dosing schedule/treatment schedule 
Vandetanib is an orally administered tablet.  The vandetanib dose is to be taken once or 
twice a day. 
Selumetinib is an orally administered capsule.  The selumetinib dose is to be taken once or 
twice a day. 
Patients should take the correct number of vandetanib tablets and selumetinib capsules at 
the same time every day. Tablets and capsules are to be taken whole and not split.  The 
vandetanib tablets and selumetinib capsules must be swallowed whole (with water) and not 
chewed, crushed, dissolved or divided. 
Selumetinib should be taken on an empty stomach - no food or drink other than water for 2 
hours prior to dosing and 1 hour after dosing. There is no restriction on dosing with food for 
vandetanib therefore vandetanib and selumetinib should be taken at the same time adhering 
to those restrictions associated with selumetinib.   
 
5.2.1 
Dose escalation phase.  
Cohorts 1-3: Vandetanib is being dose loaded for the first four days at 300 mg once daily 
(od) and then be maintained by dosing once daily with 100 mg. Dose loading of vandetanib 
will only occur once at the start of Cycle 1, at the beginning of the study treatment.  
Selumetinib will be administered twice a day (bd).  Administration will start after on Day 15 
following 14 days of treatment with vandetanib alone.  The starting dose will be 25 mg bd 
administered orally.  Cohorts of up to 6 patients will receive escalating doses of selumetinib 
(25, 50 and 75 mg bd).   
 




 
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5.3 
Dose escalation schedule 
In the dose escalation stage of the study, the Sponsor reserves the right to investigate 
alternative doses of vandetanib and selumetinib in response to emerging safety data. 
Recruitment into cohorts will follow a “rolling-six” design.  Dose assignment for each cohort  
will be carried out, using all available data, by the Sponsor in conjunction with the CI and 
PI(s).  
If MTD is not reached by the third cohort (100 mg vandetanib and 75 mg selumetinib) , 
based on emerging data from the study, 
• 
Vandetanib loading dose and steady state dose may be increased. Once or twice 
daily dosing will be considered.  
• 
Once daily selumetinib dosing may be considered if twice daily dosing results in 
unacceptable toxicity. 
Treatment will be continuous for up to 28 days for safety assessment and dose escalation 
purposes. Up to six patients will be studied at each dose level. Dose delay and reductions 
will be mandated according to protocol-defined criteria.  
Treatment of subsequent patients at each dose level should not begin until the first patient 
has completed 14 days of single agent vandetanib.  Their start of treatment date may be 
staggered by the Sponsor dependent upon emerging data. 
A rolling six design (Sklonik et al, 2008) will be used to recruit patients. Three to six 
evaluable patients will be entered at each dose level for the determination of MTD.  
The dose level of selumetinib and vandetanib will be assigned according to the number of 
patients currently enrolled at the current dose level, the number of DLTs (and any other drug 
related adverse events) observed at the current dose level and the number of patients 
enrolled who are at risk of developing a DLT.  When sufficient data, as deemed by the 
Sponsor and (Chief Investigator) CI, are available to assess these, the selumetinib and 
vandetanib dose level will be assigned according to the following: 
If the data is available from a minimum of three patients who have been treated in a cohort 
and no DLTs have been observed at that dose level for the complete duration of their first 
cycle, then dose escalation can be considered.  
If one DLT has been observed at the current dose level in the first cycle, the dose will remain 
the same.  
If two patients experience a DLT at any dose level during the first cycle, the dose will be de-
escalated and the previous dose level will be expanded to include up to 6 patients.  
If not all data are available from at least three patients in order to take a decision on dose 
escalation but an eligible patient is ready to begin treatment, the dose level will remain the 
same. Up to 6 patients may be enrolled at that dose level. 


 
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In the event of two patients experiencing a DLT at the first dose level, the dose level may be 
de-escalated following discussion of all the relevant toxicity data between the Sponsor and 
the Study Team, including the Chief Investigator.  
Dose escalation meetings will be held to determine if it is safe to escalate the dose to the 
next level.  These reviews will be triggered when sufficient patients have had the opportunity 
to complete the first cycle of combination treatment.      
The safety data including a list of DLTs and all AEs will be reviewed along with all other 
available data by the Sponsor, CI and PI(s). The decision to dose escalate or expand a 
cohort will be communicated to all investigator sites by the Sponsor.   
It is not anticipated that smaller dose escalations or de-escalations will be employed but 
would need to be considered if there is a large difference in the number of DLTs in two 
adjacent dose levels.  
Following completion of the dose escalation phase, a review of the data will be performed by 
the Sponsor (to include review by the Protocol, Safety and Review Board (PSRB) before 
approval is granted by the Sponsor that the expansion cohort can be opened.  
Once the MTD of the combination has been determined the expansion cohort will 
commence. The MTD determined in this cohort will be the dose level of the combination 
recommended for Phase II trials. 
Expansion cohort. 
Up to 30 patients with NSCLC will be enrolled to the expansion cohort.  All patients will be 
treated with the combination of vandetanib and selumetinib.  The dose of vandetanib and 
selumetinib will be the RP2D which will be determined in the dose escalation stage of the 
study. 
5.3.1 
Intra-patient dose escalations  
No intra-patient dose escalation is allowed. 
5.3.2  
Expansion of dose level(s) 
If one out of three patients experience a DLT (as defined in Section 3.1.1, up to six patients 
will be treated at that dose.  If one out of up to six patients experience a DLT, dose 
escalation will continue.  If two out of up to six (i.e. between two and six) patients experience 
a DLT dose escalation will stop and this dose will be defined as the maximum administered 
dose (MAD).  At least three more patients will be treated at a dose below the MAD to define 
the MTD. 
The MAD could also equal the MTD in the event that dose escalation is stopped before two 
DLTs are observed at a given dose level, due to the expectation that higher dose levels 
would be too toxic to administer to patients. 


 
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5.4 
Dose modifications  
5.4.1 
Dose interruptions  
In the event of drug related toxicity, drug administration must be withheld (except for skin, 
fatigue, nausea, myalgia or arthralgia, unless these specific toxicities do not respond to 
supportive measures) until Grade 1 or below or until the patient meets the eligibility criteria 
parameters. 
• 
On observation of a Grade 2 cardiac toxicity (any causality), both vandetanib and 
selumetinib should be stopped until resolution.   
• 
On observation of G3 diarrhoea, if this does not resolve within 48 hours, both 
vandetanib and selumetinib should be stopped until resolution (i.e. until Grade 0 or 1 
or until the patient meets the eligibility criteria parameters).   
• 
On observation of non-specific respiratory signs and symptoms, where infectious, 
neoplastic, and other causes are unlikely or have been excluded and a diagnosis of 
interstitial lung disease (ILD)  is likely or confirmed, both IMPs should be interrupted.  
Patients must meet eligibility criteria parameters prior to each cycle and following a 
treatment interruption if the intention is to re-treat.  
The maximum unscheduled dose interruption period is two weeks.  Patients failing to 
recover to NCI CTCAE Grade 1 or less after two weeks will be withdrawn from the study. 
There are over lapping toxicities associated with both vandetanib and selumetinib. Therefore 
it may not be clear which agent is responsible for any observed toxicity. If this is the case 
then administration of both drugs must be stopped at the same time until resolution to the 
above criteria. 
Vandetanib administration should not be interrupted if possible; the aim is to maintain 
vandetanib to reduce the requirement to repeat the ‘loading’ phase of vandetanib 
administration.  Therefore on observation of a Grade 2 drug related toxicity, selumetinib 
alone can be stopped (vandetanib can continue as a single agent administration).  The 
patient should be closely monitored (whilst on vandetanib alone) to ensure the toxicity 
resolves to Grade 1 or less within 24 hours.  If toxicity continues at same grade or increases 
within 24 hours then vandetanib should also be stopped. 
To note: selumetinib should not be given as a single agent. 
5.4.1.1 Management of vandetanib and selumetinib toxicity 
Vandetanib and selumetinib have overlapping toxicity profiles.  As this is the first time they 
have been used in combination, there is the risk that the frequency and severity of common 
toxicities could increase. 


 
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5.1.1.1.1 
Gastrointestinal toxicities 
 Initially, no prophylactic anti emetics or anti diarrhoeals will be prescribed however there will 
be ongoing review of emerging toxicity data throughout the study. If the data shows 
unacceptable GI toxicity then a change on policy will be implemented for the prescription of 
prophylactic medications.  
On observation of gastrointestinal toxicities, these are to be managed as per hospital 
guidelines.  
5.1.1.1.2 
Ocular toxicities 
If any grade of toxicity affecting the macula and/or affecting patient’s vision is observed then 
study treatment must be stopped and intensified monitoring should be implemented as per 
site ophthalmologist recommendation.  Restarting treatment will be considered on 
discussion with the PI, ophthalmologist and Sponsor. 
If Grade 1 ocular toxicity is observed which does not affect the macula or patient’s vision, 
then continue study treatment and intensify monitoring as per site ophthalmologist 
recommendation. 
If Grade 2 or above ocular toxicity is observed, not affecting the macula or patient’s vision, 
treatment must be stopped and intensified monitoring should be implemented as per site 
ophthalmologist recommendation.  Restarting treatment will be considered on discussion 
with the PI, ophthalmologist and Sponsor. 
5.1.1.1.3 
Guidelines for management of other toxicities 
Guidelines for the management of other toxicity observed during the study can be found in 
the following appendices: 
• 
Skin toxicity   
(Appendix 5) 
• 
QTc prolongation  
(Appendix 6).  Please also see Appendix 8 for medications 
 
 
 
known  to prolong QTc. 
 
 
 
Electrolyte supplementation with regular laboratory monitoring 
 
 
 
 
should be used, when appropriate, to maintain electrolytes  
 
 
 
 
within normal limits and to prevent an increased risk of QTc 
 
 
 
 
prolongation. 
 
 
 
Please also see Appendix 8 for medications with high risk of 
 
 
 
causing Torsade de Pointes (TdP). This appendix also notes 
 
 
 
guidance for wash out periods and guidelines for acceptable 
 
 
 
concomitant medications that may be associated with TdP.  


 
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• 
LVEF drop  
 
(Appendix 7).  This appendix describes suggested   
 
 
 
investigation and management of asymptomatic decreases in 
 
 
 
LVEF). 
• 
Hypertension   
Should be managed according to local trust policy. 
Anticipated vandetanib and selumetinib toxicity 
Please see the current versions of the vandetanib and selumetinib IBs and the vandetanib 
and selumetinib IB supplement for anticipated toxicities and toxicities that have been 
observed in previous clinical trials.  
5.4.2 
Dose reductions  
This section is applicable to both the dose escalation phase and also the expansion cohort. 
The dose of the combination treatment will be reduced to the previous dose level for any 
patient who experiences a DLT.  If a patient has a dose reduction, their dose should not be 
re-escalated. NCI CTCAE Version 4.02 is applicable for Section 5.4.2. 
5.4.2.1 
Vandetanib and Selumetinib dose reduction 
During single agent (vandetanib) phase 
If vandetanib administration is interrupted during the single agent phase at the start of Cycle 
1 (first 14 days): 
• 
If the interruption was unrelated to vandetanib, administration can recommence as 
per protocol with no dose reduction. 
• 
If the interruption was related to vandetanib,  
o If toxicity <G2, administration can continue as per protocol with no dose 
reduction on return to Grade 1 or baseline.   
o If toxicity is Grade 3 or above the patient must permanently discontinue study 
treatment. 
 
During combination phase 
 
If combination treatment is interrupted for <10 days during the combination treatment, on re-
starting treatment:  
• 
If the interruption was unrelated to vandetanib or selumetinib, both drugs can be 
administered together in combination following the interruption with no dose 
reduction.   
 
• 
If the interruption was related to vandetanib, on return to Grade 1 or below, 
vandetanib should be dose reduced to the next lowest dose level od*.  A dose 
reduction to selumetinib is not mandated.  
*If single agent dose is 100mg then administration of vandetanib given every other 
day can be considered however selumetinib must also be administered in 
combination (selumetinib is not to be administered as a single agent). 
  




 
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b) 
 If a patient experiences a recurrence of the same toxicity as that causing a previous 
dose interruption and/or dose reduction, selumetinib should be withheld until the 
toxicity improves to CTCAE (version 4.02) Grade 1 or baseline, except for rash 
where CTCAE Grade 2 rash is acceptable.  Upon recovery, treatment should resume 
at a permanently reduced or adjusted dose: 
1) Once daily: if no dose reduction has yet occurred 
2) Reduced dose, twice daily: (if dose reduction to once daily has already occurred) 
3) Reduced dose, once daily:  if steps (1) and (2) have already occurred.  
 
If a patient experiences recurrence of any toxicity requiring dose interruption whilst receiving 
the lowest dosing schedule for this study, the patient must discontinue study treatment. 
If a patient receiving the lowest dosing schedule experiences a novel toxicity that cannot be 
adequately managed by dose interruption and medical interventions then the patient must 
discontinue study treatment, as no further dose reductions/adjustments are permitted.  
5.5 
Missed doses 
Patients should take the correct number of vandetanib tablets and selumetinib capsules at 
the same time every day (Section 5.2). 
Should a patient miss a scheduled dose (e.g. forgetting to take the drugs) then the patient 
should wait until the next scheduled dose and continue as per normal drug administration.   
Should a patient miss a scheduled dose due to vomiting, the patient should not re-take the 
dose, either for vandetanib or selumetinib but should wait until their next scheduled dose for 
both drugs. 
5.6 
Duration of treatment 
Patients will continue on study treatment unless a) the patient asks to be withdrawn b) there 
is evidence of disease progression or c) the patient is experiencing unacceptable toxicity or 
for any of the reasons listed in Section 11. 
If a patient is benefiting from treatment with vandetanib and selumetinib (i.e. has stable or 
responding disease as measured by RECIST 1.1) and the patient is not experiencing any 
Grade 3 or greater drug-related AEs after 6 cycles of combination treatment, then the 
Chief/Principal Investigator can ask the Sponsor if the patient can continue with treatment.  
The Sponsor will request a full toxicity profile of that patient when considering the request.  
The patient may be treated for further cycles after a formal written request has been made to 
and written approval has been received from the Sponsor. If the Sponsor decides not to 
allow the patient to continue treatment, based on the information provided or on other 
information received, then the Sponsor’s decision is final. 
Patients will be followed up for 28 calendar days after the last administration of the study 
drug.  If there are adverse events that occurred while the patient was on study which are 
attributed (including possibly drug-related AEs) to the study drug and are still present 28 
calendar days after the last administration of study drug or occur in the 28 calendar days 


 
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post study drug administration; the patient will be followed up monthly afterwards until 
resolution or stabilisation of these events, unless the patient starts another anti-cancer 
treatment. 
Although the Investigator will make every reasonable effort to keep each patient on study 
until the patient progresses or receives the maximum number of cycles, the patient may be 
removed from the study for other reasons. (Refer to Section 11). 
5.7 
Replacement of patients 
Dose escalation: 
Patients will be replaced in this phase if they fulfil at least one of the following criteria: 
• 
If a patient withdraws from treatment prior to the end of Cycle1, for reasons other 
than drug related toxicity.  
• 
Patients who receive fewer than 21 of 28 daily doses of the combination treatment of 
either drug, in Cycle 1 (for reasons other than drug related toxicity) will be replaced 
by another patient at the same dose level. 
Expansion cohort: 
Patients will be replaced in the expansion cohort if they fulfil at least one of the following 
criteria: 
• 
If a patient withdraws from treatment prior to the end of Cycle1, for any reason  
• 
Patients who receive fewer than 21 of 28 daily doses of the combination treatment of 
either drug, in Cycle 1 (for any reason) will be replaced by another patient at the 
same dose level. 
5.8 
Concomitant medication and treatment 
Concomitant medication may be given as medically indicated.  Details (including doses, 
frequency, route and start and stop dates) of the concomitant medication given must be 
recorded in the patient’s medical records and the electronic case report form (eCRF). 
Radiotherapy may be given concomitantly for the control of bone pain; however these 
irradiated lesions will not be evaluable for response.  
The patient must not receive other anti-cancer therapy or investigational drugs while on the 
trial. 
5.9 
Precautions for treatment 
a) 
Electrolytes to include serum magnesium and potassium must be maintained within 
 
normal limits (potassium MUST be maintained at > 4.0mmol/L). 


 
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Monitoring to occur weekly for Cycles 1 and 2 then prior to Day 1 of subsequent 
cycles. 
b) 
Patients should avoid excessive sun exposure and use adequate sun screen 
 
protection (SPF 50) if sun exposure is anticipated. 
c) 
Patients should be informed to notify their study doctor or nurse if they experience 
 
any visual disturbances or ocular pain.  
d) 
Selumetinib capsules contain D-α- Tocopheryl polyethylene glycol 1000 succinate 
 
(TPGS, a water-soluble form of vitamin E) as an excipient.  The maximum daily dose 
 
of vitamin E that a study patient may receive from selumetinib is approximately 
 
261.6mg/day.  Therefore: 
 
Patients should not take vitamin E supplements or multivitamin supplements 
 
which provide a total daily dose in excess of 100% of the recommended daily 
 
allowance for vitamin E.  High doses of vitamin E have been reported to cause 
 
bleeding and interrupt blood coagulation processes.  
e) 
Interstitial lung disease (ILD) or pneumonitis has been observed with vandetanib, 
and deaths have been reported. Cases of ILD have also been observed with 
selumetinib when administered in combination with other agents, including 
docetaxel. A diagnosis of ILD should be considered in patients presenting with 
non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, 
cough, or dyspnoea, and in whom infectious, neoplastic, and other causes have 
been excluded by means of appropriate investigations. 
f) 
Selumetinib should be administered with caution in patients who are also receiving 
 
concomitant coumarin anticoagulant medications e.g. warfarin.  These patients 
 
should have their INR monitored/anticoagulant assessments conducted more 
 
frequently and the dose of the anticoagulant should be adjusted accordingly.   
g) 
Patients should avoid medications that are known to either induce or inhibit the 
activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and CYP3A4, as this 
may interfere with the metabolism of selumetinib.Please see link to Flockhart list 
which provides a complete list of inhibitors/inducers 
http://medicine.iupui.edu/clinpharm/ddis/). 
h) 
The administration of vandetanib with anti-arrhythmic drugs (including, but not limited 
 
to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that 
 
may prolong the QT interval (including but not limited to chloroquine, clarithromycin, 
 
dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should 
 
be avoided (see Appendix 8 for list of drugs that may cause QTc prolongation). 
i) 
Interactions between vandetanib and metformin, and vandetanib and digoxin are 
 
described in the Vandetanib IB.  Patients receiving concomitant metformin and 
 
vandetanib  or concomitant digoxin and vandetanib  should be monitored as clinically 


 
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appropriate.  Patients receiving concomitant metformin may require a lower dose of 
 
metformin.  
j) 
Study treatment is contraindicated in patients with GFR <50 mls/min. 
 
k) 
During the study, patients should avoid consuming large amounts of grapefruits, 
Seville oranges, or any other products that may contain these fruits, e.g., grapefruit 
juice, as these may affect selumetinib metabolism. 


 
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6 
PHARMACEUTICAL INFORMATION 
6.1 
Supply of Vandetanib and Selumetinib 
A complete certificate of analysis and a Qualified Person (QP) certification must be supplied 
with each shipment of vandetanib and selumetinib (IMPs) and be retained in the Pharmacy 
File. 
For information on vandetanib and selumetinib and re-ordering of supplies, contact the 
Clinical Research Associate (CRA)/Clinical Study Manager (CSM) responsible for the trial 
who will arrange further supplies. Initial supplies will be ordered for each site following the 
site initiation visit and confirmation from the Sponsor that the site is open to recruitment.    
Vandetanib and selumetinib will be supplied by: 
Fisher Clinical Services (UK) Limited 
Langhurstwood Road 
Horsham,  
West Sussex 
RH12 4QD 
Telephone number: 
01403 212700 
Email address: 
info@fisherclinicalservices.com 
 
For the reordering of supplies, the Sponsor will send a copy of the drug shipment form to 
Fisher Clinical Services (UK) Limited. Fisher Clinical Services (UK) Limited must send 
confirmation of shipment to the CSM/CRA once the IMP has been despatched to the clinical 
trial site. 
The primary and secondary packaging for the IMP will be labelled according to Eudralex 
Volume 4: Annex 13 ‘Investigational Medicinal Products’ of the European Union guide to 
Good Manufacturing Practice (GMP).  An example of the label can be found in the 
Pharmacy File.  
6.2 
Pharmaceutical data 
6.2.1 
Formulation of Vandetanib and Selumetinib 
Vandetanib will be supplied as a 100 mg tablet. The tablets are round, plain, biconvex, white 
film coated with a diameter = 8.5mm containing vandetanib 100 mg w/w, calcium hydrogen 
phosphate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate, 
with a film coating containing hypromellose, polyethylene glycol 300 and titanium dioxide. 
Vandetanib tablets are supplied in white high density polyethylene (HDPE) bottles with foil-
lined, induction-sealed, child-resistant closures.  
Selumetinib will be supplied as 25 mg capsules. The size 4 HPMC white (batches expiring 
latest June 2018) or blue (new batches) capsules (hyd sulfate formulation) contain 25 mg 
w/w of selumetinib (expressed as free base) D-α-Tocopheryl polyethylene glycol 1000 
succinate (TPGS; a water-soluble form of vitamin E). Selumetinib capsules are supplied in 
white HDPE bottles with foil-lined, induction-sealed, child-resistant closures. The container 
includes a desiccant canister. 


 
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6.2.2 
Storage conditions 
All supplies must be stored in a secure, limited access storage area.  Both vandetanib and 
selumetinib must be stored at room temperature (specifically below 30°C).   
6.2.3 
Stability of Vandetanib and Selumetinib 
Please refer to the label on the primary package for the expiry date of the IMP. 
6.2.4 
Dispensing of Vandetanib and Selumetinib 
Sufficient tablets of vandetanib and capsules of selumetinib must be dispensed on each 
occasion to cover the prescribed dose, (as described in Section 5.3 and 5.4), over the period 
to the next scheduled dispensing. 
Dispensing of each drug will generally cover one cycle (28 days) of both drugs in 
combination.  The only exception to this will be at the start of Cycle 1 where the patient will 
be dispensed vandetanib alone to cover the two weeks of the single drug administration.  
They will then be seen on Day 15 to begin their combination treatment and prescribed one 
cycles worth of vandetanib and selumetinib. Pharmacy will supply original packs of IMP to 
patients.  Packs will not be split for dispensing.   
6.2.5 
Vandetanib and Selumetinib administration 
For drug administration details please see section 5.2. 
For guidance on dose modifications please see section 5.4. 
For details on precautions of treatment and prohibited concomitant medications, please see 
section 5.6. 
6.2.6 
Vandetanib and Selumetinib Accountability 
Accurate records of all IMPs (vandetanib and selumetinib) shipments received, tablets and 
capsules dispensed, and all IMP returned must be maintained.  This inventory record must 
be available for inspection at any time by CRAs or CSMs of the Centre for Drug 
Development  (CDD).  IMP supplies are to be used only in accordance with this protocol and 
under the supervision of the Investigator. 
Patients will be given the appropriate number of tablets and capsules to take with them for 
one cycle of combination treatment from Cycle 2 onwards. For the loading phase of 
vandetanib and Cycle 1 of combination, patients will be provided with the appropriate 
number of additional vandetanib tablets. They should be asked to complete a patient diary 
card to document drug administration and to return the bottle and any remaining 
tablets/capsules at each visit. Remaining tablets/capsules will be returned to pharmacy for 
IMP reconciliation. The Investigator should make every effort to ensure patients’ compliance 
to treatment. 
The Investigator undertakes not to destroy any unused IMP unless directed to by CDD.  Any 
unused IMP must be destroyed according to hospital procedures and properly accounted for 
using the IMP Destruction Form and also on the IMP Accountability Record.  During the 


 
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course of the trial the CRA will check the numbers of bottles of tablets of vandetanib and 
bottles of capsules of selumetinib shipped to the centre, the number used and the number 
destroyed or returned.  The pharmacy will give an account of any discrepancy. 
 
 


 
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7 
INVESTIGATIONS SCHEDULE 
In cases where a patient has investigations at a different hospital, for example weekly blood 
samples, then it is the Investigator’s responsibility to ensure he/she receives and reviews the 
results.  The results must be recorded on the eCRF and the reports from the other hospitals 
must be available for source data verification.  Laboratory reference ranges, including 
effective dates, and evidence of laboratory accreditation must be obtained from all 
laboratories used. 
7.1 
Pre-treatment evaluations 
Details of all evaluations/investigations for enrolled patients, including relevant dates, 
required by the protocol must be recorded in the medical records so that the eCRF can be 
checked against the source data. 
Please also refer to the tabulated Schedule of Assessments in Section 7.5.   
7.1.1 
Obtaining written informed consent 
Written informed consent must be obtained from the patient before any protocol-specific 
procedures are carried out and within four weeks before the patient’s first dose of 
vandetanib.  The patient must be given adequate time to think about their commitment to the 
study.  
Only the PI and those Sub-Investigator(s) delegated responsibility by the PI, and have 
signed the Delegation Log, are permitted to gain informed consent from patients and sign 
the consent form.  All signatures must be obtained before the occurrence of any medical 
intervention required by the protocol (ICH GCP 4.8.8 and 8.3.1.2).  The date of the 
signatures of both the patient and the PI/Sub-Investigator must be the same. 
The PI or the Sub-Investigator must inform the patient about the background to, and present 
knowledge of the normal management of their disease and the IMPs (vandetanib and 
selumetinib) and must also ensure that the patient is aware of the following points. 
• 
The known toxicity of the IMPs and the possibility of experiencing side-effects. 
• 
That combining vandetanib and selumetinib is new and that the exact degree of 
activity is at present unknown, but that treating him/her will contribute to further 
knowledge. 
• 
The potential dangers of becoming pregnant (or the patient’s partner becoming 
pregnant) and he/she has been given information about appropriate medically 
approved contraception. (refer to Section 9.6). 
• 
That he/she may refuse treatment either before or at any time during the trial and that 
refusal to participate will involve no penalty or loss of benefits to which they are 
otherwise entitled. 
• 
Whom to contact for answers to pertinent questions about the research and their 
rights, and also who to contact in the event of a research-related injury. 
 
A copy of the informed consent form and patient information sheet must be given to the 
patient to keep and the original informed consent form and patient information sheet, must 


 
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be filed in the Investigator Trial File (ITF) (unless otherwise agreed that the original consent 
form will be filed in the medical records and the copies kept in the ITF). 
7.1.2 
Evaluations within four weeks (28 days)  
The following must be performed/obtained within the four weeks before the patient 
receives the first dose. 
• 
Written informed consent (as detailed in Section 7.1.1) 
• 
Demographic details 
• 
Medical history including prior diagnosis, prior treatment, concomitant diseases and 
concomitant treatment 
• 
Radiological Disease Assessments every 2 cycles 
o To include thoracic CT in expansion cohort 
o Radiological measurements using the most appropriate imaging for each 
patient using computerised tomography (CT) scan or magnetic resonance 
imaging (MRI) –must be performed within four weeks before the patient 
receives the first dose   
• 
Bone scan (optional as clinically indicated) 
• 
Ophthalmological exam (including slit lamp, visual acuity, visual fields, colour vision, 
optical coherence tomography (OCT) and intraocular pressure) 
o Adverse events relating to visual function have been reported in all studies 
with selumetinib to include blurred vision (please see IB supplement for 
further details of visual function toxicity).  Therefore eye exams have been 
built into the schedule of events to allow for continuous assessment 
throughout study treatment. 
Note that all adverse events (AEs), including serious adverse events (SAEs), must be 
monitored and recorded in the eCRF from the time the patient consents to any protocol-
specific procedure (see Section 9 for further details).  
7.1.3 
Evaluations within two weeks (14 days) 
The following must be performed within the two weeks before the patient receives the first 
dose of vandetanib: 
• 
Serum or urine human chorionic gonadotropin (HCG) test to rule out pregnancy at 
trial entry; results must be obtained and reviewed before the first dose of the IMP is 
administered, if applicable (i.e. women of child bearing potential). 
7.1.4 
Evaluations within one week (seven days)  
Dose escalation and expansion cohort 
 
The following must be performed within one week before the patient receives the first 
dose: 
• 
Complete physical examination;  
• 
Height, weight, WHO performance status, temperature, blood pressure (BP sitting) 
and pulse rate; 
• 
Electrocardiogram (ECG): Three to be performed within 5-10 minutes of one another; 
• 
Echocardiogram (ECHO) / Multi gated acquisition scan (MUGA) (maintain one 
method at each site); 




















 
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(q) MUGA/ECHO to be performed prior to Cycle 2 Day 1 (within 7 days prior  to C2D1 is acceptable)  then ECHOs and MUGAS to be performed every 12 weeks or more often as clinically indicated 
 
 
(s) Monthly follow-up required ONLY for those AEs and SAEs considered drug-related (highly probable, probable or possible) that are present at time that patient comes off the trial.  Monthly follow-up to continue 
until resolution, to baseline, stabilisation or patient starts another anti-cancer treatment 
(t) 
Alternate doses may be investigated – the Sponsor will confirm doses and schedule of each study drug for each new cohort. Please see section 3.2 
 
*To note: First radiological assessment to be performed at the end of Cycle 2.  Thereafter radiological assessment to be performed every two cycles. 


 
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8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS  
8.1 
Sampling summary  
Name of assay 
Purpose of 
assay 
Type of 
sample  
Vials used 
Total volume 
per patient per 
cycle  
Timings* 
Storage 
conditions 
How to ship/ 
transport 
Person/place 
responsible 
for analysis 
Frequency of 
analysis**** 
PRIMARY ASSAYS 
There are no primary assays performed for this study 
SECONDARY ASSAYS 
Blood PK 
(vandetanib) 
Cycle 1 only) 
To determine 
PK parameters 
including Cmax 
and AUC and 
metabolites 
Plasma 
Lithium 
heparin 
vacutainers 
0 hrs (pre dose) 
0.5 hrs 
2 hrs 
4 hrs 
6 hrs 
10 hrs (Days 15 
& 29 only) 
24 hrs 
 
Day 4 
6 x 2 mL =  
12 mL/day 
 
Days 15 & 29 
7 x 2 mL = 
14 mL/day 
 
= 40 mL total 
• Day 4 
• Day 15 (pre-
selumetinib dose) 
• Day 29 (two 
weeks post D1 of 
combination) 
-200C 
Contact CRA 
to arrange 
courier to 
CRO. 
AZ sub 
contractor 
Batched (by 
patient for first 
two patients) 
 
Thereafter 
analysis will 
be performed 
following 
completion of 
each cohort. 
Blood PK 
(selumetinib) 
(Cycle 1 only) 
To determine 
PK parameters 
including Cmax 
and AUC and 
metabolites 
Plasma 
EDTA 
vacutainers 
0 hrs (pre dose) 
0.5 hrs 
2 hrs 
4 hrs 
6 hrs 
10 hrs 
24 hrs 
 
7 x 3 mL =  
21 mL/day 
= 42 mL total 
 
• Day 15 (pre-
selumetinib dose) 
• Day 29 (two 
weeks post D1 of 
combination) 
-800C 
Contact CRA 
to arrange 
courier to 
CRO. 
AZ sub 
contractor 
Batched (by 
patient for first 
two patients) 
 
Thereafter 
analysis will 
be performed 
following 
completion of 
each cohort. 






 
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8.2 
Primary assays 
There are no primary assays associated with this protocol.   
8.3 
Secondary assays (dose escalation cohort only) 
8.3.1 
Pharmacokinetic analysis - Cycle 1 only 
Vandetanib and selumetinib will be measured in plasma according to agreed standard 
operating procedures and validated methods.  Validated high-performance liquid 
chromatography-mass spectrometry assays following liquid-liquid or protein precipitation 
extraction will be employed to measure plasma vandetanib and selumetinib and its 
metabolite, N-desmethyl metabolite. 
Vandetanib PK  
Parameters to be measured include plasma vandetanib and other metabolites may be 
measured as determined during the study. 
A two mL blood sample will be collected into lithium heparin vacutainers at detailed below.  
Day 4, Day 15 (pre first dose selumetinib) and Day 29 (two weeks following Day 1 of 
combination) at the following time points: 
• 
0 hrs (pre dose) 
• 
0.5 hrs (+/- 5 min) 
• 
2 hrs (+/- 10 min) 
• 
4 hrs (+/- 30 min) 
• 
6 hrs (+/- 30 min) 
• 
10 hrs  (Not to be measured on Cycle 1, Day 4.  Sampling at 10 hrs is required 
 
on Cycle 1 Days 15 and 29 only). 
• 
24 hrs  (+/- 1 hr) 
 
Selumetinib PK  
Parameters to be measured include plasma selumetinib and N-desmethyl metabolite. If 
warranted, other metabolites may be measured as determined during the study. 
A three mL blood sample will be collected into EDTA vacutainers at detailed below.  
To note, PK sampling time points for selumetinib will start prior to and following 
administration of the first dose (morning dose). 
Day 15 (pre first dose selumetinib) and Day 29 (two weeks following Day 1 of combination) 
at the following time points: 
• 
0 hrs (pre dose) 
• 
0.5 hrs (+/- 5 min) 
• 
2 hrs (+/- 10 min) 
• 
4 hrs (+/- 30 min) 










 
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8.5.3 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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9 
ASSESSMENT OF SAFETY 
9.1 
Adverse event definitions 
Adverse event 
For screening failures, serious adverse events (SAEs) will be reported to the 
Pharmacovigilance (PV) Department, Centre for Drug Development CDD) from the date of 
consent until the date the patient is confirmed as ineligible. 
For eligible patients, SAE and adverse event (AE) collection and monitoring commences 
from the time the patient gives their written consent to participate in the trial and continues 
for 28 days after the last administration of vandetanib and selumetinib (investigational 
medicinal products [IMPs]).   
An AE is any untoward, undesired or unplanned occurrence in a patient administered an 
IMP, a comparator product or an approved drug.  An AE can be a sign, symptom, disease, 
and/or laboratory or physiological observation that may or may not be related to the IMP or 
comparator.   
An AE includes but is not limited to those in the following list.  
• A clinically significant worsening of a pre-existing condition.  This includes conditions 
that may resolve completely and then become abnormal again.  
• AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• AEs occurring from lack of efficacy of an IMP, for example, if the Investigator 
suspects that a drug batch is not efficacious or if the Investigator suspects that the 
IMP has contributed to disease progression. 
 
Other reportable events that must be treated as SAEs are listed below.   
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a patient or a patient’s 
partner during treatment with an IMP or occurring within six months of the last IMP 
administration, must be reported to the Pharmacovigilance Department in the same 
timelines as an SAE.  These should be reported even if the patient is withdrawn from 
the trial. 
• 
Overdose with or without an AE. 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for 
example, spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the 
conduct of the trial. 
 
Serious adverse events (SAEs) 
An SAE is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life-threatening; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation 
(some hospitalisations are exempt from SAE reporting – see Section 9.2); 
• 
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• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event.* 
*A medically important event is defined as any event that may jeopardise the patient or 
may require intervention to prevent one of the outcomes listed above. 
Medically important events 
The following should be reported to the PV department of the CDD as Medically Important 
SAEs regardless of causality to the IMP. 
• 
Skin toxicity, CTCAE Grade 3 or above. 
• 
Diarrhoea, CTCAE Grade 3 or above. 
• 
Eye disorders involving the retina, CTCAE Grade 1 or above (e.g. retinal 
detachment, retinal tear, retinal vascular disorder, retinopathy). 
• 
All other eye disorders, CTCAE Grade 2 or above. 
 (NCI CTCAE version 4.02) 
If during the course of the study, other medically important events are identified and there 
is a requirement to report specific events outside of the standard criteria, this will be 
communicated to site and the protocol will be updated to reflect this. 
Determining adverse event causality 
The relationship of an AE to the IMP is determined as follows. 
Highly probable 
Starts within a time related to the IMP administration and 
No obvious alternative medical explanation. 
Probable 
Starts within a time related to the IMP administration and 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
Starts within a time related to the IMP administration and 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
The time association or the patient’s clinical state is such that the trial drug is not likely to have had 
an association with the observed effect. 
Not related 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of 
the AE (i.e. IMP, other illness, progressive malignancy etc) and must provide his/her opinion 
of the causal relationship between each AE and IMP.  This may require instituting 
supplementary investigations of significant AEs based on their clinical judgement of the likely 


 
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causative factors and/or include seeking a further opinion from a specialist in the field of the 
AE. 
Expectedness 
Assessment of expectedness will be made by the PV Department against the current 
version of the Investigator Brochures (IB) for vandetanib and selumetinib and the IB 
Supplement for this trial.   
Suspected, unexpected, serious, adverse reactions (SUSARs) 
A SUSAR is a suspected, unexpected, serious adverse reaction.  All AEs and SAEs will be 
assessed by CDD for seriousness, causality and expectedness.  The PV Department will 
expedite all SUSARs to the relevant Competent Authority/Authorities and the relevant Ethics 
Committee(s) within the timelines specified in legislation (SI 2004/1031 as amended). 
9.2 
Expedited reporting of serious adverse events  
All SAEs, regardless of causality, must be reported to the PV Department in an expedited 
manner. 
SAEs should be documented on an SAE report form, using the completion guidelines 
provided.  
The SAE report form should be faxed to Pharmacovigilance Department within 24 
hours of site staff becoming aware of the SAE. 
 
Each episode of an SAE must be recorded on a separate SAE report form.  The NCI CTCAE 
Version 4.02 must be used to Grade each SAE, and the worst Grade recorded.  If new or 
amended information on a previously reported SAE becomes available, the Investigator 
should report this to the PV Department on a new SAE report form. 
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 to the PV Department. 
Should the Investigator become aware of any drug related SAEs after the patient goes ‘off 
study’, these must also be reported to the PV Department within the specified timelines 
above. 
Events exempt from being reported as SAEs to the Pharmacovigilance Department 
Events specified in this section do not require reporting as SAEs in this trial, unless 
hospitalisation is prolonged for any reason and then an SAE form must be completed.  The 
events must still be recorded in the appropriate section of the electronic case report form 
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Elective admissions – Elective admissions to hospital for procedures which were planned 
and documented in the medical records at the time of consent are not SAEs, and do not 
require SAE reporting.  Hospitalisation for administration of the IMP according to the trial 
protocol is also exempt from being reported as an SAE. 
Prolongation of hospitalisation without an associated adverse event - (for example, 
prolonged hospitalisation while appropriate social care is set up for elderly patients)” 
 
Death due to disease progression - Cases of death due to disease progression do not 
require SAE reporting, unless considered related to the IMP.  
 
9.3 
Recording of adverse events and serious adverse events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients.  All concomitant 
medications, including herbal medications and supplements must be recorded.  Any therapy 
used to treat the event must be recorded.  The eCRF will be reconciled with the safety 
database during and at the end of the trial.  Therefore, the sites should ensure the data 
entered on the SAE report form and the data entered into the eCRF are consistent.  The 
CDD Medical Advisor and the Investigator(s) will regularly review the safety data from both 
the safety and the clinical database. 
9.4 
Follow-up of adverse events 
Follow-up will continue until all the necessary safety data for the event has been gathered 
and until the drug-related AE or SAE has either resolved, returned to baseline or stabilised.  
The PV Department will make requests for further information to the trial site at regular 
intervals.  Requested follow-up information should be reported to the PV Department in a 
timely manner and as soon as possible after receipt of the follow-up request.  For fatal or 
life-threatening cases, follow-up information should be reported to the PV Department as 
soon as possible. 
9.5 
Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order 
to protect the patient of a clinical trial against any immediate hazard to their health or safety.  
This includes procedures taken to protect patients from pandemics or infections that pose 
serious risk to human health.  
USMs may be taken without prior authorisation from the competent authority. 
The Medicines and Healthcare products Regulations Agency (MHRA) and the main 
Research Ethics Committee (REC) must be notified within three days of such measures 
being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either 
by: 
• 
 




 
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pregnancy including the outcome of the pregnancy and the baby’s health following birth, on 
a Pregnancy Outcome Form. In case the partner of a patient becomes pregnant, a consent 
form should be provided to the patient’s partner in order to obtain consent for collecting 
privacy data in accordance with the data protection act.  The Investigator should offer 
counselling to the patient and/or the partner, and discuss the risks of continuing with the 
pregnancy and the possible effects on the foetus.  Monitoring of the patient and the baby 
should continue until the conclusion of the pregnancy, if the patient or patient’s partner has 
consented to this. 


 
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10 
ASSESSMENT OF EFFICACY 
10.1 
Measurement of disease 
Disease must be measured according to the RECIST (version 1.1) criteria given in Appendix 3. 
10.2 
Timing and type of tumour assessments 
A thorough clinical and radiological evaluation of malignancy, as judged appropriate by the 
Investigator, and in line with the protocol, must be performed before starting the 
investigational medicinal product (IMP).  The same methods that detect evaluable lesions at 
baseline must be used to follow these lesions throughout the trial.  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. 
All radiological assessments must be performed within four weeks before starting treatment.  
The interval between the last anti-cancer therapy and these measurements must be at least 
four weeks (28 days).  All clinical measurements to assess response must be done within 
one week before the patient starting treatment. 
All complete (CR) and partial responses (PR) must be confirmed by two consecutive 
observations not less than four weeks apart.  All stable disease (SD) must be confirmed by 
two consecutive observations not less than six weeks apart. 
Copies of the scans must be available for external independent review if requested by the 
Centre for Drug Development  (CDD). 
Baseline evaluations 
These must include radiological measurements as indicated (chest computerised 
tomography (CT) scan, abdominal CT scan, magnetic resonance imaging (MRI), bone scan) 
and/or clinical measurements as appropriate.  All areas of disease present must be 
documented (even if specific lesions are not going to be followed for response) and the 
measurements of all measurable lesions must be recorded clearly 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 
strongly recommended, as this aids external independent review of responses. (See Section 
1.2.1 of RECIST (version 1.1) criteria) 
Evaluations during and at ‘off-study’ 
Tumour assessments must be repeated every six weeks or more frequently, when clinically 
indicated.  All lesions measured at baseline must be measured at every subsequent disease 
assessment, and recorded clearly on the scan reports.  All non-measurable lesions noted at 
baseline must be noted on the scan report as present or absent. 


 
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All patients, who are removed from the trial for reasons other than progressive disease, must 
be re-evaluated at the time of treatment discontinuation, unless a tumour assessment was 
performed within the previous four weeks. 
It is the responsibility of the Principal Investigator to 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 RECIST criteria. 
10.3 
Tumour response 
All patients who meet the eligibility criteria and receive at least one cycle of trial medication 
and have a baseline assessment of disease will be evaluable for response.  To be assigned 
a status of CR or PR, changes in tumour measurements must be confirmed by repeat 
measurements performed no less than four weeks after the response criteria are met.  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 the initial dose of the investigational 
medicinal product (IMP) is given. 
Should rapid tumour progression occur before the completion of the first cycle of combination 
treatment (vandetanib and Selumetinib for 28 days) 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, for example, when baseline and/or follow-up 
assessment is not performed or not performed appropriately.  
Expert reviewers appointed by CDD may undertake an independent review of all the 
Investigator’s assessed objective responses (CR and PR).  The expert reviewers will include 
at least one specialist who is not an Investigator in the trial.  In case of disagreement 
between the Investigator’s and the expert reviewers’ assessment, discussion will take place 
between the two parties in order to reach a consensus.  However, if it is not forthcoming, the 
assessment of the expert reviewers will be retained in the clinical study report.  The eCRF 
will reflect the Investigator’s opinion. 
Recording of response in the eCRF 
The applicable overall response category for each visit that includes disease assessment 
must be recorded in the eCRF, even though the criteria for determination of CR or PR by the 
protocol must be confirmed after two consecutive observations, no less than four weeks 
apart. 
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 4 weeks of combination treatment (that is not a toxic 
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11 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT SCHEDULE 
The Investigator must make every reasonable effort to keep each patient on trial for the 
whole duration of the trial (i.e. until 28 days after last vandetanib and selumetinib 
administration).  However, if the Investigator removes a patient from the trial or if the patient 
declines further participation, final ‘off-study’ assessments should be performed before 
initiating any new anti-cancer treatment..  All the results of the evaluations and observations, 
together with a description of the reasons for withdrawal from the trial, must be recorded in 
the medical records and in the eCRF. 
Patients who are removed from the trial due to adverse events (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 eCRF and on the serious 
adverse event (SAE) report form where necessary. 
The following are justifiable reasons for the Investigator to withdraw a patient from trial. 
• 
AE/SAE including unacceptable toxicity 
• 
Withdrawal of consent 
• 
Serious violation of the trial protocol (including persistent patient attendance failure 
and persistent non-compliance) 
• 
Sponsor’s decision to terminate the trial 
• 
Withdrawal by the Investigator for clinical reasons not related to the IMP (vandetanib 
or selumetinib) including symptomatic deterioration 
• 
Evidence of disease progression 
• 
Pregnancy 
 
 


 
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12 
DEFINING THE END OF TRIAL  
The ‘end of trial’ is defined as the date when the last patient has completed the ‘off-study’ 
visit or the final follow-up visit (whichever is the latter). 
It is the responsibility of the CDD to inform the Medicines and Healthcare products 
Regulations Agency (MHRA) and the Main Research Ethics Committee (REC) within 90 
days of the ‘end of the trial’ that the trial has closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by 
the CDD, the CDD will notify the MHRA and the Main REC within 15 days of the decision 
and a detailed, written explanation for the termination/halt will be given.  The pharmaceutical 
company (Astra Zeneca) will also be informed of early termination/halt. 
The entire trial will be stopped when: 
• 
The drugs are considered too toxic to continue treatment before the required number 
of patients being recruited. 
• 
The stated number of patients to be recruited is reached. 
• 
The stated objectives of the trial are achieved. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation 
of treatment must be documented.   
In terminating the trial, CDD and the Investigators must ensure that adequate consideration 
is given to the protection of the patient’s interest. 
 


 
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13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The final analysis will be conducted after one of the following conditions is met. 
• 
The trial is terminated early (for example, due to toxicity). 
• 
All patients have completed their ‘off-study’ visit (i.e. 28 days after the last dose of 
vandetanib and selumetinib) and have been followed up for survival for one year 
from the first dose of IMP (Cycle 1 Day 1). 
 A clinical data cut-off date will be established to allow for primary analysis clinical study 
report (CSR) reporting once all recruited patients have been followed up for survival for a 
minimum of one year after the date of first IMP administration (Cycle 1 Day 1). The primary 
analysis CSR will include data from all treated patient visits/assessments up to and including 
the clinical cut-off date.  
 
Any patients who continue to receive the combination therapy in the absence of disease 
progression or unacceptable toxicity after the clinical cut-off date will be included in an 
addendum to the final CSR. Only long-term safety data will be included in an addendum to 
the CSR.   
 
PFS rate at 12 weeks will also be analysed for expansion cohort patients, according to the 
RECIST criteria.  Assuming that the PFS rate in vandetanib alone is 9%, to test the 
hypotheses that the combination will increase the PFS rate to 23% under identical 
conditions, recruiting a total of 30 patients with NSCLC in a single arm design will give 82% 
power and 10% 1-side significant level. 
The survival rate of NSCLC patients will also be analysed at one year.  In addition to 
reporting the proportion of patients alive at 12 months, a Kaplan Meier curve will be plotted 
with 95% CI together with median survival provided.  
13.1 
Presentation of data 
Data will be presented in a descriptive fashion.  Variables will be analysed to determine 
whether the criteria for the trial conduct are met.  This will include a description of patients 
who did not meet all the eligibility criteria, an assessment of protocol violations, IMP 
accountability and other data that impact on the general conduct of the trial. 
Baseline characteristics will be summarised (number and frequency) for all enrolled patients.  
Patients who died or withdrew before treatment started or did not complete the required 
safety observations will be described and evaluated separately. 
Treatment administration will be described for all cycles.  Dose administration, dose 
modifications or delays and the duration of therapy will be described. 
13.2 
Safety 
Safety data will be collected from the date of written consent.  Safety variables will be 
summarised by number and frequency as data listings.  Laboratory variables will be 


 
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described using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.02. 
Adverse events (AEs) will be reported for each dose level and presented as tables of 
frequency of AEs by body system and by worse severity grade observed.  Tables should 
indicate related and unrelated events.  Laboratory data will be presented by patient and 
reviewed alongside the AE listings. 
13.3 
Pharmacokinetics 
The plasma concentration/time data will be analysed using non-compartmental methods.  
The PK parameters to be determined for vandetanib, selumetinib and other metabolites 
include the maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), and 
the area under the plasma concentration time curve (AUC). 
13.4 
Pharmacodynamics 
The following biomarkers will be measured in tumour tissue and blood pre and post 
treatment with the combination of vandetanib and selumetinib.   
 
 
 
   
 
 
 
 
 
   
 
 
Imaging 
FDG- PET scan 
PET-CT scanning will be performed according to SOPs. The order of events for further 
imaging sessions will be a duplicate of the first dose and imaging.  Full technical details of 
the imaging protocols will be found within the Imaging Manual. 
The PET-CT images will be reported independently by two nuclear medicine trained 
radiologists. If there is discrepancy between the radiologists a third nuclear medicine 


 
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radiologist will be used as an arbiter. Semi-quantitative analysis will be performed 
expressing the uptake of tracer within tumour deposit as a standardized uptake value (SUV). 
Both maximum and mean values will be recorded.   
SUV will be measured by drawing volumes of interest (VOI) using a minimum threshold 
value method for delineation of the tumour using Advantage Workstation 4.4 software (GE 
Healthcare) and calculating uptake according to a standardized formula incorporating body 
weight, timing and injected dose.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.5 
Anti-tumour activity 
Documenting anti-tumour activity is a secondary objective of this trial.  Patients must receive 
at least one cycle of the trial medication to be evaluable for response.  Objective responses 
and the best tumour response achieved by each patient while on trial will be presented in the 
data listings. 


 
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Progression free survival and overall survival will be described for all patients and presented 
in data listings. 
 


 
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14 
ADMINISTRATION 
This trial is conducted under a clinical trial authorisation (CTA) and approval from the 
Medicines and Healthcare products Regulations Agency (MHRA) and the relevant Research 
Ethics Committee(s) will be obtained before the start of this trial.  This trial is sponsored and 
monitored by the Cancer Research UK, Centre for Drug Development Office (CDD).  
Applicable regulatory requirements are described in this section. 
14.1 
Protocol deviations and amendments 
Do not deviate from the protocol unless approval has been obtained from the CDD.  The 
CDD has a no waiver policy with regard to inclusion and exclusion criteria.  All proposed 
deviations from the protocol must be discussed and approved by the Sponsor. 
Amendments to the protocol may only be made with the approval of the CDD.  A protocol 
amendment may be subject to review by Cancer Research UK’s Protocol Safety & Review 
Board (PSRB) and the assigned Ethics Committee.  Depending on the type of protocol 
amendment, MHRA approval may also be required.  Written documentation of the Ethics 
Committee (and if appropriate the MHRA) ‘favourable opinion’ (i.e. approval) must be 
received before the amendment can be implemented and incorporated into the protocol if 
necessary. 
14.2 
Completion of the electronic case report form (eCRF) 
Electronic CRFs approved by the CDD will be used to collect the data. The Investigator is 
responsible for ensuring the accuracy, completeness, clarity and timeliness of the data 
reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Delegation Log provided by 
the CDD and have been authorised by the Investigator should enter or change data in the 
eCRFs.  Authorised users will be included on a Master User List in order to be provided 
access to the eCRF.  All protocol required investigations must be reported in the eCRF.  The 
Investigators must retain all original reports, traces and images from these investigations for 
future reference.   
Data will be entered directly into electronic screens by authorised site personnel.  
Amendments to eCRF data will be made directly to the system and the system audit trail will 
retain details of the original value(s), who made the change, a date and time, and a reason 
for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using 
manual and automated checks.  Queries will be issued electronically to the site.  Authorised 
personnel must answer the queries by making relevant amendments to data or providing a 
response.  Answered queries will be closed or reissued as appropriate. 
Once the patient is ‘off study’ and the eCRF has been fully completed, the Investigator must 
provide an electronic signature to authorise the complete subject casebook. 


 
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At the end of the trial all eCRFs are retained and archived by the CDD and a portable 
document format (PDF) copy provided to the Investigator who is responsible for archiving at 
site. 
14.3 
Trial performance and monitoring 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified 
and the organisational preparations made with the trial centre.  CDD must be informed 
immediately of any change in the personnel involved in the conduct of the trial. 
During the trial the CDD Clinical Research Associate (CRA) is responsible for monitoring 
data quality in accordance with CDD’s standard operating procedures (SOPs) and all data 
pertaining to a patients participation in a trial must be available to the CRA.  Before the trial 
start, the Investigator will be advised of the anticipated frequency of the monitoring visits.  
The Investigator will receive reasonable notification before each monitoring visit. 
It is the responsibility of the CRA to: 
• 
review trial records and compare them with source documents; 
• 
check pharmacokinetic and pharmacodynamic samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; 
and 
• 
verify that the available facilities remain acceptable. 
The Investigator undertakes not to destroy any unused IMP unless directed to by CDD.  Any 
unused IMP must be destroyed according to hospital procedures and properly accounted for 
using the IMP Destruction Form and also on the IMP Accountability Record.  During the 
course of the trial the CRA will check the numbers of bottles of tablets of Vandetanib and 
bottles of capsules of Selumetinib shipped to the centre, the number used and the number 
destroyed or returned.  The pharmacy will give an account of any discrepancy. 
It is the responsibility of the Sponsor to inform the Main REC within 90 days of the ‘end of 
the trial’ that the trial has closed.  (See definition in Section 12). 
14.4 
Source document verification 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source 
data.  Therefore it is the Investigator’s responsibility to ensure that both he/she and his/her 
study team records all relevant data in the medical records.  The Investigator must allow the 
CRA direct access to relevant source documentation for verification of data entered into the 
eCRF, taking into account data protection regulations.  Entries in the eCRF will be compared 
with patients’ medical records and the verification will be recorded in the eCRF, documented 
on the source data verification (SDV) form and the monitoring report.   


 
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Some source data may exist only electronically and be entered, or loaded directly into the 
eCRF.   
The patients’ medical records, and other relevant data, may also be reviewed by appropriate 
qualified personnel independent from the CDD appointed to audit the trial, and by regulatory 
authorities.  Details will remain confidential and patients’ names will not be recorded outside 
the hospital. 
14.5 
Clinical study report 
At appropriate intervals, interim data listings will be prepared to give the Investigator the 
possibility to review the data and check the completeness of information collected.  All 
clinical data will be presented at the end of the trial on final data listings.  CDD will prepare a 
clinical study report based on the final data listings.  The report will be submitted to the 
Investigator(s) for review and confirmation it accurately represents the data collected during 
the course of the trial.  A summary of the final clinical report must be provided by the CDD to 
the MHRA and to the Research Ethics Committee within one year of submission of the ‘end 
of trial’ notification to the MHRA. 
14.6 
Record retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and 
accurate records to enable both the conduct of a clinical trial and the quality of the data 
produced to be evaluated and verified.  These essential documents (as detailed in 
Chapter V of Volume 10 (Clinical Trials) of The Rules Governing Medicinal Products in the 
European Union based upon Section 8 of the ICH GCP Guidelines), including source 
documents such as scans, trial related documents and copies of the eCRFs, associated 
audit trail and serious adverse event (SAE) report forms, shall show whether the Investigator 
has complied with the principles and guidelines of Good Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way 
that ensures that they are readily available, upon request, to the Regulatory Agency or 
Sponsor, for the minimum period required by national legislation or for longer if needed by 
CDD.  Records must not be destroyed without prior written approval from CDD. 
The medical files of trial subjects shall be retained in accordance with national legislation 
and in accordance with the maximum period of time permitted by the hospital, institution or 
private practice. 
14.7 
Ethical considerations 
Before starting the trial, the protocol, patient information sheet and consent form must go 
through the CDD’s external review process, undergo review by the PSRB and the 
appropriate Ethics Committee. 
It is the Chief/Principal 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 


 
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Chief/Principal Investigator must ensure this is documented in the patient’s medical notes 
and the patient is re-consented. 
The Sponsor and Chief/Principal Investigator must ensure that the trial is carried out in 
accordance with the GCP principles and requirements of the UK Clinical Trials regulations 
(SI 2004/1031 and SI 2006/1928 as amended), the ICH GCP guidelines and the Declaration 
of Helsinki (Appendix 2). 
14.8 
Indemnity 
This trial is being carried out under the auspices of Cancer Research UK and therefore injury 
to a patient caused by the compounds under trial will not carry with it the right to seek 
compensation from the pharmaceutical industry.  Cancer Research UK will provide patients 
with compensation for adverse side effects, in accordance with the principles set out in the 
Association of the British Pharmaceutical Industry (ABPI) guidelines on compensation for 
medicine-induced injury. 
14.9 
Publication policy and press releases 
Results of this trial must be submitted for publication.  The CDD must be involved in 
reviewing all drafts of the manuscripts, abstracts, press releases and any other publications.  
Manuscripts must be submitted to CDD at least 35 days in advance of being submitted for 
publication to allow time for CDD to schedule a review and resolve any outstanding issues.  
Abstracts and press releases must be submitted to CDD at least 20 days in advance of 
being released.  The Chief Investigator should be the principal author and any Investigator 
recruiting ≥ 10% of patients should be listed as an author.  Imaging experts performing 
central review of imaging should also be listed as authors as applicable.  Authors must 
acknowledge that the trial was sponsored by and performed with the support of CDD. 
The contribution of CDD must be recognised by a member of staff being included as an 
author on the publication.   
 


 
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15 
REFERENCES 
Note for Guidance on Good Clinical Practice.  ICH Topic E6.  CSMP/ICH/135/95.  EMEA, 
May 1996, updated September 1997 with post Step 4 errata included  
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 
April 2001 on the approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice in the conduct of 
clinical trials on medicinal products for human use. Official Journal of the European 
Communities L121/34-44 
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product 
for human use to the competent authorities, notification of substantial amendments and 
declaration of the end of the trial. October 2005.  ENTR/F2/BL D(2003) CT 1 (Revision 2) 
Detailed guidance on the application format and documentation to be submitted in an 
application for an Ethics Committee opinion on the clinical trial on medicinal products for 
human use. February 2006. ENTR/CT 2 (Revision 1) 
Detailed guidance on the collection, verification and presentation of adverse reaction reports 
arising from clinical trials on medicinal products for human use. April 2006.  ENTR/CT 3 
(Revision 2) 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 
1031) 
COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for good clinical practice as regards investigational medicinal products for human 
use, as well as the requirements for authorisation of the manufacturing or importation of 
such products.  Official Journal of the European Union L 91/13 
The Medicines for Human use (Clinical Trials) Amendment Regulations 2006 (Statutory 
Instrument 2006/1928). 
1. Adjei, A.A., Cohen, R.B., Franklin, W., Morris, C., Wilson, D., Molina, J.R., Hanson, L.J., 
Gore, L., Chow, L., Leong, S., Maloney, L., Gordon, G., Simmons, H., Marlow, A., Litwiler, K., 
Brown, S., Poch, G., Kane, K., Haney, J., Eckhardt, S.G. (2008) Phase I Pharmacokinetic and 
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Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers. J Clin 
Onc, 26(13), 2139-2146. 
2. Buonaccorsi, G. A.,  O'Connor, J. P., Caunce, A., Roberts, C., Cheung, S., Watson, Y., 
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driven registration for dynamic contrast-enhanced MRI time-series data. Magn. Reson. Med, 
58(5): 1010-1019 
 


 
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3. de Boer, R., Humblet, Y., Wolf, J., Nogova, L., Ruffert, K., Milenkova, T., Smith, R., Godwood, 
A., Vansteenkiste, J. (2009) An open-label study of vandetanib with pemetrexed in patients 
with previously treated non-small-cell lung cancer. Ann Oncol, 20(3), 486-491. 
4. Cancer Research UK, Cancer Stats, Lung Cancer Report accessed 2011. 
5. Dummer, R., Robert, C., Chapman, P., Sosman, J., Middleton, M., Bastholt, L. (2008) 
AZD6244 (ARRY-142886) vs temozolomide in patients with advanced melanoma: An open-
label, randomized, multicentre, phase II study. J Clin Onc, 26, suppl abstr 9033.  
6. Herbst, R.S., Sun, Y., Eberhardt, W.E.E., Germonpre, P., Saijo, N., Zhou, C., Wang, J., 
Longyun, L., Kabbinavar, F., Ichinose, Y., Qin, S., Zhang, L., Biesma, B., Heymach, J.V., 
Langmuir, P., Kennedy, S.J., Tada, H., Johnson, B.E. (2010) Vandetanib plus docetaxel 
versus docetaxel as second line treatment for patients with advanced non small cell lung 
cancer (Zodiac): a double blind randomised Phase III trial. Lancet Onc, 11(7), 619-626. 
7. Heymach, J.V., Johnson, B.E., Prager, D., Csada, E., Roubec, J., Pesek, M., Spasova, I., 
Belani, C.P., Bodrogi, I., Gadgeel, S., Kennedy, S.J., Hou, J., Herbst, R.S. (2007) 
Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously 
Treated Non–Small-Cell Lung Cancer. J Clin Onc, 25(27), 4270-4277. 
8. International Agency for Research on Cancer, Globocan 2008 website accessed 15 August 
2011. 
9. Investigator brochure selumetinib (AZD6244) version 10 dated 18April2011. 
10. Investigator brochure vandetanib (ZD6474) version 11 dated 26May2010. 
11. Kety, SS. (1951). The theory and application of the exchange of inert gas at the lungs and 
tissues. Pharmacol Rev 3, 1−41. 
12. Mok, T., Wu, Y.L. ,Zhang, L. (2009).  A small step towards personalized medicine for non-
small cell lung cancer.  Discov Med, 8(43), 227-31. 
13. Naish, J.H., Kershaw, L.E., Buckley, D.L., Jackson, A.,  Waterton, J.C., Parker, G.J. (2009)  
Modeling of contrast agent kinetics in the lung using T1-weighted dynamic contrast enhanced 
MRI. Magn. Reson. Med, 61: 1507-1514 
14. Naish, J. H., Parker, G.J., Beatty, P.C.,  Jackson, A.,  Young, S.S., Waterton, J.C., Taylor, 
C.J. (2005)  Improved quantitative dynamic regional oxygen enhanced pulmonary imaging 
using image registration. Magn. Reson. Med, 54: 464-469 
15. Natale, R.B., Bodkin, D., Govindan, R., Sleckman, B.G., Rizvi, N.A., Capo, A., Germonpre, 
P., Eberhardt, W.E.E., Stockman, P.K., Kennedy, S.J., Ranson, M. (2009) Vandetanib Versus 
Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Two-Part, 
Double-Blind, Randomized Phase II Study. J Clin Onc, 27(15), 2523-2529. 


 
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16. Reck, M., von Pawel, J., Zatlukal, P., Ramlau, R., Gorbounova, V., Hirsh, V., Leighl, N., 
Mezger, J., Archer, V., Moore, N., Manegold, C. (2009) Phase III trial of cisplatin plus 
gemcitabine with either placebo or bevacizumab as first line therapy for nonsquamous non-
small cell lung cancer: AVAiL. J Clin Onc, 27 (8), 1227-1234. 
17. Roberts, P.J., Stinchcombe, T.E., Der, C.J., Socinski, M.A. (2010) Personalised medicine in 
non-small cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth 
factor receptor-targeted therapy? J Clin Onc, 28(31), 4769-4777. 
18. Sandler, A., Gray, R., Perry, M.C., Brahmer, J., Schiller, J.H. et al (2006).  Paclitaxel-
carboplatin alone or with bevacizumab for non-small-cell lung cancer.  N Engl J Med, 355(24), 
2542-50. 
19. Sklonik, J.M., Barrett, J.S., Jayaraman, B., Patel, D. and Adamson, P. (2008).  Shortening the 
timeline of pediatric Phase I trials: The rolling six design.  J Clin Onc, 26(2), 190-195. 
20. Takahashi, O., Komaki, R., Smith, P.D., Jurgensmeier, J.M., Ryan, A.J., Bekele, B.N., 
Wistuba, I.I., Jacoby, J.J., Korshunova, M.V., Biernacka, A., Erez, B., Hosho, K., Herbst, R.S., 
O’Reilly, M.S. (2011) MEK inhibition by selumetinib (AZD6244) inhibits progression with a 
multicentric antiangiogenic effect and enhances the efficacy of cediranib in orthotopic human 
lung cancer models. Abstract No, 629. AACR 2011. 
21. Talbot, D., von Pawel, J., Cattell, E., Yule, S.M., Johnston, C., Zandvliet, A.S., Huitema, 
A.D.R., Norbury, C.J., Ellis, P., Boosquee, L., Reck, M. (2007). A randomised Phase II 
pharmacokinetic and pharmacodynamic study of Indisulam as second line therapy in patients 
with advanced non small cell lung cancer.  Clin Cancer Research, 13 (6), 1816-1822. 
22. Talbot, D., Ranson, M., Davies, J., Lahn, M., Callies, S., Andre, V., Kadam, S., Burgess, M., 
Slapak, C., Olsen, A.L., McHugh, P.J., de Bono, J.S., Matthews, J., Saleem, A., Price, P. 
(2010) Tumour survivin is downregulated by the antisense oligonucleotide LY2181308: A 
proof-of-concept, first-in-human dose study.  Clinical Cancer Research, 16 (24), 6150-6158. 
23. Tofts, P.S., Brix, G., Buckley, D.L., Evelhoch, J.L., Henderson, E., Knopp, M.V., Larsson, 
H.B., Lee, T.Y., Mayr, N.A., Parker, G.J., Port, R.E., Taylor, J., Weisskoff, R.M. (1999) 
Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a 
diffusible tracer: standardized quantities and symbols. J Magn Reson Imaging 10, 223–232. 
 
 




 
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16.2 
DECLARATION OF HELSINKI 
Recommendations guiding physicians in biomedical 
research involving human subjects 
 
Adopted by the 18th World Medical Assembly, 
Helsinki, Finland, June 1964 
amended by the 29th World Medical Assembly 
Tokyo, Japan, October 1975, 
and 
the 35th World Medical Assembly, 
Venice, Italy, October 1983 
and 
the 41st World Medical Assembly, 
Hong-Kong, September 1989 
and 
the 48th General Assembly, 
Somerset West, Republic of South Africa, October 1996 
INTRODUCTION 
 
It is the mission of the physician to safeguard the health of the people.  His or her knowledge 
and conscience are dedicated to the fulfilment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, “The health of my patient will be my first consideration”, and the International Code of 
Medical Ethics declares that, “A physician shall act only in patient’s interest when providing 
medical care which might have the effect of weakening the physical and mental condition of 
the patient”. 
 
The purpose of biomedical research involving human subjects must be to improve 
diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology 
and pathogenesis of disease. 
 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards.  This applies especially to biomedical research. 
 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognised between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research. 
 
Special caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human beings 
to further scientific knowledge and to help suffering humanity, the World Medical Association 
has prepared the following recommendations as a guide to every physician in biomedical 
research involving human subjects.  They should be kept under review in the future.  It must 
be stressed that the standards as drafted are only a guide to physicians all over the world.  
Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of 
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I - BASIC PRINCIPLES 
 
1. Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
 
2. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted for 
consideration, comment and guidance to a specially appointed committee independent 
of the investigator and the sponsor provided that this independent committee is in 
conformity with the laws and regulations of the country in which the research experiment 
is performed. 
 
3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
his or her consent. 
 
4. Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
 
5. Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others.  Concern for the interests of the subject must always prevail over 
the interests of science and society. 
 
6. The right of the research subject to safeguard his or her integrity must always be 
respected.  Every precaution should be taken to respect the privacy of the subject to 
minimise the impact of the study on the subject’s physical and mental integrity and on 
the personality of the subject. 
 
7. Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits. 
 
8. In publication of the results of his or her research, the physician is obliged to preserve 
the accuracy of the results.  Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
 
9. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail.  He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time.  The physician should then obtain the subject’s 
freely given informed consent, preferably in writing. 
 
10. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 


 
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this official relationship. 
 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation.  Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation. 
 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
 
II - MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
(Clinical research) 
 
1.  In the treatment of the sick person, the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgement it offers hope of saving life, re-
establishing health or alleviating suffering. 
 
2. The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
 
3. In any medical study, every patient - including those of a control group, if any - should be 
assured of the best proven diagnostic and therapeutic method. This does not exclude the 
use of inert placebo in studies where no proven diagnostic or therapeutic method exists. 
 
4. The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship. 
 
5. If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent Committee (1,2). 
 
6. The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
 
III - NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 
(Non-clinical biomedical research) 
 
1. In the purely scientific application of medical research carried out on a human being, it is 
the duty of the physician to remain the protector of the life and health of that person on 
whom biomedical research is being carried out. 
 
2. The subjects should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness. 
 
3. The investigator or the investigating team should discontinue the research if in his/her or 
their judgement it may, if continued, be harmful to the individual. 
 
4. In research on man, the interest of science and society should never take precedence 
over considerations related to the well-being of the subject. 


 
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16.3 
MEASUREMENT OF DISEASE 
New response evaluation criteria in solid tumours (RECIST criteria): 
Revised RECIST guideline (version 1.1) 
E.A. Eisenhauer et al. (2009) European Journal of Cancer 45: 228-247 
Note that this is an abridged version of the RECIST criteria.  Please refer to the above article 
for detailed appendices and if in doubt. 
 
1. 
Measurability of tumour at baseline 
 
1.1. 
Definitions 
 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable 
as follows: 
 
1.1.1. Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 
10mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II 
on imaging guidance). 
• 10mm calliper measurement by clinical exam (lesions which cannot be accurately 
measured with callipers should be recorded as non-measurable). 
• 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.   
 
1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with 10 to <15mm short axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
1.1.3. Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 


 
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• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumour lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable.  
 
1.2. Specifications by methods of measurements 
 
1.2.1. Measurement of lesions 
All measurements should be recorded in metric notation, using callipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
 
1.2.2. Method of assessment 
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up.  Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  
Clinical lesions will only be considered measurable when they are superficial and ≥10mm 
diameter as assessed using callipers (e.g. skin nodules).  For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also 
be reviewed at the end of the study. 
 
Chest X-ray:  
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung.  
 
CT, MRI:  
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5mm or less.  When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  More 


 
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details concerning the use of both CT and MRI for assessment of objective tumour response 
evaluation are provided in the publication from Eisenhauer et al. 
 
Ultrasound:  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment 
to the next (described in greater detail in Appendix II).  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is advised.  If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
 
Endoscopy, laparoscopy: 
The utilisation of these techniques for objective tumour evaluation is not advised.  However, 
they can be useful to confirm complete pathological response when biopsies are obtained or 
to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
Tumour markers:  
Tumour markers alone cannot be used to assess objective tumour response.  If markers are 
initially above the upper normal limit, however, they must normalise for a patient to be 
considered in complete response.   
 
Cytology, histology:  
These techniques can be used to differentiate between PR and CR in rare cases if required 
by protocol (for example, residual lesions in tumour types such as germ cell tumours, where 
known residual benign tumours can remain).  When effusions are known to be a potential 
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumour has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
 
2. Tumour response evaluation 
 
2.1 Assessment of overall tumour burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements.  
Measurable disease is defined by the presence of at least one measurable lesion (as 
detailed above in Section 1).   
 
2.2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a 
maximum of two and four lesions respectively will be recorded).  For evidence to support the 
selection of only five target lesions, see analyses on a large prospective database in the 


 
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article by Bogaerts et al.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected.  An example in Fig. 3 of the publication by Eisenhauer et al. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour.  Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumour.  Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagital or coronal).  The smaller of these 
measures is the short axis.  For example, an abdominal node which is reported as being 
20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. 
In this example, 20 mm should be recorded as the node measurement.  All other 
pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-
target lesions.  Nodes that have a short axis <10 mm are considered non- pathological and 
should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the 
sum. The baseline sum diameters will be used as reference to further characterise any 
objective tumour regression in the measurable dimension of the disease.  
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’ (more details to follow). In addition, it is possible to record multiple 
non-target lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
2.3. Response criteria 
 
2.3.1. Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note: the appearance of one or more 
new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 


 
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2.3.2. Special notes on the assessment of target lesions 
Lymph nodes.  
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of <10 mm.  Case report forms or other data collection methods may therefore be 
designed to have target nodal lesions recorded in a separate section where, in order to 
qualify for CR, each node must achieve a short axis <10 mm.  For PR, SD and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
 
Target lesions that become ‘too small to measure’. 
 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small (e.g. 
2 mm).  However, sometimes lesions or lymph nodes which are recorded as target lesions at 
baseline become so faint on CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being ‘too small to measure’.  When this occurs it 
is important that a value be recorded on the case report form.  If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 
0 mm.  If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  (Note: It is less likely that this rule will be used 
for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well).  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness).  The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will 
prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, 
even if it is below 5 mm. 
 
Lesions that split or coalesce on treatment: 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane 
between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion.  If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’. 
 
2.3.3. Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of 
tumour marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
 


 
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Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions.  (Note: the appearance of one or more new lesions is also considered 
progression). 
 
2.3.4. Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
 
When the patient also has measurable disease. 
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, 
there must be an overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumour burden has increased 
sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in the size of one or 
more non-target lesions is usually not sufficient to quality for unequivocal progression status.  
The designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
 
When the patient has only non-measurable disease. 
This circumstance arises in some phase III trials when it is not a criterion of study entry to 
have measurable disease.  The same general concepts apply here as noted above, 
however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in non-
target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required 
to declare PD for measurable disease: i.e. an increase in tumour burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to 
‘large’, an increase in lymphangitic disease from localised to widespread, or may be 
described in protocols as ‘sufficient to require a change in therapy’.  If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point.  
While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so; therefore the increase must be 
substantial. 
 
2.3.5. New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For 
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion, which it is not. 
 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases.  The patient’s brain metastases are considered to 
be evidence of PD even if he/she did not have brain imaging at baseline. 
 


 
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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease).  New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
• 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  A ‘positive’ FDG-PET scan lesion means one which is FDG avid 
with an uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
• 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
 


 
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2.4. Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
Should a response not be documented until after the end of therapy in this trial, post-
treatment assessments may be considered in the determination of best overall response as 
long as no alternative anti-cancer therapy has been given. The patient’s best overall 
response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions.   
 
2.4.1. Time point response 
It is assumed that at each protocol-specified time point, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline.   
 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used. 
 
2.4.2. Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response.  This would be most likely to happen in the case 
of PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions 
and at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the 
patient will have achieved PD status, regardless of the contribution of the missing lesion. 
 
2.4.3. Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
 
Best response determination in this trial (in which confirmation of complete or partial 
response IS NOT required):  
 
Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR).  When SD is believed to be best 
response, it must also meet the protocol specified minimum time from baseline.  If the 
minimum time is not met when SD is otherwise the best time point response, the patient’s 
best response depends on the subsequent assessments.  For example, a patient who has 
SD at first assessment, PD at second and does not meet minimum duration for SD, will have 
a best response of PD.  The same patient lost to follow-up after the first SD assessment 
would be considered inevaluable.  A ‘positive’ FDG-PET scan lesion means one which is 
FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 






 
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even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status 
of such patients is to be determined by evaluation of target and non-target disease as shown 
in Tables 1 to 3. 
 
Conditions that define ‘early progression, early death and inevaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, 
treatment periodicity). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response.  FDG-PET may be used to upgrade a response to 
a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring.  The use of FDG-PET in this circumstance should 
be prospectively described in the protocol and supported by disease specific medical 
literature for the indication.  However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
 
2.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
 
2.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD).   
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16.4 
 
NEW YORK HEART ASSOCIATION (NYHA) SCALE 
Class I – patients with cardiac disease but without resulting limitation of physical activity; 
ordinary physical activity does not cause undue dyspnoea (or fatigue, palpitation or anginal 
pain) 
Class II – patients with cardiac disease resulting in slight limitation of physical activity; they 
are comfortable at rest; ordinary physical activity results in dyspnoea (or fatigue, palpitation 
or anginal pain) 
Class III – patients with cardiac disease resulting in marked limitations of physical activity; 
they are comfortable at rest; less than ordinary physical activity causes dyspnoea (or fatigue, 
palpitation or anginal pain) 
Class IV – patients with cardiac disease resulting in inability to carry out physical activity 
without discomfort; symptoms of dyspnoea (or of angina) may be present even at rest; if any 
physical activity is undertaken, discomfort is increased.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16.5 
MANAGEMENT OF SKIN TOXICITY 
Dermatological toxicity is anticipated for both vandetanib and selumetinib therefore the 
following guidance is recommended for patients on study and also guidance once study 
treatment has been discontinued.  It is strongly recommended that all patients follow a 
program of sun protective measures while receiving study therapy and for 3-4 weeks after 
discontinuing study therapy.  The aim is to reduce the risk of development of skin rash, 
minimize the severity of skin rash, and to minimize the requirement for dose reduction of 
study therapy.  If a patient develops a skin rash, the following actions are recommended for 
the management of this reaction: 
• 
A variety of agents can be used to manage skin rashes. These include mild to 
moderate strength steroid creams, either topical or systemic antibiotics, topical or 
systemic antihistamines, and occasionally retinoid creams. Patients with severe skin 
rashes, e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythema 
multiforme, and toxic skin eruptions, should be treated with systemic glucocorticoids 
and should not continue treatment, even at a lower dose. 
• 
The rash should be graded/assessed by a physician as soon as possible according 
to the NCI CTCAE (version 4.02) cutaneous toxicity criteria and documented 
accordingly 
• 
If the rash is CTCAE Grade 1, consider starting with mild to moderate topical steroids 
(e.g., betamethasone), topical antibiotics such as clindamycin gel, systemic 
antibiotics or no treatment if the patient is asymptomatic.   
• 
Please note: Use of topical steroid cream with higher potency may be considered 
early in patients with moderate rash on the face. Topical or systemic antihistamines, 
and occasionally retinoid creams can also be considered.  
• 
If a rash of CTCAE Grade 2 or higher is detected, immediate symptomatic treatment 
should be provided e.g. topical steroid or pimecrolimus cream and consider adding 
an oral tetracycline or a similar agent. 
• 
If a rash of CTCAE Grade 3 or higher is detected, study treatment must be withheld 
until recovery to Grade 1 or below (See Section 5.4).   The addition of topical steroids 
is recommended.  
Pruritus of any grade may be treated with an antihistamine, such as diphenhydramine or 
hydroxyzine hydrochloride. 
Secondary infection may complicate or worsen skin toxicity.  To reduce the likelihood of 
nasal infection, intranasal mupirocin may be considered.  Infected rash may be treated with 
a short course of an oral tetracycline, such as doxycycline.  Sun exposure should be avoided 
in patients receiving doxycycline or other tetracycline antibiotics. 


 
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If there is a clinical diagnosis of impetigo, or an infection with Staphylococcus aureus is 
confirmed, topical mupirocin might be used.  Infected lesions suspected to be 
treatment-resistant should be cultured.  If there is no improvement after two weeks of 
treatment, therapy for the rash should be considered ineffective and discontinued and study 
treatment should not re start.  
Xerosis can be treated with classical emollients.  
If severe cutaneous toxicity recurs at reduced dose of vandetanib and selumetinib, the 
patient will permanently discontinue study treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16.6 
MANAGEMENT OF QTc PROLONGATION 
For a list of medications known to prolong QTc, please see Appendix 8. 
The electrocardiogram (ECG) must be evaluated by the local cardiologist or Investigator or 
qualified personnel at site, for the presence of QTcB prolongation or other abnormalities, in 
particular any changes in the T Wave morphology that would suggest a higher likelihood for 
the development of any arrhythmia. 
Any clinically significant abnormal findings of QTcB prolongations will be recorded as 
adverse events.  
On study monitoring 
For a single QTcB value >480ms, withhold vandetanib (and selumetinib if in combination 
phase). 
ECGs will be followed at least once a week (performed on the same day each week) along 
with electrolytes, until QTcB falls below 480ms.  Vandetanib may then be resumed at a 
permanently lower dose (dosing every other day at same dose level), after the QTcB returns 
to <480ms.   
If vandetanib is restarted after the QTcB prolongation has resolved, ECGs (along with 
electrolytes) should be performed two weeks following restarting study treatment and then 
prior to Day 1 of each cycle thereafter. 
Serum potassium levels should be maintained at 4.0mmol/L or higher and serum 
magnesium and calcium should be kept within normal range to reduce the risk of QTc 
prolongation.  
Vandetanib treatment may be resumed at a lower dose after the QTcB recovers to less than 
480 ms. 
 
 
 
 
 
 
 
 
 
 


 
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16.7 
INVESTIGATION OF ASYMPTOMATIC DECREASES IN LVEF. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16.8 
MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL AND/OR INDUCE 
TORSADES DE POINTES  
Concomitant use of medications generally accepted as having a risk of causing Torsades de 
Pointes (Table 1) are not allowed within 2 weeks of first dose or during study (at least 4 
weeks for Levomethadyl).  These drugs should also be avoided for up to 4 weeks following 
discontinuation of study treatment. 
If after reviewing the list of drugs in Table 1, the investigator finds that any ongoing patient is 
now taking a Group 1 drug, the investigator is to manage the patient immediately as follows: 
• 
The investigator should switch the patient to an alternative drug as soon as 
possible. 
• 
If it is not possible to switch the patient to an alternative drug, the patient will have 
to stop study treatment. 
Table 1 Group 1 Drugs 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
Amiodarone 
Anti-arrhythmic / abnormal heart 
rhythm 
TdP risk regarded as low 
Arsenic trioxide 
Anti-cancer / Leukemia 
  
Astemizole 
Antihistamine / Allergic rhinitis 
No Longer available in U.S. 
Bepridil 
Anti-anginal / heart pain 
 
Chloroquine 
Anti-malarial / malaria infection 
  
Chlorpromazine 
Anti-psychotic/ Anti-emetic / 
schizophrenia/ nausea 
  
Cisapride 
GI stimulant / heartburn 
Restricted availability 
Clarithromycin 
Antibiotic / bacterial infection 
  
Disopyramide 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Dofetilide 
Anti-arrhythmic / abnormal heart 
rhythm 
  
Domperidone 
Anti-nausea / nausea 
Not available in the U.S. 
Droperidol 
Sedative; Anti-nausea / 
anesthesia adjunct, nausea 
  
Erythromycin 
Antibiotic; GI stimulant / 
bacterial infection; increase GI 
motility 
 
Halofantrine 
Anti-malarial / malaria infection 
 
Haloperidol 
Anti-psychotic / schizophrenia, 
agitation 
When given intravenously or at 
higher-than- recommended 
doses, risk of sudden death, QT 
prolongation and torsades 
increases. 
Ibutilide 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Levomethadyl 
Opiate agonist / pain control, 
narcotic dependence 
  


 
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Table 1 Group 1 Drugs 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
Mesoridazine 
Anti-psychotic / schizophrenia 
  
Methadone 
Opiate agonist / pain control, 
narcotic dependence 
 
Moxifloxacin 
Antibiotic / bacterial infection 
  
Pentamidine 
Anti-infective / pneumocystis 
pneumonia 
 
Pimozide 
Anti-psychotic / Tourette's tics 
 
Probucol 
Antilipemic / 
Hypercholesterolemia 
No longer available in U.S. 
Procainamide 
Anti-arrhythmic / abnormal heart 
rhythm 
  
Quinidine 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Sotalol 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Sparfloxacin 
Antibiotic / bacterial infection 
  
Terfenadine 
Antihistamine / Allergic rhinitis 
No longer available in U.S. 
Thioridazine 
Anti-psychotic / schizophrenia 
  
Vandetanib (*Does not apply to 
this study) 
Anti-cancer / Thyroid cancer 
"Zactima®" is the proposed 
brand name 
 
Table 2: Drugs that in some reports may be associated with Torsades de Pointes but 
at this time lack substantial evidence of causing Torsades de Pointes. 
Co-administration of drugs that in some reports might be associated with TdP but at this time 
lack substantial evidence (Table 2) should be avoided within 2 weeks of first dose and 
during study.  However, these drugs will be allowed, at the discretion of the Investigator, if 
considered absolutely necessary.  In such cases, the subject must be closely monitored 
including regular checks of QTc and electrolytes.  For patients who start on the drugs in this 
group while on the study treatment, the ECG must be checked within 24 hours of 
commencing the concomitant medication and then at least once per week while the patient 
remains on the medication.  The frequency of ECG monitoring could revert to the standard 
schedule if no QTc prolongation has been noted during 4 weeks of co-administration of a 
drug from Table 2.  The electrolytes should be maintained within the normal range using 
supplements if necessary. 
 
 
 
 


 
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Table 2 Group 2 Drugs 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Alfuzosin 
Alpha1-blocker / Benign 
prostatic hyperplasia 
 
Amantadine 
Dopaminergic/Anti-viral / Anti-
infective/ Parkinson's Disease 
  
Atazanavir 
Protease inhibitor / HIV 
  
Azithromycin 
Antibiotic / bacterial infection 
  
Chloral hydrate 
Sedative / sedation/ insomnia 
  
Clozapine 
Anti-psychotic / schizophrenia 
  
Dolasetron 
Anti-nausea / nausea, vomiting 
  
Dronedarone 
Anti-arrhythmic / Atrial 
Fibrillation 
  
Escitalopram 
Anti-depressant / Major 
depression/ Anxiety disorders 
  
Famotidine 
H2-receptor antagonist / Peptic 
ulcer/ GERD 
  
Felbamate 
Anti-convulsant / seizure 
  
Flecainide 
Anti-arrhythmic / abnormal heart 
rhythm 
  
Foscarnet 
Anti-viral / HIV infection 
  
Fosphenytoin 
Anti-convulsant / seizure 
  
Gatifloxacin 
Antibiotic / bacterial infection 
  
Gemifloxacin 
Antibiotic / bacterial infection 
  
Granisetron 
Anti-nausea / nausea and 
vomiting 
  
Indapamide 
Diuretic / stimulate urine & salt 
loss 
  
Isradipine 
Anti-hypertensive / high blood 
pressure 
  
Lapatinib 
Anti-cancer / breast cancer, 
metastatic 
  
Levofloxacin 
Antibiotic / bacterial infection 
  
Lithium 
Anti-mania / bipolar disorder 
  
Moexipril/HCTZ 
Anti-hypertensive / high blood 
pressure 
  
Nicardipine 
Anti-hypertensive / high blood 
pressure 
  
Nilotinib 
Anti-cancer / Leukemia 
  
Octreotide 
Endocrine / acromegaly, 
carcinoid diarrhea 
  
Ofloxacin 
Antibiotic / bacterial infection 
  
Ondansetron 
Anti-emetic / nausea and 
vomiting 
  
Oxytocin 
Oxytocic / Labor stimulation 
  
Paliperidone 
Antipsychotic, atypical / 
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Table 2 Group 2 Drugs 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Perflutren lipid microspheres 
Imaging contrast agent / 
Echocardiography 
  
Quetiapine 
Anti-psychotic / schizophrenia 
  
Ranolazine 
Anti-anginal / chronic angina 
  
Risperidone 
Anti-psychotic / schizophrenia 
  
Roxithromycin* 
Antibiotic / bacterial infection 
*not available in the United 
States 
Sertindole 
Antipsychotic, atypical / Anxiety, 
Schizophrenia 
  
Sunitinib 
Anti-cancer / RCC, GIST 
  
Tacrolimus 
Immunosuppressant / Immune 
suppression 
  
Tamoxifen 
Anti-cancer / breast cancer 
  
Telithromycin 
Antibiotic / bacterial infection 
  
Tizanidine 
Muscle relaxant / 
  
Vardenafil 
phosphodiesterase inhibitor / 
vasodilator 
  
Venlafaxine 
Anti-depressant / depression 
  
Voriconazole 
Anti-fungal / anti-fungal 
  
Ziprasidone 
Anti-psychotic (schizophrenia)